WO2023209141A1

WO2023209141A1 - Benzo[d]imidazo[1,2-a]imidazoles and their use in diagnosis

Info

Publication number: WO2023209141A1
Application number: PCT/EP2023/061215
Authority: WO
Inventors: Andreas Faust; Johannes Roth; Thomas Vogl; Sven Hermann; Simon STEINER; Michael SCHÄFERS
Original assignee: Westfaelische Wilhelms Universitaet Muenster
Current assignee: Westfaelische Wilhelms Universitaet Muenster
Priority date: 2022-04-29
Filing date: 2023-04-28
Publication date: 2023-11-02
Anticipated expiration: 2024-10-29

Abstract

The present invention relates to a compound of formula (I), or a salt, isomer, or tautomer thereof; wherein R_A, R_B and R_C are as defined herein; L is a linker; and R_L is a label. Such compounds can be used in the diagnosis of an inflammatory disease at a local site.

Description

BENZ0[D]IMIDAZ0[1 ,2-A]IMIDAZ0LES AND THEIR USE IN

DIAGNOSIS

CROSS-REFERENCE TO RELATED APPLICATIONS

[001] The present application claims the benefit of priority of European Patent Application No. 22170869.6 filed 29 April 2022, the content of which is hereby incorporated by reference in its entirety for all purposes.

FIELD OF THE INVENTION

[002] The present invention relates to compounds of formula (I) comprising a label, and their use in diagnosis. The present invention further relates to a method of diagnosing an inflammatory disease in a subject, comprising (a) administering a compound of formula (I) comprising a label, (b) detecting the administered compound using in vivo non-invasive molecular imaging techniques, thereby collecting imaging data, and (c) comparing the imaging data received in step (b) to reference imaging data. Provided is also a non-invasive method of detecting or imaging accumulation of S100A9 in the body of a subject to whom a compound of formula (I) comprising a label has been pre-delivered. The present invention is further directed to the use of a compound of formula (I) comprising a label for the preparation of a diagnostic composition for diagnosing an inflammatory process. A method for evaluating whether a subject may be at risk of developing an inflammatory disease associated with phagocyte and/or epithelial cell activation and S100A9 accumulation is also envisaged. The present invention also relates to a method of monitoring or evaluating the progression of an inflammatory reaction in a patient. A method of imaging an inflammatory disease associated with phagocyte and/or epithelial cell activation in a subject is further comprised by the present invention. Provided is also an in vitro method of diagnosing an inflammatory disease in a subject to whom a compound of formula (I) comprising a label has been pre-delivered.

BACKGROUND OF THE INVENTION

[003] Inflammatory diseases are of high relevance in daily clinical practise and often dominated and driven by activated phagocytes. The alarmin S100A8/S100A9 is expressed and secreted in high concentrations by immigrating phagocytes at sites of inflammation and is known to trigger sterile as well as infectious inflammatory processes. S100A8 and S100A9 belong to the S100-family of Ca²⁺-binding proteins and are involved in many immune processes. The physiological relevant forms are heterodimers and upon calcium-binding heterotetramers, both forms are also described as calprotectin. S100A8/S100A9 complexes promote inflammatory processes but helps also in tissue repair or immune defence reactions by interaction with TLR4 and other receptors.

[004] Inflammation is the driving force in a broad spectrum of clinically relevant disorders and disease severity often correlates with the number of immigrated activated phagocytes. The alarmin S100A8/A9 is highly expressed and locally secreted by activated phagocytes at an early stage in the inflammatory cascade enabling early and sensitive detection of inflammation. High local S100A8/A9 concentrations arise at the site of inflammation and are typically up to 50-fold higher than those occurring in the systemic circulation. Therefore, the local assessment of S100A8/A9 by imaging strategies as surrogate marker for phagocyte activity is of interest to provide sensitive and specific monitoring of changes in the local expression of these molecules and thus of inflammatory activity.

[005] Using a Cy5.5 labelled antibody directed against S100A9 it could be already shown, that the S100A9 subunit of the heterodimeric complex is a valuable and sensitive phagocyte marker for quantifying inflammatory disease activities (Vogl T, Eisenblatter M, Voller T, Zenker S, Hermann S, van Lent P, Faust A, Geyer C, Petersen B, Roebrock K, Schafers M, Bremer C, Roth J. Alarmin S100A8/S100A9 as a biomarker for molecular imaging of local inflammatory activity. Nat Commun 2014;5: 4593.) More recently, instead of the antibodybased approach, a small molecule drug of the 3-quinolinecarboxamide family, which specifically binds to S100A9, was used (WO 2016/067238 A1; Faust A, Voller T, Busch F, Schafers M, Roth J, Hermann S, Vogl T. Development and evaluation of a non-peptidic ligand for the molecular imaging of inflammatory processes using S100A9 (MRP14) as a novel target. Chem Commun (Camb) 2015;51: 15637-15640; and Voller T, Faust A, Roth J, Schafers M, Vogl T, Hermann S. A Non-Peptidic S100A9 Specific Ligand for Optical Imaging of Phagocyte Activity In Vivo. Mol Imaging Biol 2018;20: 407-416).

[006] There is an ongoing need to provide new means and methods that help to diagnose inflammatory diseases, in particular inflammatory diseases associated with an increased accumulation of S100A9 at local site of inflammation at molecular level. The technical problem underlying the present application is thus to comply with this need. The technical problem is solved by providing the embodiments reflected in the claims, described in the description and illustrated in the examples and figures that follow. SUMMARY OF THE INVENTION

[007] The present invention relates to a compound of formula (I)

or a salt, isomer, or tautomer thereof; wherein

R_A, R_B, and R_c are each independently selected from H, halogen, cyano, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by R-iO, R₂C(O), R₃S, R₄S(O)₂, R₅OC(O), (R₆ON)C(R₇), R₈R₉NC(O), R10R11N, RI₂S(O)₂NR₁₃, RI₄S(O)₂NR₁₅C(O), phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆; or one of R_A and R_c together with R_B forms a group -(CH₂)_m- wherein m is an integer of from 3 to 5, and the other one of R_A and R_c is selected from H, halogen, cyano, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by R1O, R₂C(O), R₃S, R₄S(O)₂, R₅OC(O), (R₆ON)C(R₇), R₈R₉NC(O), R10R11N, RI₂S(O)₂NR₁₃, R₁₄S(O)₂NR₁₅C(O), phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆; each R₁₆ is independently selected from halogen, cyano, nitro, RI₇O, C1-C6 alkyl optionally substituted by RI₇O, C3-C6 cycloalkyl optionally substituted by RI₇O, RI₈C(O), R₁₉S, R₂₀S(O)₂, R₂IOC(O), (R₂₂ON)C(R₂₃), R₂₄R₂₅NC(O), R₂₆R₂₇N, R₂₈S(O)₂NR₂₉, and R₃OS(0)₂NR₃₁C(0); each one of R1-R15 and RI₇-R₃I is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl;

L is a linker; and R_L is a label.

[008] The present invention also relates to a diagnostic composition comprising a compound according to the invention and a pharmaceutically or diagnostically acceptable excipient.

[009] The present invention also relates to a compound according to the invention for use in a method of diagnosis. In some embodiments, the diagnosis may be diagnosis of an inflammatory disease in a subject.

[0010] The present invention also relates to a method of diagnosing an inflammatory disease in a subject, comprising: a) administering to said subject a compound according to the invention, b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data.

[0011] The present invention also relates to a non-invasive method of detecting or imaging accumulation of S100A9 in the body of a subject to whom a compound of the invention has been pre-delivered, comprising: a) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, b) comparing the imaging data received in step a) to reference imaging data.

[0012] The present invention also relates to the use of a compound according to the invention for the preparation of a diagnostic composition for diagnosing an inflammatory disease associated with phagocyte and/or epithelial cell activation in a subject.

[0013] The present invention also relates to a method for evaluating whether a subject may be at risk of developing an inflammatory disease associated with phagocyte and/or epithelial cell activation, the method comprising: a) administering to said subject a compound according to the invention, b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data. [0014] The present invention also relates to a method of monitoring or evaluating the progression of an inflammatory disease associated with phagocyte and/or epithelial cell activation in a patient, the method comprising: a) administering to said subject a compound according to the invention, b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data obtained from said patient at an earlier date, wherein the result of the comparison of c) provides an evaluation of the progression of the inflammatory disease associated with phagocyte and/or epithelial cell activation in said patient.

[0015] The present invention also relates to a method of imaging an inflammatory disease in a subject, comprising: a) administering to said subject a compound according to the invention, b) detecting the administered compound using an in vivo non-invasive molecular imaging method, thereby collecting imaging data.

[0016] The present invention also relates to an in vitro method of diagnosing an inflammatory disease in a subject to whom a compound according to the invention has been pre-delivered, comprising: a) analyzing a sample taken from said subject, b) detecting said pre-delivered compound using a non-invasive molecular imaging method, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data.

[0017] The present invention also relates to a process for the preparation of a compound of the formula (I*) or its salts, isomers, tautomers or solvates thereof, comprising reacting a compound of the formula (X*)

with a compound of the formula (XI)

and a compound of the formula (XII)

to give a compound of the formula (I*)

wherein R₅₀₀ is C1-C6 alkyl, preferably methyl or ethyl, more preferably ethyl;

L* is a linker capable of forming a covalent attachment to a label R_L; or

L* is a part of a linker capable of forming a covalent attachment to another part of a linker; and

R_A, R_B and R_c are as defined herein.

[0018] The present invention also relates to a process for the preparation of a compound of the formula (I) or its salts, isomers, tautomers or solvates thereof, as described herein, comprising reacting a compound of the formula (X)

and a compound of the formula (XII)

to give a compound of the formula (I)

wherein R₅₀₀ is C1-C6 alkyl, preferably methyl or ethyl, more preferably ethyl; and RA, B, RC, L and R_L are as defined herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 shows in vivo imaging using the compound Cy5.5-SST110 in an ear inflammation mouse model of irritant contact dermatitis.

[0020] Figure 2 shows the murine and human blood serum stability of the compound [¹⁸F]SST034 over 120 min.

[0021] Figure 3 shows the murine and human blood serum stability of the compound [¹⁸F]SST096 over 120 min.

[0022] Figure 4 shows the murine and human blood serum stability of the compound [¹⁸F]SST120 over 120 min.

[0023] Figure 5 shows in vivo biodistribution studies with the compound [¹⁸F]SST034. Figure 5A shows maximum intensity projections of selected time frames (in vivo). Figure 5B shows an ex vivo gamma counter analysis (110 min p.i.).

[0024] Figure 6 shows in vivo biodistribution studies with the compound [¹⁸F]SST096. Figure 6A shows Maximum Intensity Projections of selected time frames (in vivo). Figure 6B shows an ex vivo gamma counter analysis (110 min p.i.).

[0025] Figure 7 shows in vivo biodistribution studies with the compound [¹⁸F]SST120. Figure 7A shows Maximum Intensity Projections of selected time frames (in vivo). Figure 7B shows an ex vivo gamma counter analysis (110 min p.i.).

[0026] Figure 8 shows three separate runs for determining the equilibrium binding constant K_d of fluorescein-labelled derivative 6-FAM-SST177 towards mS100A9 in accordance with Example 2. Depicted is the fluorescence intensity (Fl, vertical axis) depending of the concentration of mS100A9 in pM (horizontal axis).

[0027] Figure 9 shows saturation binding curves (“one-site - specific binding” model) determining the K_D of AF488-SST193 towards A) mS100A9 in HPS buffer, B) mS100A9 in Tris buffer, C) hS100A9C3S in Tris buffer and D) mS100A8 in HPS buffer as a negative control. Each curve refers to an individual experiment with date given in the legend. DETAILED DESCRIPTION

[0028] Unless otherwise stated, the following terms used in this document, including the description and claims, have the definitions given below.

[0029] It is to be noted that as used herein, the singular forms "a", "an", and "the", include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "a reagent" includes one or more of such different reagents and reference to "the method" includes reference to equivalent steps and methods known to those of ordinary skill in the art that could be modified or substituted for the methods described herein.

[0030] Those skilled in the art will recognize, or be able to ascertain, using not more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the present invention.

[0031] Unless otherwise indicated, the term "at least" preceding a series of elements is to be understood to refer to every element in the series. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the methods and uses described herein. Such equivalents are intended to be encompassed by the present invention.

[0032] Several documents are cited throughout the text of this disclosure. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. To the extent the material incorporated by reference contradicts or is inconsistent with this specification, the specification will supersede any such material. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0033] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integer or step. When used herein the term "comprising" can be substituted with the term "containing" or sometimes when used herein with the term "having". [0034] When used herein "consisting of" excludes any element, step, or ingredient not specified in the claim element. When used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. In each instance herein any of the terms "comprising", "consisting essentially of' and "consisting of' may be replaced with either of the other two terms.

[0035] As used herein, the conjunctive term "and/or" between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by "and/or", a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term "and/or" as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term "and/or" as used herein.

[0036] The word “about” as used herein refers to a value being within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. The term “about” is also used to indicate that the amount or value in question may be the value designated or some other value that is approximately the same. The phrase is intended to convey that similar values promote equivalent results or effects according to the invention. In this context “about” may refer to a range above and/or below of up to 10%. The word “about” refers in some embodiments to a range above and below a certain value that is up to 5%, such as up to up to 2%, up to 1%, or up to 0.5 % above or below that value. In one embodiment “about” refers to a range up to 0.1 % above and below a given value.

[0037] The present invention is, at least partly, based on the surprising finding that compounds of formula (I) comprising a label, i.e. compounds comprising a benzimidazole moiety, are well suited for diagnostic use. In particular, the present invention demonstrates that compounds of formula (I) comprising a label are applicable for use in the diagnosis of an inflammatory disease associated with accumulation of S100A9 at local site of inflammation, using non-invasive molecular imaging techniques for detecting said compounds in vivo. In this regard, the inventors of the present application surprisingly found that compounds of formula (I) comprising a label can thus be used for diagnosing inflammatory diseases with high molecular sensitivity. This can be explained by specific binding of the compounds to S100A9. In some embodiments, the compounds may not bind to or interact with S100A8, or may bind to or interact with S100A8 only to a low extent. However, the results presented herein were unforeseeable. WO 2015/177367 A1 describes benzo[d]imidazo[1,2-a]imidazole compounds exclusively for therapeutic use in the therapeutic treatment of diseases. However, to best of the inventors’ knowledge, a diagnostic approach using compounds in which a benzo[d]imidazo[1,2-a]imidazole moiety is covalently linked to a label has never been reported so far.

[0038] To analyze inflammatory processes at local site of inflammation, the present inventors synthesized novel S100A9-specific ligands, which are well suited for use in various molecular imaging methods. As provided by the present invention, such compounds of formula (I) are well suited for use in in vivo non-invasive molecular imaging techniques.

[0039] In particular, an optical (fluorescent) probe based on the S100A9 ligand benzo[d]imidazo[1,2-a]imidazole (Cy5.5-SST110) could be successfully synthesised. Imaging experiments in a mouse models showed significant accumulation at the sites of inflammatory active diseases, e.g. in a mouse models of dermatitis. The inventors have further demonstrated stability of radiotracers in murine and human blood serum over the time. Further, biodistribution studies have been carried out indicating properties favorable for diagnostic applications in vivo.

[0040] The present invention is at least partly based on the surprising fact that compounds of formula (I) comprising a label are well suited for use in diagnosis of inflammatory diseases associated with an increased phagocyte and/or epithelial cell activity and an increased accumulation of S100A9. In this regard, these compounds could be successfully used for in vivo non-invasive molecular imaging in a model of dermatitis.

[0041] Accordingly, the present invention relates to a compound of formula (I)

or a salt, isomer, or tautomer thereof; wherein

R_A, R_B, and R_c are each independently selected from H, halogen, cyano, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by R-iO, R₂C(O), R₃S, R₄S(O)₂, R₅OC(O), (R₆ON)C(R₇), R₈R₉NC(O), R10R11N, RI₂S(O)₂NR₁₃, RI₄S(O)₂NR₁₅C(O), phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆; or one of R_A and R_c together with R_B forms a divalent group -(CH₂)_m- wherein m is an integer of from 3 to 5, and the other one of R_A and R_c is selected from H, halogen, cyano, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by RTO, R₂C(O), R₃S, R₄S(O)₂, R₅OC(O), (R₆ON)C(R₇), R₈R₉NC(O), R10R11N, RI₂S(O)₂NR₁₃,

RI₄S(O)₂NR₁₅C(O), phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6- membered heterocyclyl optionally substituted by one or more moieties R₁₆; each R₁₆ is independently selected from halogen, cyano, nitro, RI₇O, C1-C6 alkyl optionally substituted by RI₇O, C3-C6 cycloalkyl optionally substituted by RI₇O, RI₈C(O), R₁₉S, R₂₀S(O)₂, R₂IOC(O), (R₂₂ON)C(R₂₃), R₂₄R₂₅NC(O), R₂₆R₂₇N, R₂₈S(O)₂NR₂₉, and R₃OS(0)₂NR₃₁C(0); each one of R1-R15 and RI₇-R₃I is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl;

L is a linker; and

R_L is a label. [0042] In some embodiments, R_A, R_B and R_c are independently selected from H, halogen, cyano, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by RA R₂C(O), R₃S, R₄S(O)₂, R₅OC(O), (R₆ON)C(R₇), R₈R₉NC(O), R RnN, RI₂S(O)₂NR₁₃, R₁₄S(O)₂NR₁₅C(O), phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆.

[0043] In some other embodiments, one of R_A and R_c together with R_B forms a divalent group -(CH₂)_m- wherein m is an integer of from 3 to 5, and the other one of R_A and R_c is selected from H, halogen, cyano, RA C1-C6 alkyl optionally substituted by RA C3-C6 cycloalkyl optionally substituted by RA R₂C(O), R₃S, R₄S(O)₂, R₅OC(O), (R₆ON)C(R₇), R₈R₉NC(O), R10R11N, R₁₂S(O)₂NR₁₃, R₁₄S(O)₂NR₁₅C(O), phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆.

[0044] Thus, the moiety R_A may be selected from H, halogen, cyano, RA C1-C6 alkyl optionally substituted by RA C3-C6 cycloalkyl optionally substituted by R R₂C(O), R₃S, R₄S(O)₂, R₅OC(O), (R₆ON)C(R₇), R₈R₉NC(O), R10R11N, RI₂S(O)₂NR₁₃, R₁₄S(O)₂NR₁₅C(O), phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆; or forms together with R_B a divalent group -(CH₂)_m- wherein m is an integer of from 3 to 5.

[0045] In some embodiments, R_A is selected from H, halogen, cyano, RA C1-C6 alkyl optionally substituted by RA C3-C6 cycloalkyl optionally substituted by R R₂C(O), R₃S, R₄S(O)₂, R₅OC(O), (R₆ON)C(R₇), R₈R₉NC(O), R10R11N, RI₂S(O)₂NR₁₃, R₁₄S(O)₂NR₁₅C(O), phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆.

[0046] In some embodiments, R_A is selected from H, halogen, cyano, RA C1-C6 alkyl optionally substituted by RA C3-C6 cycloalkyl optionally substituted by R R₂C(O), R₃S, R₄S(O)₂, R₅OC(O), (R₆ON)C(R₇), R₈R₉NC(O), R10R11N, RI₂S(O)₂NR₁₃, and

RI₄S(O)₂NR₁₅C(O).

[0047] In some embodiments, R_A is selected from H, halogen, cyano, C1-C6 alkyl optionally substituted by RA C3-C6 cycloalkyl optionally substituted by RA R₂C(O), R₃S, R₄S(O)₂, R₅OC(O), RI₂S(O)₂NR₁₃, and R₁₄S(O)₂NR₁₅C(O). [0048] In some embodiments, R_A is selected from H, halogen, C1-C6 alkyl and R₂C(O), e.g.

H, halogen, and C1-C6 alkyl, or H and halogen.

[0049] In some embodiments, R_A is H.

[0050] In some other embodiments, R_A is selected from halogen, C1-C6 alkyl and R₂C(O), e.g. C1 -C6 alkyl and R₂C(O), e.g. R_A is R₂C(O), or R_A is C1-C6 alkyl.

[0051] In some embodiments, R_A is selected from H, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, R₂C(O), R₄S(O)₂, R₅OC(O), RI₂S(O)₂NR₁₃, R₁₄S(O)₂NR₁₅C(O), phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆; e.g. from H, halogen, phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆, e.g. from H, phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆, or from phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆.

[0052] In some embodiments, when R_A is phenyl optionally substituted by one or more moieties R₁₆, or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆, it more particularly is phenyl optionally substituted by one or more moieties R₁₆. In some embodiments, when R_A is phenyl optionally substituted by one or more moieties R₁₆, or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆, it more particularly is 5- or 6-membered heterocyclyl optionally substituted by one or more moieties Rl6-

[0053] The moiety R_B may be selected from H, halogen, cyano, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by RTO, R₂C(O), R₃S, R₄S(O)₂, R₅OC(O), (R₆ON)C(R₇), R₈R₉NC(O), R RuN, RI₂S(O)₂NR₁₃, R₁₄S(O)₂NR₁₅C(O), phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆; or may form together with either R_A or R_c a divalent group -(CH₂)_m- wherein m is an integer of from 3 to 5.

[0054] In some embodiments, R_B is selected from H, halogen, cyano, RTO, C1 -C6 alkyl, optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by R1O, R₂C(O), R₃S, R₄S(O)₂, R₅OC(O), (R₆ON)C(R₇), R₈R₉NC(O), R10R11N, RI₂S(O)₂NR₁₃, R₁₄S(O)₂NR₁₅C(O), phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆.

[0055] In some embodiments, R_B is selected from H, halogen, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by RTO, phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆.

[0056] In some embodiments, R_B is phenyl optionally substituted by one or more moieties R₁₆, or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆.

[0057] In some embodiments, R_B is selected from H, halogen, RTO, C1-C6 alkyl optionally substituted by RTO, and C3-C6 cycloalkyl optionally substituted by RTO, e.g. from H, halogen, and C1-C6 alkyl optionally substituted by RTO.

[0058] In some embodiments, R_B is selected from H, halogen, C1-C6 alkyl optionally substituted by RTO, and C3-C6 cycloalkyl optionally substituted by RTO, e.g. from H and halogen.

[0059] In some embodiments, R_B is selected from H, halogen, C1-C6 alkyl and C3-C6 cycloalkyl, e.g. from H, halogen, and C1-C6 alkyl, e.g. from H and C1-C6 alkyl.

[0060] In some embodiments, R_B is selected from halogen, C1-C6 alkyl optionally substituted by RTO, and C3-C6 cycloalkyl optionally substituted by RTO, e.g. from halogen, and C1-C6 alkyl optionally substituted by RTO; or from halogen, and C1-C6 alkyl, e.g. R_B is halogen.

[0061] In some embodiments, R_B is H.

[0062] The moiety R_c may be selected from H, halogen, cyano, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by RTO, R₂C(O), R₃S, R₄S(O)₂, R₅OC(O), (R₆ON)C(R₇), R₈R₉NC(O), R RuN, RI₂S(O)₂NR₁₃, RI₄S(O)₂NR₁₅C(O), phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆, or may form together with R_B a divalent group -(CH₂)_m- wherein m is an integer of from 3 to 5.

[0063] In some embodiments, R_c is selected from H, halogen, cyano, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by R1O, R₂C(O), R₃S, R₄S(O)₂, RSOC(O), (R₆ON)C(R₇), R₈R₉NC(O), R10R11N, R₁₂S(O)₂NR₁₃, RI₄S(O)₂NR₁₅C(O), phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆.

[0064] In some embodiments, R_c is selected from H, halogen, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by RTO, R₂C(O), phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆.

[0065] In some embodiments, R_c is phenyl optionally substituted by one or more moieties R₁₆, or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆.

[0066] In some embodiments, R_c is selected from H, halogen, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by RTO, and R₂C(O).

[0067] In some embodiments, R_c is selected from H, halogen, RTO, C1-C6 alkyl optionally substituted by RTO, and C3-C6 cycloalkyl optionally substituted by RTO, e.g. from H, halogen, C1-C6 alkyl optionally substituted by RTO, and C3-C6 cycloalkyl optionally substituted by R1O, or from H, halogen, C1 -C6 alkyl, and C3-C6 cycloalkyl, in particular from H, halogen and C1-C6 alkyl, or from H and C1-C6 alkyl.

[0068] In some embodiments, R_c is H.

[0069] In some embodiments, one of R_A and R_c forms together with R_B a divalent group - (CH₂)_m- wherein m is an integer of from 3 to 5, e.g. m is 3 or 4, or m is 3. In such embodiments, the other one of R_A and R_c may be selected from H, halogen, cyano, RTO, CI- 06 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by RTO, R₂C(O), R₃S, R₄S(O)₂, R₅OC(O), (R₆ON)C(R₇), R₈R₉NC(O), R10R11N, RI₂S(O)₂NR₁₃, RI₄S(O)₂NR₁₅C(O), phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6- membered heterocyclyl optionally substituted by one or more moieties R₁₆. In these embodiments, the other one of R_A and R_c preferably is selected from H, halogen, cyano, R1O, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by R1O, R₂C(O), R₃S , R₄S(O)₂, R₅OC(O), (R₆ON)C(R₇), R₈R₉NC(O), R10R11N, RI₂S(O)₂NR₁₃, and R₁₄S(O)₂NR₁₅C(O); e.g. from H, halogen, cyano, RTO, C1 -C6 alkyl optionally substituted by R R₂C(O), R₃S, R₄S(O)₂, R₅OC(O), (R₆ON)C(R₇), R₈R₉NC(O), R10R11N, R₁₂S(O)₂NR₁₃, and R₁₄S(O)₂NR₁₅C(O); e.g. from H, halogen and C1-C3 alkyl; such as H, F and methyl; or H and F, in particular H. [0070] In some embodiments, at least one of R_A, R_B and R_c is phenyl optionally substituted by one or more moieties R₁₆, or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆.

[0071] In some embodiments, one of R_A, R_Band R_c is phenyl optionally substituted by one or more moieties R₁₆, or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆.

[0072] In some embodiments, when one of R_A, R_B and R_c is phenyl optionally substituted by one or more moieties R₁₆, or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆, the two others of R_A, R_B and R_c are as defined herein above, but are not phenyl optionally substituted by one or more moieties R₁₆, or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆.

[0073] For example, in some embodiments, when one of R_A, R_B and R_c is phenyl optionally substituted by one or more moieties R₁₆, or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆, the two others of R_A, R_B and R_c are selected from H, halogen, C1 -C6 alkyl, C3-C6 cycloalkyl and R₂C(O), or from H, halogen C1-C6 alkyl and R₂C(O), e.g. from H, F, Cl, and C1 -C3 alkyl; or from H, F and methyl; e.g. both are H or F, or both are H.

[0074] In some embodiments, R_A, R_B and R_c are independently selected from H, halogen, cyano, C1-C4 alkyl, RTO, R₂C(O), R₃S, and R₄S(O)₂; or one of R_A and R_c, together with R_B, forms a divalent group -(CH₂)_m- wherein m is an integer of from 3 to 5, and the other one of R_A and R_c is selected from H, halogen, cyano, C1-C4 alkyl, RTO, R₂C(O), R₃S, and R₄S(O)₂.

[0075] In some embodiments, when anyone of R_A, R_B and R_c is selected from halogen, it more particularly may be selected from F, Cl or Br, or from F and Cl, in particular Cl.

[0076] In some embodiments, when anyone of R_A, R_B and R_c is selected from C1-C6 alkyl optionally substituted by R-iO and C3-C6 cycloalkyl optionally substituted by RTO, it more particularly may be selected from C1-C6 alkyl optionally substituted by RTO, e.g. from C1-C4 alkyl optionally substituted by RTO, or C1-C3 alkyl optionally substituted by RTO, in particular methyl optionally substituted by RTO. [0077] In some embodiments, when anyone of R_A, R_B and R_c is selected from C1-C6 alkyl optionally substituted by RiO and C3-C6 cycloalkyl optionally substituted by RTO, it more particularly may be selected from C1-C6 alkyl, or from C1-C4 alkyl, or C1-C3 alkyl, in particular methyl.

[0078] In some embodiments, when anyone of R_A, R_B and R_c is selected from C3-C6 cycloalkyl optionally substituted by RTO, it more particularly may be selected from C3-C6 cycloalkyl, or from C3-C5 cycloalkyl, or from C3-C4 cycloalkyl, e.g. cyclopropyl.

[0079] In some embodiments, R_A, R_B and Rc are all H, i.e. the compound of formula (I) is a compound of formula (la):

wherein L and R^L are as defined herein.

[0080] In some other embodiments, at least one of R_A, R_B and R_c is different from H.

[0081] In some embodiments, R_A is as defined herein above, but is different from H; or R_B is as defined herein above, but is different from H.

[0082] In some embodiments, two of R_A, R_B and R_c are different from H, i.e. R_A and R_B are different from H, or R_A and R_c are different from H, or R_B and R_c are different from H.

[0083] In some embodiments, R_A is H and the compound may then be represented by formula (lb)

wherein R_B, R_c, L and R_L are as defined herein, e.g. R_B and R_c are as defined herein above, but neither R_B nor R_c is H.

[0084] In some other embodiments, R_A is different from H. In some embodiments, R_A and R_B are different from H and R_c is H. In some other embodiments, R_A and R_c are different from H and R_B is H.

[0085] In some embodiments, R_A is different from H and R_B and R_c are both H, i.e. the compound may be represented by formula (Ic)

wherein R_A, L and R_L are as defined herein.

[0086] In some embodiments, when anyone of R_A, R_B, and R_c is RTO, C1-C6 alkyl optionally substituted by RTO, or C3-C6 cycloalkyl optionally substituted by RTO, the moiety R-i may be selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, e.g. from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl. In some embodiments, the moiety R-i may be selected from H and C1-C6 alkyl, e.g. from H and C1-C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH3, in particular H.

[0087] In some embodiments, the moiety R-i is as defined herein above, but is not H; e.g. R-, is CH₃.

[0088] In some embodiments, when anyone of R_A, R_B, and R_c is selected from RTO, C1-C6 alkyl optionally substituted by RTO and C3-C6 cycloalkyl optionally substituted by RTO, it more particularly may be selected from RTO and C1-C6 alkyl optionally substituted by RTO, e.g. from RTO and C1-C3 alkyl optionally substituted by RTO, or from RTO and C1-C2 alkyl optionally substituted by RTO, e.g. it may be selected from RTO, RIOCH₂, and R₁OCH(CH₃), in particular RTO. [0089] In some embodiments, when anyone of R_A, R_B, and R_c is R₂C(O), R₂ may be H, CI- 06 alkyl, or C3-C6 cycloalkyl. In some embodiments, R₂ is selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl. In some embodiments, R₂ is selected from H and C1 -C6 alkyl, e.g. from H and 01-04 alkyl, or from H and 01-03 alkyl, such as from H, CH₃ and (CH₃)₂CH, in particular CH₃. In some embodiments, the moiety R₂ is as defined herein above, but is not H.

[0090] In some embodiments, when anyone of R_A, R_B, and R_c is R₃S, R₃ may be H, 01-06 alkyl, or 03-06 cycloalkyl. In some embodiments, R₃ is selected from H, 01-04 alkyl, and 03-04 cycloalkyl, or from H, 01-03 alkyl and cyclopropyl. In some embodiments, R₃ is selected from H and 01-06 alkyl, e.g. from H and 01-04 alkyl, or from H and 01-03 alkyl, such as from H and CH₃, in particular CH₃. In some embodiments, the moiety R₃ is as defined herein above, but is not H.

[0091] In some embodiments, when anyone of R_A, R_B, and R_c is R4SO₂, R₄ may be H, CI- 06 alkyl, or 03-06 cycloalkyl. In some embodiments, R₄ is selected from H, 01 -04 alkyl, and 03-04 cycloalkyl, or from H, 01-03 alkyl and cyclopropyl. In some embodiments, R₄ is selected from H and 01-06 alkyl, e.g. from H and 01 -04 alkyl, or from H and 01-03 alkyl, such as from H and CH₃, in particular CH₃. In some embodiments, the moiety R₄ is as defined herein above, but is not H.

[0092] In some embodiments, when anyone of R_A, R_B, and R_c is R₅OC(O), R₅ may be H, CI- 06 alkyl, or 03-06 cycloalkyl. In some embodiments, R₅ is selected from H, 01-04 alkyl, and 03-04 cycloalkyl, or from H, 01-03 alkyl and cyclopropyl. In some embodiments, R5 is selected from H and 01-06 alkyl, e.g. from H and 01 -04 alkyl, or from H and 01 -03 alkyl, such as from H and CH₃, in particular H.

[0093] In some embodiments, when anyone of R_A, R_B, and R_c is (R₆ON)C(R₇), R₆ may be H, 01-06 alkyl, or 03-06 cycloalkyl. In some embodiments, R₆ is selected from H, 01 -04 alkyl, and 03-04 cycloalkyl, or from H, 01-03 alkyl and cyclopropyl. In some embodiments, R₆ is selected from H and 01-06 alkyl, e.g. from H and 01-04 alkyl, or from H and 01-03 alkyl, such as from H and CH₃, in particular H. R₇ may be H, 01 -06 alkyl, and 03-06 cycloalkyl. In some embodiments, R₇ is selected from H, 01-04 alkyl, and 03-04 cycloalkyl, or from H, CI- 03 alkyl and cyclopropyl. In some embodiments, R₇ is selected from H and 01-06 alkyl, e.g. from H and 01 -04 alkyl, or from H and 01-03 alkyl, such as from H and CH₃, in particular CH₃. In some embodiments, the moiety R₇ is as defined herein above, but is not H. In some embodiments, R₆ is H and R₇ is as defined herein above, but different from H, e.g. R₇ is CH₃. [0094] In some embodiments, when anyone of R_A, R_B, and R_c is R₈R₉NC(O) or R₁₀Rn, each one of R₈, R₉, R₁₀ and Rn may be independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, e.g. from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl. In some embodiments, when anyone of R_A, R_B, and R_c is R₈R₉NC(O) or R₁₀RnN, each one of R₈, R₉, R₁₀ and Rn may be independently selected from H and C1-C6 alkyl, e.g. from H and C1-C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH₃.

[0095] In some embodiments, when anyone of R_A, R_B, and R_c is R₁₂S(O)₂NR₁₃, or RI₄S(O)₂NR₁₅C(O), each one of R₁₂, R₁₃, R₁₄ and R₁₅ may be independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, e.g. from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl. In some embodiments, when anyone of R_A, R_B, and R_c is RI₂S(O)₂NR₁₃, or R₁₄S(O)₂ RI₅C(O), each one of R₁₂, R₁₃, R₁₄ and R₁₅ is independently selected from H and C1-C6 alkyl, e.g. from H and C1-C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH3. In some embodiments, R₁₂ is as defined herein above, but is not H, and R₁₃ is H. In some embodiments, R₁₄ is as defined herein above, but is not H, and R₁₅ is

H. In some embodiments, R₁₂ and R₁₄ are as defined herein above, but are not H, and R₁₃ and R₁₅ are both H.

[0096] In some embodiments, when anyone of R_A, R_B and R_c is phenyl optionally substituted by one or more moieties R₁₆, or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆, said phenyl or heterocyclyl is substituted by 0, 1 , 2 or 3 moieties R₁₆, e.g. 0, 1 or 2 moieties R₁₆, or 0 or 1 moiety R₁₆, e.g. 1 moiety R₁₆.

[0097] In some embodiments, when anyone of R_A, R_B and R_c is phenyl optionally substituted by one or more moieties R₁₆, or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆, it more particularly is phenyl substituted by 0, 1 , 2 or 3 moieties R₁₆, or 0, 1 or 2 moieties R₁₆.

[0098] In some embodiments, when anyone of R_A, R_B and R_c is phenyl optionally substituted by one or more moieties R₁₆, or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆, it more particularly is 5- or 6-membered heterocyclyl substituted by 0,

I , 2 or 3 moieties R₁₆, or e.g. 0, 1 or 2 moieties R₁₆.

[0099] In some embodiments, when anyone of R_A, R_B and R_c is phenyl substituted by one moiety R₁₆, said moiety is in para position on said phenyl ring. [00100] In some embodiments, R_A is phenyl optionally substituted by one or more moieties R₁₆, or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆. In some of these embodiments, the compound of formula (I) may be represented by formula (Id)

wherein ring B is phenyl or 5- or 6-membered heterocyclyl, k is an integer of from 0 to 3, and Ri6, RB, RC, L and R_L are as defined herein.

[00101] In some embodiments, ring B is phenyl, and the compound of formula (Ic) may be represented by formula (le)

wherein k, R₁₆, R_B, Rc, L and R_L are as defined herein.

[00102] In some embodiments of a compound of formula (le), k is 1 and R₁₆ is in para position, compound may be represented by formula (If)

wherein R₁₆, R_B, Rc, L and R_L are as defined herein.

[00103] In some embodiments of a compound of formula (Ic), (Id), (le) and (If), R_B and R_c are both H.

[00104] In some embodiments, when anyone of of R_A, R_B and R_c is 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆, said heterocyclyl is 5- membered. In some embodiments, when anyone of of R_A, R_B and R_c is 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆, said heterocyclyl is 6- membered. Any 5- or 6-membered heterocyclyl comprises 1 or more heteroatoms in the ring, e.g. 1 , 2, 3 or 4 heteroatoms. In some embodiments, the heterocycyl is aromatic. In some other embodiments, the heterocyclyl is non-aromatic, and saturated or unsaturated, e.g. the heterocyclyl is non-aromatic and mono-unsaturated. For example, the heterocyclyl may be selected from

[00105] In some embodiments, when anyone of R_A, R_B and R_c is phenyl optionally substituted by one or more moieties R₁₆, or 5- or 6-membered heterocyclyl optionally substituted by one or more moieties R₁₆, each moiety R₁₆ may be independently selected from halogen, cyano, nitro, R17O, C1-C6 alkyl optionally substituted by R17O, C3-C6 cycloalkyl optionally substituted by RI₇O, R19S, R2oS(0)₂, R₂IOC(O), (R₂₂ON)C(R₂₃), R₂₄R₂₅NC(O), R26R27N, R₂₈S(O)₂NR₂₉, and R₃QS(O)2NR₃IC(O). [00106] In some embodiments, each R₁₆ is independently selected from halogen, cyano, nitro, R₁₇O, C1-C6 alkyl optionally substituted by R17O, C3-C6 cycloalkyl optionally substituted by RI₇O, R19S, R2oS(0)₂, R₂IOC(O), and R₂₆R₂₇N.

[00107] In some embodiments, each R₁₆ is independently selected from halogen, cyano, nitro, RI₇O, C1-C6 alkyl optionally substituted by RI₇O, R19S, R₂oS(0)₂, R₂IOC(O), and R₂₆R₂₇N.

[00108] In some embodiments, each R₁₆ is independently selected from halogen, cyano, nitro, RnO, C1-C6 alkyl optionally substituted by RI₇O, R19S, R₂oS(0)₂, R₂IOC(O), and R₂₆R₂₇N.

[00109] In some embodiments, each R₁₆ is independently selected from RI₇O, C1-C6 alkyl optionally substituted by RI₇O, and C3-C6 cycloalkyl optionally substituted by RI₇O, e.g. from RI₇O, C1-C6 alkyl optionally substituted by RI₇O, in particular from RI₇O.

[00110] In some embodiments, when R₁₆ is C1-C6 alkyl optionally substituted by RI₇O, it e.g. may be C1-C4 alkyl optionally substituted by RI₇O, e.g. C1-C3 alkyl optionally substituted by RI₇O.

[00111] In some embodiments, each R16 is independently selected from F, Cl, cyano, nitro, CH₃, CF₃, (CH₃)₃C, CH₃0, CH₃S, CH₃S(O)₂, COOH, NH₂, and (CH₃)₂N.

[00112] In some embodiments, when any R₁₆ is RI₇O, C1-C6 alkyl optionally substituted by RI₇O, or C3-C6 cycloalkyl optionally substituted by RI₇O, the moiety R₁₇ may be H, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, R₁₇ is selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl. In some embodiments, R₁₇ selected from H and C1 -C6 alkyl, e.g. from H and C1-C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH₃, in particular H.

[00113] In some other embodiments, the moiety R₁₇ is as defined herein above, but is not H; e.g. R₁₇ is CH₃.

[00114] In some embodiments, when any R₁₆ is R₁₈C(O), the moiety R₁₈ may be H, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, R₁₈ is selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1 -C3 alkyl and cyclopropyl. In some embodiments, R₁₈ is selected from H and C1-C6 alkyl, e.g. from H and C1-C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH₃, in particular H. In some other embodiments, the moiety R₁₈ is as defined herein above, but is not H; e.g. R₁₈ is CH₃.

[00115] In some embodiments, when any R₁₆ is R19S, the moiety R₁₉ may be H, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, R₁₉ is selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl. In some embodiments, R₁₉ is selected from H and C1-C6 alkyl, e.g. from H and C1-C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH₃, in particular H. In some other embodiments, the moiety R₁₉ is as defined herein above, but is not H; e.g. R₁₉ is CH₃.

[00116] In some embodiments, when any R₁₆ is R2oS(0)₂, the moiety R₂o may be H, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, R₂₀ is selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl. In some embodiments, R₂₀ is selected from H and C1 -C6 alkyl, e.g. from H and C1-C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH₃, in particular H. In some other embodiments, the moiety R₂₀ is as defined herein above, but is not H; e.g. R₂₀ is CH₃.

[00117] In some embodiments, when any R₁₆ is R₂₁OC(O), the moiety R₂₁ may be H, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, R₂₁ is selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1 -C3 alkyl and cyclopropyl. In some embodiments, R₂₁ is selected from H and C1-C6 alkyl, e.g. from H and C1-C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH₃, in particular H. In some other embodiments, the moiety R₂₁ is as defined herein above, but is not H; e.g. R₂₁ is CH₃.

[00118] In some embodiments, when any R₁₆ is (R₂₂ON)C(R₂3), R₂₂ may be H, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, R₂₂ is selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl. In some embodiments, R₂₂ is selected from H and C1-C6 alkyl, e.g. from H and C1-C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH₃, in particular H. R₂₃ is H, C1-C6 alkyl, or C3-C6 cycloalkyl. In some embodiments, R₂₃ is selected from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl. In some embodiments, R₂₃ is selected from H and C1-C6 alkyl, e.g. from H and C1-C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH₃, in particular CH₃. In some embodiments, the moiety R₂₃ is as defined herein above, but is not H. In some embodiments, R₂₂ is H and R₂₃ is as defined herein above, but different from H, e.g. R₂₃ is CH₃. [00119] In some embodiments, when any R₁₆ is R₂4R2sNC(O) or R26R27N, each one of R24, R25, R26 and R₂7 may be independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, e.g. from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl. In some embodiments, when any R₁₆ is R24R25 C(O) or R26R27N, each one of R24, R25, R26 and R₂7 is independently selected from H and C1-C6 alkyl, e.g. from H and C1- C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH₃.

[00120] In some embodiments, when any R₁₆ is R₂8S(O)₂NR₂9 or R₃₀S(O)2NR₃₁C(O), each one of R₂₃, R29, R30 and R₃₁ may be independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl, e.g. from H, C1-C4 alkyl, and C3-C4 cycloalkyl, or from H, C1-C3 alkyl and cyclopropyl. In some embodiments, when any R₁₆ is R₂8S(O)₂NR₂9, or R₃₀S(O)₂NR₃₁C(O), each one of R₂8, R29, R30 and R₃1 is independently selected from H and C1-C6 alkyl, e.g. from H and C1 -C4 alkyl, or from H and C1-C3 alkyl, such as from H and CH₃. In some embodiments, R₂8 and R₃₀ are as defined herein above, but are not H, and R29 and R₃₁ are both H.

[00121] In some embodiments, when one of R_A and R_c, together with R_B, forms a divalent group -(CH₂)_m- wherein m is an integer of from 3 to 5, m e.g. is 3 or 4, in particular 3, e.g. R_B and R_c may form together a group -(CH₂)3-.

[00122] For example, in some embodiments of a compound of formula (I), one of R_A, R_B and R_c is H and the other two are independently selected from halogen, cyano, C1-C4 alkyl, RTO, R₂C(O), R₃S, and R₄S(O)₂; or, if adjacent, in some embodiments the two other form a biradical -(CH₂)_m-wherein m is an integer of from 3 to 5.

[00123] In some embodiments, one of R_A, R_B and R_c is H, and the other two are selected from halogen, cyano, C1-C4 alkyl, and RTO, e.g. from halogen, C1-C3 alkyl, and C1-C3 alkoxy, e.g. from F, Cl, methyl and methoxy; or from halogen and C1-C3 alkyl, such as F, Cl, and methyl.

[00124] In some embodiments, one of R_A, R_B and R_c is H and the other two are both selected from halogen, e.g. both are F or Cl, or both are Cl.

[00125] In other embodiments, the two of R_A, R_B and R_c that are different from H are both selected from C1-C3 alkyl and RTO, e.g. both are selected from methyl and methoxy. In some embodiments, the two of R_A, R_B and R_c that are different from H are identical with each others, e.g. both are Cl, or both are methyl, or both are RTO, e.g. methoxy. [00126] For example, in some embodiments of a compound of formula (I), e.g. a compound of formula (lb), R_B and R_c are both selected from halogen, cyano, C1-C4 alkyl, and RTO. For example, R_B and R_c may be both selected from halogen, e.g. both R_B and R_c are F or Cl, or both R_B and R_c are Cl. In other embodiments, R_B and R_c are both selected from C1-C4 alkyl and RTO, e.g. both R_B and R_c are selected from methyl and methoxy, e.g. both are methyl. In a compound of formula (I), e.g. of formula (lb), R_B and R_c may be different from each other, or may be identical.

[00127] Some definitions of terms used herein are provided herein below. The listing is not exhaustive and it is noted that any term and expression used herein should be given its usual meaning, unless otherwise specified or clearly apparent from the context. Thus, for example, the term alkyl, either alone or as part of a group, includes straight or branched chain alkyl of the general formula C_nH_2n+i-

[00128] The term alkenyl refers to a divalent group of formula -(C_nH_2n)-. For example, a

C2 alkenyl is a moiety of formula -CH₂CH₂-, i.e. :

[00129] The term C1-C6 alkyl includes any alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.

[00130] The term C1-C4 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, secbutyl, isobutyl and tert-butyl.

[00131] The term C1-C3 alkyl includes methyl, ethyl, n-propyl and isopropyl.

[00132] The term cycloalkyl refers to a cyclic alkyl group of the general formula C_nH_2n. i-

[00133] The term cycloalkenyl refers to a cyclic alkenyl group of the general formula C_nH_2n-3.

[00134] The term C3-C6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. [00135] The term phenyl refers to a C₆H₅ group of the formula

[00136] The term heterocyclyl refers to a saturated or unsaturated and aromatic or non-aromatic cyclic moiety containing at least one heteroatom in the ring.

[00137] The term heteroaryl refers to an aromatic heterocyclyl, e.g. a pyridyl (also referred to as pyridinyl), tetrazolyl, furyl or pyridiminyl.

[00138] The term pyridyl refers to a C₅NH₅ group of formula

including 2-pyridyl, 3 -pyridyl and 4-pyridyl.

[00139] The term pyrimidinyl refers to a C₄N₂H₄ group of formula

including 2-pyrimidinyl, 4-pyrimidinyl and 5-pyrimidinyl.

[00140] The term thiazolyl refers to 1 ,2-thiazolyl and 1 ,3-thiazolyl.

[00141] The term 1 ,2-thiazolyl refers to a group of formula

including 1 ,2-thiazol-3-yl, 1 ,2-thiazoly-4-yl, and 1 ,2-thiazoly-5-yl.

[00142] The term 1 ,3-thiazolyl refers to a group of formula

including 1 ,3-thiazol-2-yl, 1 ,3-thiazol-4-yl and 1 ,3-thiazol-5-yl.

[00143] The term halogen refers to F, Cl, Br and I, preferably F, Cl and Br, more preferably Cl or Br, still more preferably Cl.

[00144] The term hydroxy refers to a group of the formula -OH.

[00145] The term alkoxy refers to a group of the formula RO, wherein R is alkyl.

[00146] The term RO refers to a group of formula

[00147] The term cyano refers to a group of the formula -C=N (i.e. -CN). The term RC(O) refers to a moiety of formula

[00149] The group RS is a group of formula

[00150] The term RS(O)₂ refers to a group of formula

[00151] The term ROC(O) refers to a group of formula

[00152] The term (RON)C(R') refers to a group of formula

The term RR'N refers to a group of formula

[00154] The term RR'NC(O) refers to a group of formula

[00155] The term RS(O)₂NR' refers to a group of formula

[00156] The term RS(O)₂NR'C(O) refers to a group of formula

[00157] In some embodiments, the compound is not

these compounds, each F is

¹⁹F, i.e. the naturally occurring isotope of fluorine.

[00158] In some embodiments, R_L is not ¹⁹F. The case that R_L is ¹⁹F can be also depicted as

, wherein the wavy line indicates attachment to the linker L.

Accordingly, it is noted that the term “R_L is not ¹⁹F” does not exclude labels which merely comprise ¹⁹F, such as e.g. BODIPY, which can be used as a label in the compounds of formula (I) described herein.

[00159] In some embodiments, R_A, R_B and R_c are each independently selected from the group consisting of H, R₁₄S(O)₂NR₁₅C(O), phenyl optionally substituted by one or more moieties R₁₆, R₅OC(O), halogen, and C1-C6 alkyl. In these embodiments, R₁₄S(O)₂NR₁₅C(O) may

some of these embodiments, phenyl optionally substituted by one or more moieties R₁₆ may be phenyl optionally substituted by R17O. In some of these embodiments phenyl optionally substituted by one or more moieties R₁₆ may be

In some of these embodiments, R₅OC(O) may

some of these embodiments, halogen may be F, Cl, Br or I, preferably F, Cl or Br, more preferably Cl. In some of these embodiments, C1-C6 alkyl may be methyl.

[00160] Preferably, R_A is H. More preferably, R_A is H, R_B is H and R_c is H.

[00161] Preferably, R_A is R₁₄S(O)₂NR₁₅C(O). More preferably, R_A is

some of these embodiments, R_B may be H, and R_c may be H. [00162] Preferably, R_A is phenyl optionally substituted by one or more moieties R₁₆. More preferably R_A is phenyl optionally substituted by R17O. Still more preferably, R_A is

. In some of these embodiments, R_B may be H, and R_c may be H.

[00163] Preferably, R_A is R₅OC(O). More preferably,

some of these embodiments, R_B may be H, and R_c may be H or halogen, preferably Cl. In some of these embodiments, R_B may be H and R_c may be halogen, preferably Cl.

[00164] Preferably, R_B is halogen, more preferably Cl. In these embodiments, R_A may be H. In these embodiments, R_c may be, independently, halogen, preferably Cl. In some more preferred embodiments, R_A is H, R_B is halogen, and R_c is halogen. Still more preferably, R_A is H, R_B is Cl, and R_c is Cl.

[00165] Preferably, R_B is C1-C6 alkyl, more preferably methyl. In some of these embodiments, R_A may be H. In some of these embodiments, R_c may be, independently, C1- C6 alkyl, preferably methyl.

[00166] The group L is a linker. Virtually any linker moiety (linker) can be used. The linker may, for example, be a straight or branched hydrocarbon based moiety. The linker can also comprise cyclic moieties. If the linking moiety is a hydrocarbon-based moiety the main chain of the linker may comprise only carbon atoms but can also contain heteroatoms such as oxygen (O), nitrogen (N) or sulfur (S) atoms. The linker may for example include a C1-C20 carbon atom chain or a polyether based chain such as polyethylene glycol based chain with -(O-CH₂-CH₂)- repeating units. In typical embodiments of hydrocarbon based linkers, the linking moiety may comprise between 1 to about 150, 1 to about 100, 1 to about 75, 1 to about 50, or 1 to about 40, or 1 to about 30, or 1 to about 20, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, and 19 main chain atoms. As indicated in formula (I), the linker L is attached to a carbonyl carbon atom, and to a label R_L.

[00167] Preferably, the linker L is (L1):

(L1), wherein indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to the label R_L.

[00168] Preferably, the linker L is (L2):

wherein o is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 1 or 2, even more preferably o is 1; indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to the label R_L. More preferably, the linker L is (L2*):

(L2*), wherein indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to the label R_L.

[00169] Preferably, the linker L is (L3):

(L3), wherein: o is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 1 or 2, even more preferably o is 1; p is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably p is 2 or 3, even more preferably p is 2;

J⁵* indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to the label R_L. More preferably, the linker L is (L3*):

wherein indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to the label R_L.

[00170] Preferably, the linker L is (L4):

wherein

R200 is H or C1-C6 alkyl; preferably R_2Oo is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;

R₂₀I is H or C1-C6 alkyl; preferably R₂₀I is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;

X is an anion; preferably X is a halogenide, more preferably bromide (Br ); o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5; p is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably p is 1 or 2, even more preferably p is 1; q is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably q is 2 or 3, even more preferably q is 2; indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to the label R_L. Im some of these embodiments, R₂₀₀ and R₂₀I are the same; preferably R₂₀₀ is methyl and R₂₀I is methyl. More preferably, the linker L is (L4*):

wherein indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to the label R_L. [00171] Preferably, the linker L is (L5):

(L5), wherein

R200 is H or C1-C6 alkyl; preferably R₂oo is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl; o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5; indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to the label R_L. More preferably, the linker L is (L5*):

wherein indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to the label R_L.

[00172] Preferably, the linker L is (L6):

wherein

R_2OO is H or C1-C6 alkyl; preferably R₂₀₀ is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;

R_3OO is H or C1-C6 alkyl; preferably R₃₀₀ is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;

R₃₀I is H or C1-C6 alkyl; preferably R₃₀I is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl; o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5; p is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 2 or 3, even more preferably p is 2; indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to the label R_L. In some of these embodiments, R_2Oo, R₃₀₀ and R₃₀I are the same; preferably R₂oo is methyl, R₃₀₀ is methyl and R₃₀I is methyl. More preferably, the linker L is (L6*):

wherein indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to the label R_L.

[00173] Preferably, the linker L is (L7):

wherein

R200 is H or C1-C6 alkyl; preferably R₂oo is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;

R201 is H or C1-C6 alkyl; preferably R201 is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl; o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5; indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to the label R_L. In some of these embodiments, R₂oo and R201 are the same; preferably R₂oo is methyl and R201 is methyl. More preferably, the linker L is (L7*):

wherein indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to the label R_L.

[00174] Preferably, the linker L is (L8):

wherein

R201 is H or C1-C6 alkyl; preferably R201 is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;

R₃oo is H or C1-C6 alkyl; preferably R₃₀₀ is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;

R301 is H or C1-C6 alkyl; preferably R₃₀I is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl; o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5; p is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 2 or 3, even more preferably p is 2; indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to R_L. In some of these embodiments, R_2Oo, R201, R300 and R301 are the same; preferably R₂oo is methyl, R₂₀I is methyl, R₃₀₀ is methyl and R₃₀I is methyl. More preferably, the linker L is (L8*):

wherein indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to the label R_L.

[00175] Preferably, the linker L is (L9):

wherein o is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 1 or 2, even more preferably o is 1 ; p is an integer ranging from 1 to 10, preferably from 1 to 8, more preferably from 2 to 5, still more preferably p is 3 or 4, even more preferably p is 3; q is an integer ranging from 1 to 5, preferably from 1 to 3; indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to the label R_L. More preferably, the linker L is (L9*):

wherein q is an integer ranging from 1 to 3; indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to the label R_L.

[00176] Preferably, the linker L is (L10):

(L10), wherein o is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 1 or 2, even more preferably o is 1; p is an integer ranging from 1 to 10, preferably from 1 to 8, more preferably from 2 to 5, still more preferably p is 3 or 4, even more preferably p is 3; indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to the label R_L. More preferably, the linker L is (L10*):

wherein indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to the label R_L. [00177] Preferably, the linker L is (L11):

wherein o is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 1 or 2, even more preferably o is 1; p is an integer ranging from 1 to 10, preferably from 2 to 8, more preferably from 2 to 6, still more preferably p is 2 or 4, even more preferably p is 3; indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to the label R_L. More preferably, the linker L is (L11*):

(L11*), wherein indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to the label R_L.

[00178] Preferably, the linker L is (L12):

wherein o is an integer ranging from 1 to 20, preferably from 2 to 15, more preferably from 3 to 10, still more preferably from 4 to 6, even more preferably o is 5;

R₂OO is H or C1-C6 alkyl; preferably R_2Oo is H; indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to the label R_L. In some embodiments, R₂₀₀ is C1-C3 alkyl, preferably methyl or ethyl, more preferably methyl. Still more preferably, R₂₀₀ is H. Even more preferably, the linker L is (L12*):

(L12*), wherein indicates the attachment point to the carbonyl carbon atom; and

# indicates the attachment point to the label R_L.

[00179] Any linker L described herein can be combined with any label R_L described herein.

[00180] The group R_L is a label. As used herein the term “label” in general refers to a moiety that allows detection and/or imaging. The label is not particularly limited and may include, for example, labels suitable for use in molecular imaging techniques. By way of example the label may be a label suitable for single photon emission tomography (SPECT), positron emission tomography (PET), optical imaging, ultrasound and/or photoacoustic imaging. When used herein, the term "label" can also be replaced by the term “tracer”. As will be known to the person of skill in the art, any suitable known label modality, for use with any suitable imaging or detection method as described herein, are possible. By way of nonlimiting example, any suitable label moiety known to the person of skill in the art for use in optical imaging (non-limiting examples may include a fluorescent label such as Cy5.5®, Cy3®, Cy3.5®, Cy5®, or Cy7®)), PET (non-limiting examples may include a label having a ¹⁸F group), SPECT (non-limiting examples may include a label having a ¹²³l, ¹²⁴l, ¹²⁵l, "^mTc, ¹⁸⁶Re or ¹⁸⁸Re group), or photoacoustic imaging (non-limiting examples may include an absorber such as polymethine dyes (non-limiting examples include cyanine dyes), phthalocyanines, or naphthalocyanines) may be used. Chelators may be used, including different albumin-tags and sulfonic acids bearing site chains to give optimized pharmacokinetic behaviour. Some non-limiting embodiments of possible components of R' are shown in Figure 2. In an embodiment, suitable labels for optical imaging may include dyes such as, for example, fluorescein isothiocyanate (FITC), 1 ,T-dioctadecyl-3,3,3',3'-tetramethyl indotricarbocyanine iodide (DiR), a coumarin dye, a rhodamine dye, a carbopyronin dye, an oxazine dye, a fluorescein dye, a cyanine dye, a boron-dipyrromethene (BODIPY) dye, a squaraine dye, and a squaraine rotaxane dye. Coumarin dyes, rhodamine dyes, carbopyronin dyes and oxazine dyes are, for example, commercially available under the trade name ATTO® from ATTO-TEC GmbH. Furthermore, coumarin dyes, rhodamin dyes, fluorescein dyes and cyanine dyes are, for example, commercially available under the trade name Alexa Fluor® from Molecular Probes, Inc. Coumarin dyes, rhodamin dyes, fluorescein dyes and cyanine dyes are, for example, also commercially available under the trade name DyLight® Fluor from Dyomics in collaboration with Thermo Fisher Scientific, Inc. Boron-dipyrromethene dyes are, for example commercially available under the tradename BODIPY® from Life Technologies. Squaraine dyes are, for example, commercially available under the trade name SETA® from SETA BioMedicals. Squaraine rotaxane dyes are, for example, comercially available under the trade name SeTau® from SETA BioMedicals. In another embodiment suitable labels for MRI may include a perfluorinated ¹⁹F label and Gd(DOTA), wherein DOTA denotes 1 ,4,7,10- tetraazacyclododecane-1 ,4,7,10-tetraacetic acetic acid and any conjugated base thereof. In a further embodiment suitable labels for ultrasound imaging may include gas filled microbubbles which are stabilized by a shell, wherein the shell may, for example, be comprised of proteins, lipids or polymers.

[00181] Suitable labels for SPECT may include an ¹²³l, ¹²⁴l, ¹²⁵l and/or "^mTc. Nonlimiting examples may include:

and wherein each R⁹ is independently selected from the group consisting of -CH₃,

preferably wherein each R⁹ is the same. In some embodiments R⁹ is methyl. In some embodiments the SPECT label is negatively or positively charged, preferably negatively charged.

[00182] Suitable labels for PET may include an ¹⁸F or a ⁶⁸Ga. Non limiting examples may include :

In some embodiments the PET label contains an acidic group, preferably a sulfonic acid group.

[00183] Labels for optical imaging may include any suitable fluorophore or dye known in the art. Non-limiting examples may include a cyanine dye such as cyanine 3, cyanine 3.5, cyanine 5, cyanine 5.5 and cyanine 7 or related analogues. For example, the commercially available Cy3®, Cy3.5®, Cy5®, Cy5.5®, Cy7® dyes provided by GE Healthcare may be used. Other fluorophores may include 7-amino-4-methylcoumarin (AMC), fluorescein isothiocyanate (FITC), fluorescein carboxylic acid, 5-carboxytetramethylrhodamine (TAMRA), indocyanine green, a DyLight® Fluor dye, an ATTO® dye, a BODIPY® dye, a SETA® dye, a SeTau® dye, an Alexa Fluor® dye from Invitrogen, an IRdye® dye from Li-COR Bioscience, an SRfluor® dye from Molecular Targeting Technologies, a HyLyte™ Fluor dye from Anaspec, CF™633 from Biotium, and an indotricarbocyanine (ITCC) dye. See, for example, B. P. Joshi, T. D. Wang, Exogenous Molecular Probes for Targeted Imaging in Cancer: Focus on Multi-modal Imaging, Cancers 2010, 2(2), 1251-1287.

[00184] In some embodiments the label R_L is a metal binding group with a metal coordinated by said binding group. Accordingly, the label R_L may be a metal binding group for a metal selected from "^mTc, ¹⁸⁶Re, ¹⁸⁸Re, ¹¹¹ In, ⁶⁷Ga, ⁶⁸Ga, ⁶⁴Cu and/or ⁸⁹Zr. The metal binding group for the metal can be any group which is able to coordinate to the metal like "^mTc, ¹⁸⁶Re, ¹⁸⁸Re, ¹¹¹1 n, ⁶⁷Ga, ⁶⁸Ga, ⁶⁴Cu and/or ⁸⁹Zr and at the same time bound covalently to L of formula (I). In some embodiments the binding group is a monodentate, bidentate, tridentate or polydentate binding group able to coordinate the metal at one, two, three or several coordination sites of said metal. In some embodiments the binding group is negatively or positively charged. The metal binding group may coordinate said metal together with an additional binding group. Accordingly, in some embodiments the binding group coordinates the metal together with an additional metal binding group, wherein the additional binding group is preferably not bound to the compound according to formula (I). In some embodiments the additional binding group is a monodentate, bidentate, tridentate or polydentate binding group able to coordinate the metal at one, two, three or several coordination sites of said metal, preferably a bidentate binding group, more preferably bathophenanthrolinedisulfonic acid disodium salt hydrate. In some embodiments the binding group is negatively or positively charged, preferably negatively charged. In some embodiments the binding group and the metal or the binding group, the additional binding group and the metal are a SPECT label. [00185] In some embodiments, the label R_L is a positron emission tomography (PET) label. In some embodiments, the label R_L is a single photon emission tomography (SPECT) label. In some embodiments, the label R_L is an optical imaging label. In some embodiments, the label R_L is a magnetic resonance imaging (MRI) label. In some embodiments, the label R_L is an ultrasound label. In some embodiments, the label R_L is a photoacoustic label. In some embodiments, the label RL comprises a group selected from the group consisting of ¹⁸F, ⁶⁸Ga, ¹²³l, ¹²⁴l, ¹²⁵l, "^mTc, ¹¹¹ln, ⁶⁷Ga, ⁶⁴Cu, ¹¹C, ⁸⁹Zr, fluorescent dyes, phosphorescent dyes, and photoacoustic absorbers.

[00186] In some embodiments, the label R_L is a positron emission tomography (PET) label.

[00187] In some preferred embodiments, the label R_L is ¹⁸F. The case that the label R_L — ¹⁸F is ¹⁸F can be also depicted as , wherein the wavy line indicates attachment to the linker L. When the label is ¹⁸F, in some embodiments the ¹⁸F labelled compound may be present in a mixture with a compound having ¹⁹F at the position of the ¹⁸F. As an illustrative non-limiting example, the ratio of the ¹⁸F compound to the ¹⁹F compound may be about 1 to 10.

[00188] More preferably, when the label is ¹⁸F, the linker L is selected from the group consisting of (L1), (L3), (L3*), (L4), (L4*), (L5), (L5*), (L6), (L6*), (L7), (L7*), (L8) and (L8*), wherein (L1), (L3), (L3*), (L4), (L4*), (L5), (L5*), (L6), (L6*), (L7), (L7*), (L8) and (L8*) are as defined herein. Accordingly, when the label is ¹⁸F, the linker may be (L1), wherein (L1) is as defined herein. When the label is ¹⁸F, the linker may be (L3), wherein (L3) is as defined herein. When the label is ¹⁸F, the linker may be (L3*), wherein (L3*) is as defined herein. When the label is ¹⁸F, the linker may be (L4), wherein (L4) is as defined herein. When the label is ¹⁸F, the linker may be (L4*), wherein (L4*) is as defined herein. When the label is ¹⁸F, the linker may be (L5), wherein (L5) is as defined herein. When the label is ¹⁸F, the linker may be (L5*), wherein (L5*) is as defined herein. When the label is ¹⁸F, the linker may be (L6), wherein (L6) is as defined herein. When the label is ¹⁸F, the linker may be (L6*), wherein (L6*) is as defined herein. When the label is ¹⁸F, the linker may be (L7), wherein (L7) is as defined herein. When the label is ¹⁸F, the linker may be (L7*), wherein (L7*) is as defined herein. When the label is ¹⁸F, the linker may be (L8), wherein (L8) is as defined herein. When the label is ¹⁸F, the linker may be (L8*), wherein (L8*) is as defined herein.

[00189] The compound of formula (I) may be:

or a salt, isomer, or tautomer thereof.

[00190] The compound of formula (I) may be:

or a salt, isomer, or tautomer thereof.

[00191] The compound of formula (I) may be:

or a salt, isomer, or tautomer thereof.

[00192] In some embodiments, the label R_L is:

wherein * indicates the attachment point to the linker L. In some of these embodiments, the linker L may be (L9), wherein (L9) is as defined herein. In some of these embodiments, the linker L may be (L9*), wherein (L9*) is as defined herein.

[00193] In some embodiments, the label R_L is:

[00194] In some embodiments, the label R_L is:

[00195] The compound of formula (I) may be:

or a salt, isomer, or tautomer thereof.

[00196] The compound of formula (I) may be:

or a salt, isomer, or tautomer thereof.

[00197] The compound of formula (I) may be:

or a salt, isomer, or tautomer thereof.

[00198] In some embodiments, the label R_L is a single photon emission tomography (SPECT) label.

[00199] In some embodiments, the label R_L is:

wherein * indicates the attachment point to the linker L. In some of these embodiments, the linker L may be (L10), wherein (L10) is as defined herein. In some of these embodiments, the linker L may be (L10*), wherein (L10*) is as defined herein.

[00200] The compound of formula (I) may be:

or a salt, isomer, or tautomer thereof.

[00201] In some embodiments, the label R_L is:

wherein * indicates the attachment point to the linker L. In some of these embodiments, the linker L may be (L2), wherein (L2) is as defined herein. In some of these embodiments, the linker L may be (L2*), wherein (L2*) is as defined herein.

[00202] In some embodiments, the label R_L is:

[00203] The compound of formula (I) may be:

or a salt, isomer, or tautomer thereof.

[00204] The compound of formula (I) may be:

or a salt, isomer, or tautomer thereof. [00205] In some embodiments, the label R_L may be or may comprise a photoacoustic imaging label. In some embodiments the photoacoustic label is a phthalocyanine. In some embodiments the photoacoustic label is a naphthalocyanine. In some embodiments the photoacoustic label is a polymethine dye. In some embodiments the label comprises a photoacoustic imaging label which is an absorber selected from the group consisting of:

wherein each R¹⁰ is independently selected from the group consisting of sulphonic acids, ammonium salts, and thioethers, preferably wherein each R¹⁰ is the same; wherein o is an integer from 0 to 20, preferably from 1- to 10, more preferably from 1- to 5, most preferably o is 3; and wherein M²⁺ is Fe, Cu, Ni, or V(=O). [00206] In some embodiments, the label R_L may comprise or may be an optical imaging label. In some embodiments the optical imaging label is a dye. In some embodiments the dye is fluorescein isothiocyanate (FITC). In some embodiments the dye is 1 ,T-dioctadecyl-3,3,3',3'-tetramethyl indotricarbocyanine iodide (DiR). In some embodiments the dye is a coumarin dye. In some embodiments the dye is a rhodamine dye. In some embodiments the dye is a carbopyronin dye. In some embodiments the dye is an oxazine dye. In some embodiments the dye is a fluorescein dye. In some embodiments the dye is a cyanine dye. In some embodiments the dye is a boron-dipyrromethene (BODIPY) dye. In some embodiments the dye is a squaraine dye. In some embodiments the dye is a squaraine rotaxane dye. In some embodiments the dye is an Alexa Fluor® dye. In some embodiments the dye is a DyLight® Fluor dye. In some embodiments the dye is an ATTO® dye. In some embodiments the dye is a BODIPY® dye. In some embodiments the dye is a SETA® dye. In some embodiments the dye is a SeTau® dye. In some embodiments the dye is Alexa Fluor® 488.

[00207] In some embodiments, the optical imaging label is a fluorophore. In some embodiments the fluorophore is a polymethine dye. In some embodiments the polymethine dye is a cyanine dye. In some embodiments the cyanine dye is cyanine 3. In some embodiments the cyanine dye is cyanine 3.5. In some embodiments the cyanine dye is cyanine 5. In some embodiments the cyanine dye is cyanine 5.5. In some embodiments the cyanine dye is cyanine 7.

[00208] In some embodiments, the label R_L is:

wherein * indicates the attachment point to the linker L. In some of these embodiments, the linker L may be (L11), wherein (L11) is as defined herein. In some of these embodiments, the linker L may be (L11*), wherein (L11*) is as defined herein.

[00209] In some embodiments, the label R_L is:

wherein * indicates the attachment point to the linker L. In some of these embodiments, the linker L may be (L11), wherein (L11) is as defined herein. In some of these embodiments, the linker L may be (L11*), wherein (L11*) is as defined herein. [00210] In some embodiments, the label R_L is:

[00211] In some embodiments, the label R_L is:

[00212] The compound of formula (I) may be:

or a salt, isomer, or tautomer thereof.

[00213] The compound of formula (I) may be:

or a salt, isomer, or tautomer thereof. [00214] The compound of formula (I) may be:

or a salt, isomer, or tautomer thereof.

[00215] The compound of formula (I) may be:

or a salt, isomer, or tautomer thereof. [00216] In some embodiments, the label R_L is:

wherein * indicates the attachment point to the linker L. In some of these embodiments, the linker L may be (L11), wherein (L11) is as defined herein. In some of these embodiments, the linker L may be (L11*), wherein (L11*) is as defined herein. In some of these embodiments, the linker L may be (L12), wherein (L12) is as defined herein. In some of these embodiments, the linker L may be (L12*), wherein (L12*) is as defined herein.

[00217] The compound of formula (I) may be:

or a salt, isomer, or tautomer thereof. [00218] Compounds of the invention may also include the following.

Increased number of ionic charges with focus on balanced net charge (¹⁸F-labelling for PET)

Peptide-sequences with balanced net-charge at pH 7.4 (¹⁸F-, ⁶⁸Ga- and "^mTc-labelling for PET and SPECT)

"^mTc-labelled derivatives for SPECT by labelling varied hydrophilic his-tags or carboxylated chelators

[00219] According to another aspect of the present invention, the compounds disclosed herein are diagnostic compounds.

[00220] In another aspect, the present invention further relates to a diagnostic composition comprising any of the compounds as described herein above and a pharmaceutically or diagnostically acceptable excipient.

[00221] According to a further aspect, the present invention provides the use of any of the compounds as disclosed herein above in a method of diagnosis. In some embodiments the diagnosis is a diagnosis of an inflammatory disease in a subject. Preferably the method of diagnosing an inflammatory disease is a non-invasive molecular imaging method. In a preferred embodiment the non-invasive molecular imaging method is an in vivo molecular imaging method. In some embodiments the non-invasive molecular imaging method is an in vitro molecular imaging method. In some embodiments the non-invasive molecular imaging method is single photon emission tomography (SPECT). In some embodiments the non- invasive molecular imaging method is positron emission tomography (PET). In some embodiments the non-invasive molecular imaging method is optical imaging. In some embodiments the non-invasive molecular imaging method is magnetic resonance imaging (MRI). In some embodiments the non-invasive molecular imaging method is ultrasound. In some embodiments the non-invasive molecular imaging method is photoacoustic imaging.

[00222] As provided herein, the inflammatory disease is associated with phagocyte and/or epithelial cell activation in said subject. In some embodiments the inflammatory disease is further associated with an overexpression and accumulation of S100A9 in said subject. In some embodiments the inflammatory disease is dermatitis, preferably irritant dermatitis (ICD). In some embodiments the inflammatory disease is atherosclerosis. In some embodiments the inflammatory disease is psoriasis. In some embodiments the inflammatory disease is an autoimmune disease. In some embodiments the inflammatory disease is arthritis. In some embodiments the inflammatory disease is allergies. In some embodiments the inflammatory disease is cardiovascular processes. In some embodiments the inflammatory disease is local and systemic infections. In some embodiments the inflammatory disease is a neuroinflammatory disease. In some embodiments the inflammatory disease is acute lung injury (ALI). In some embodiments the inflammatory disease is a tumor.

[00223] The method of diagnosis as described herein is typically a method of an early stage diagnosis. In a preferred embodiment, the inflammatory disease diagnosed by the method of the present invention is at local site.

[00224] The subject of the present invention is typically a mammal. In some embodiments the mammal is a mouse. In some embodiments the mammal is a rat. In some embodiments the mammal is a guinea pig. In some embodiments the mammal is a rabbit. In some embodiments the mammal is a cat. In some embodiments the mammal is a dog. In some embodiments the mammal is a horse. Preferably the mammal is human.

[00225] In some embodiments the method of the present invention comprises administering any of the compounds as disclosed herein above to the subject. The administration of the compound may be carried out variously. In some embodiments the administration is carried out intravenously. In some embodiments the administration is carried out subcutaneously. In some embodiments the administration is carried out intralesionally. In some embodiments the administration is carried out by application to mucous membranes. In some embodiments the administration is carried out orally. In some embodiments the administration is carried out parenterally. In some embodiments the administration is carried out intramuscularly. In some embodiments the administration is carried out intraperitoneally. In some embodiments the administration is carried out by intranasal instillation. In some embodiments the administration is carried out by implantation. In some embodiments the administration is carried out by intracavitary instillation. In some embodiments the administration is carried out by intravesical instillation. In some embodiments the administration is carried out intraocularly. In some embodiments the administration is carried out intraarterially. In some embodiments the administration is carried out transdermally. Preferably, the administration is carried out intravenously, subcutaneously, intralesionally, or by application to mucous membranes.

[00226] According to another aspect, the present invention relates to a method of diagnosing an inflammatory disease in a subject, comprising: a) administering to said subject any of the compounds as disclosed herein above, b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data.

[00227] In a further aspect the present invention provides a non-invasive method of detecting or imaging accumulation of S100A9 in the body of a subject to whom any of the compounds as disclosed herein above has been pre-delivered, comprising: a) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, b) comparing the imaging data received in step a) to reference imaging data.

[00228] According to the methods of the present invention described herein above, an increased signal in the imaging data from the subject as compared to reference imaging data indicates the presence of an inflammatory disease in said subject, wherein no difference in the signal in the imaging data from the subject as compared to reference imaging data indicates no presence of an inflammatory disease in said subject.

[00229] According to another aspect, the present invention relates to the use of any of the compounds as disclosed herein above for the preparation of a diagnostic composition for diagnosing an inflammatory disease associated with phagocyte and/or epithelial cell activation in a subject.

[00230] In a further aspect, the present invention also provides a method for evaluating whether a subject may be at risk of developing an inflammatory disease associated with phagocyte and/or epithelial cell activation, the method comprising: a) administering to said subject any of the compounds as disclosed herein above, b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data.

In this regard, a significantly increased signal in the imaging data from the subject as compared to reference imaging data indicates that said subject is at higher risk of developing an inflammatory disease associated with phagocyte and/or epithelial cell activation. On the other hand, a signal in the imaging data at a normal level as compared to reference imaging data indicates that said subject is at lower risk of developing an inflammatory disease associated with phagocyte and/or epithelial cell activation.

[00231] According to another aspect, also provided herein is a method of monitoring or evaluating the progression of an inflammatory disease associated with phagocyte and/or epithelial cell activation in a patient, the method comprising: a) administering to said subject any of the compounds as disclosed herein above, b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data obtained from said patient at an earlier date, wherein the result of the comparison of c) provides an evaluation of the progression of the inflammatory disease associated with phagocyte and/or endothelial cell activation in said patient.

In this regard, a significantly increased signal in the imaging data from the patient as compared to reference imaging data obtained from said patient at an earlier date indicates a progression of the inflammatory disease associated with phagocyte and/or endothelial cell activation in said patient. On the other hand, no change in the signal of the imaging data from the patient or a decreased signal in the imaging data from the patient as compared to reference imaging data obtained from said patient at an earlier date indicates no progression or a regression of the inflammatory disease associated with phagocyte and/or endothelial cell activation in said patient.

[00232] In a further aspect, the present invention provides a method of imaging an inflammatory disease in a subject, comprising: a) administering to said subject any of the compounds as disclosed herein above, b) detecting the administered compound using an in vivo non-invasive molecular imaging method, thereby collecting imaging data.

[00233] Also provided herein is an in vitro method of diagnosing an inflammatory disease in a subject to whom any of the compounds as disclosed herein above has been pre-delivered, comprising: a) analyzing a sample taken from said subject, b) detecting said pre-delivered compound using a non-invasive molecular imaging method, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data. [00234] According to the in vitro method described herein, an increased signal in the imaging data from the subject as compared to reference imaging data indicates the presence of an inflammatory disease in said subject, wherein no difference in the imaging signal in the imaging data from the subject as compared to reference imaging data indicates no presence of an inflammatory disease in said subject.

[00235] The imaging data of the present invention underline the applicability of the compounds of formula (I) comprising a label in the diagnosis of inflammatory and cardiovascular diseases associated with S100A9 overexpression and accumulation at local site of inflammation.

[00236] Therefore, in one aspect, the present invention provides the use of any of the compounds of formula (I) comprising a label as disclosed herein for use in a method of diagnosis, wherein the diagnosis is typically a diagnosis of an inflammatory disease. The term “diagnosing” or “diagnosis” when used herein means determining or detecting if a subject suffers from an inflammatory disease or disorder. However, where reference is made to "diagnosis" of an inflammatory disease, this should be taken to include both diagnosis of the disease itself, as well as susceptibility to the disease. Accordingly, the methods of diagnosis disclosed herein may also be employed as methods of providing indications useful in the diagnosis of an inflammatory disease. Typically, the inflammatory disease or disorder as described herein is associated with phagocyte and/or epithelial cell activation in said subject. This activation is accompanied by an increased expression and secretion of S100A9 by said cells, which binds to both the extracellular matrix and receptors such as TLR4 or RAGE on the immune cell surface, thereby amplifying inflammatory reactions. Thus, in a preferred embodiment, the inflammatory disease or disorder of the present invention is further associated with an overexpression and accumulation of S100A9 in said subject. The term “overexpression” is used herein to mean above the normal expression level of S100A9 protein in a particular tissue or at a local stage in said subject. The term “accumulation” when used herein refers to the enrichment of the overexpressed S100A9 protein in a particular tissue or at a local stage in said subject.

[00237] When applying the labeled compounds of the present invention for use in a method of diagnosing an inflammatory disease in a subject, in some embodiments the inflammatory disease is at local site of the inflammation. “At local site” when used herein means that S100A9 can be visualized in vivo at spatially limited areas in the tissue of a subject whereas biomarkers measured in the blood only reflect the systemic states, which is however strongly affected by factors like metabolism or blood clearance, limiting the specificity and sensitivity of these approaches. Accordingly, the compounds of the present invention in combination with the imaging techniques described elsewhere herein allow for the reliable detection of S100A9 when locally expressed during an inflammatory disease. Moreover, visualization of the compounds as disclosed herein enables the proof of local inflammation with unique sensitivity, allowing even the detection of sub-clinical, residual disease activity. Accordingly, in a preferred embodiment of the present invention, the inflammatory disease can be diagnosed at an early stage of inflammation. The term “early stage” as used herein encompasses, but is not limited to medical conditions in which the afflicted subject, e.g. the afflicted human subject, shows little to no perceptible exterior sign or symptoms of inflammation and the overall physical condition of said subject is apparently preserved, although some accumulation of S100A9 may be evident. Exterior signs or symptoms of inflammation include, but are not limited to classical signs of inflammation such as pain, heat, redness, rash, swelling, skin lesions or fever, which however are strongly dependent on the type of inflammatory disease and the place of occurrence in the body.

[00238] The term "disease" or “disorder” as used herein, refers to any physical state of a subject connected with incorrectly functioning organ, part, structure, or system of the body resulting from the effect of genetic or developmental errors, infection, poisons, nutritional deficiency or imbalance, toxicity, or unfavorable environmental factors, illness, sickness, or ailment. The term "disease" or “disorder” further includes any impairment of the normal physical state of the subject or one of its parts that interrupts or modifies the performance of vital functions that are typically manifested by distinguishing signs and symptoms. The term “inflammatory” or “inflammation” when used herein refers to a part of complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. In this context, inflammation is a protective response involving host cells, blood vessels, and proteins and other mediators that is intended to eliminate the initial cause of cell injury, as well as the necrotic cells and tissues resulting from the original insult, and to initiate the process of repair. Within the scope of the present invention, the inflammation described herein can be generally classified as either acute or chronic. The acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes (especially granulocytes) from the blood into the injured tissues, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation, also known as chronic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process. Thus, the term “Inflammatory diseases” or “inflammatory disorder” when used herein refer to any physical state of the subject of the present invention which is related to a disease or a physical reaction connected with the occurrence of inflammation in said subject. Particularly, the inflammatory disease or disorder of the present invention is preferably related to an increased phagocyte and/or epithelial cell activation and a S100A9 overexpression and accumulation in said subject.

[00239] Many inflammatory and cardiovascular diseases or disorders are known as to be associated with an increased phagocyte and/or epithelial cell activation and are within the scope of the present invention. Since these cells express and locally secrete high levels of the S100 protein complex S100A8/S100A9 which acts as so called alarmin or Danger Associated Molecular Pattern (DAMP) molecule with potent pro-inflammatory capacities, many inflammatory and cardiovascular diseases are associated with an overexpression and accumulation of S100A9 (Vogl et al. 2007, Loser et al. 2010, Chan et al. 2012). In some embodiments the inflammatory disease of the present invention is dermatitis. In some embodiments the inflammatory disease is atherosclerosis. In some embodiments the inflammatory disease is psoriasis. In some embodiments the inflammatory disease is an autoimmune disease. In some embodiments the inflammatory disease is arthritis. In some embodiments the inflammatory disease is allergies. In some embodiments the inflammatory disease is cardiovascular processes. In some embodiments the inflammatory disease is local and systemic infections. In some embodiments the inflammatory disease is a neuroinflammatory disease. In some embodiments the inflammatory disease is acute lung injury (ALI). In some embodiments the inflammatory disease is a tumor.

[00240] A subject when used herein includes mammalian and non-mammalian subjects. Preferably the subject of the present invention is a mammal, including human, domestic and farm animals, nonhuman primates, and any other animal that has mammary tissue. In some embodiment the mammal is a mouse. In some embodiment the mammal is a rat. In some embodiment the mammal is a guinea pig. In some embodiment the mammal is a rabbit. In some embodiment the mammal is a cat. In some embodiment the mammal is a dog. In some embodiment the mammal is a monkey. In some embodiment the mammal is a horse. In a most preferred embodiment the mammal of the present invention is a human. A subject also includes human and veterinary patients.

[00241] According to another aspect, the present invention provides a method of diagnosing an inflammatory disease in a subject, comprises (a) administering to said subject any of the labelled compounds of formula (I) described herein above, (b) detecting the administered compounds using in vivo non-invasive molecular imaging techniques, thereby collecting imaging data, and (c) comparing the imaging data received in step (b) to reference imaging data. Here, the method of diagnosing comprises an active administration of any of the compounds according to the present invention to a subject. The administration of the compound may be carried out variously. In some embodiments the compounds as disclosed herein above are administered intravenously. In some embodiments the administration of the compound is carried out orally. In some embodiments the administration is carried out parenterally. In some embodiments the administration is carried out subcutaneously. In some embodiments the administration is carried out intramuscularly. In some embodiments the administration is carried out intraperitoneally. In some embodiments the administration is carried out by intranasal instillation. In some embodiments the administration is carried out by implantation. In some embodiments the administration is carried out by intracavitary instillation. In some embodiments the administration is carried out by intravesical instillation. In some embodiments the administration is carried out intraocularly. In some embodiments the administration is carried out intraarterially. In some embodiments the administration is carried out intralesionally. In some embodiments the administration is carried out transdermally. In some embodiments the administration is carried out by application to mucous membranes. Preferably, the administration is carried out intravenously, subcutaneously, intralesionally, or by application to mucous membranes. In some embodiments, also the use of any of the compounds according to the present invention in a method of diagnosis comprises administering said compound to the subject.

[00242] According to another aspect, the present invention further provides a non- invasive method of detecting or imaging accumulation of S100A9 in the body of a subject to whom any of the labeled compounds described herein above has been pre-delivered, comprising (a) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, and (b) comparing the imaging data received in step (a) to reference imaging data. Accordingly, the method of detecting or imaging S100A9 in the body of a subject does not comprise an active administration of any of the compounds according to the present invention, but refers to a situation, where any of the compounds according to the present invention has been pre-delivered to said subject. "Pre-delivered" includes in this regard, that the compounds comprising a label have been delivered to the subject prior to the methods and uses of the present invention (and all associated embodiments), i.e. before the methods of the invention are to be carried out. The term “detecting” when used herein refers to the visualization and the qualitative analysis of the presence or absence of S100A9 in vivo using the compounds of the present invention and any of the molecular imaging techniques described elsewhere herein. [00243] The signal in the imaging data received from the subject during the detection step as described in various aspects of the present invention can be considered as the reflected signal received from the label of the administered compound of formula (I) comprising a label. Accordingly, when comparing the collected imaging data to reference imaging data, the method equally comprises comparing the signal received from the label of the administered compound to a detected reference signal. Thus, in particular, the methods and uses of the present invention allow the comparison and quantification of in vivo signals. The reference imaging data or the detected reference signal typically derives from a reference subject, which is a healthy subject to whom the same labelled compound of the present invention has been delivered. The term “healthy subject” when used herein refers to a subject not suffering from an inflammatory disease or disorder associated with phagocyte and/or epithelial cell activation and overexpression and accumulation of S100A9. In this regard, the collected imaging data of the subject as described herein indicate the level of S100A9 in said subject, and the reference imaging data indicate the level of S100A9 in the reference subject. Accordingly, an increased signal in the imaging data from the subject as compared to reference imaging data indicates the presence of an inflammatory disease in said subject. Alternatively, no difference in the signal in the imaging data from the subject as compared to reference imaging data indicates no presence of an inflammatory disease in said subject.

[00244] To visualize biological processes non-invasively in vivo and to be able to do quantifications, an injectable imaging agent is required. According to the present invention, compounds of formula (I) comprising a label can be applied to visualize inflammatory processes associated with an increased accumulation of S100A9 at local site, using non- invasive molecular imaging techniques to collect imaging data. These compounds comprise a label, which can be detected highly sensitive and a ligand exhibiting high affinity towards the desired target. "Non-invasive" as used herein means that no break in the skin of a subject is created, for example, an incision, and there is no contact with the mucosa, or skin break, or internal body cavity beyond a natural or artificial body orifice.

[00245] Using different imaging labels such as SPECT labels, PET labels, optical imaging labels, ultrasound labels or photoacoustic labels, the compounds of the present invention are well suited to detect molecular level of S100A9 at local site of inflammation when applying various molecular imaging techniques. As demonstrated by the data described herein, the combination of known imaging techniques and the compounds of formula (I) comprising a label allow for the necessary cellular and molecular specificity and sensitivity to detect inflammatory disease activity itself, and image S100A9 at molecular level in inflammatory disease models.

[00246] Various aspects of the present invention comprise the detection of labelled compounds using different non-invasive molecular imaging techniques. In vivo optical molecular imaging is typically performed on small animals to study the physiologic, pathologic or pharmacologic effects of various drugs or diseases. Molecular imaging can also be performed on humans, and the present invention underlines that molecular imaging provides substantial advances in diagnostic imaging. The benefits of in vivo imaging of small animals are significant because it allows processes and responses to be visualized in realtime in their native environments, and allows longitudinal studies to be performed using the same small animal over time, allowing evaluation of disease progression or response to treatment. Further, in vivo imaging of small animals reduces the number of animals required for a study, and can reduce the variance in studies where disease manifestation varies from animal to animal.

[00247] In some embodiments, the compounds of the present invention comprise a single photon emission tomography (SPECT) label, e.g. labels comprising "^mTc, ¹²³l, or ¹²⁵l, as described elsewhere herein. These labels particularly allow for the application of said compounds in SPECT imaging, a nuclear medicine tomographic imaging technique using gamma rays. SPECT is very similar to conventional nuclear medicine planar imaging using a gamma camera, but is also able to provide true 3D information. This information is typically presented as cross-sectional slices through the patient, but can be freely reformatted or manipulated as required. The technique requires delivery of a gamma-emitting radioisotope into the patient, normally through injection into the bloodstream. Most of the time, a marker radioisotope is attached to a specific ligand to create a radioligand, whose properties bind it to certain types of tissues. This marriage allows the combination of ligand and radiopharmaceutical to be carried and bound to a place of interest in the body, where the ligand concentration is seen by a gamma-camera.

[00248] In some embodiments the compounds of the present invention comprise a positron emission tomography (PET) label, e.g. a label comprising ¹⁸F, as described elsewhere herein, which allows for the use of said compounds in the non-invasive molecular imaging technique PET. PET is a nuclear medicine, functional imaging technique that produces a three-dimensional image of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide (tracer), which is introduced into the body on a biologically active molecule. Three-dimensional images of tracer concentration within the body are then constructed by computer analysis. In modern PET-CT scanners, three dimensional imaging is often accomplished with the aid of a CT X- ray scan performed on the patient during the same session, in the same machine. As described in the state of the art, the biologically active molecule chosen for PET is generally fluorodeoxyglucose (FDG), an analogue of glucose, the concentrations of tracer imaged will indicate tissue metabolic activity by virtue of the regional glucose uptake. However, many other radioactive tracers can be used in PET to image the tissue concentration of many other types of molecules of interest.

[00249] In further embodiments, the compounds of the present invention comprise optical imaging labels such as dyes, e.g. FITC, DiR or Alexa Fluor® 488 as described elsewhere herein. These dyes are particularly useful in intraoperative applications such as abscess excision, tumor location and size and endoscopy. In some embodiments the compounds of the present invention are covalently linked to fluorophores, e.g. polymethine dyes. Such optical imaging labels allows for the use of the compounds of the invention in optical imaging techniques. Classical optical imaging techniques rely on the use of visible, ultraviolet, and infrared light in imaging. Chemical imaging or molecular imaging involves inference from the deflection of light emitted from e.g. a laser or infrared source to structure, texture, anatomic and chemical properties of material. The skilled person is aware of different optical imaging systems applicable in combination with the compounds of the present invention. These systems are mainly divided into diffusive and ballistic imaging systems, which can all be used within the scope of the present invention.

[00250] In some embodiments, compounds of the invention comprise an ultrasound label as disclosed elsewhere herein, which allows for the use of the compounds in diagnostic sonography. Ultrasonography is an ultrasound-based diagnostic imaging technique used for visualizing internal body structures including tendons, muscles, joints, vessels and internal organs for possible pathology or lesions.

[00251] In some embodiments, the compounds of the present invention comprise photoacoustic labels (absorbers) as described elsewhere herein. Photoacoustic imaging, as a hybrid biomedical imaging modality, is developed based on the photoacoustic effect. In this context photoacoustic labels with and without fluorescence properties can be applied. Generally, in photoacoustic imaging, non-ionizing laser pulses are delivered into biological tissues. When radio frequency pulses are used, the technology is referred to as thermoacoustic imaging. Some of the delivered energy will be absorbed and converted into heat, leading to transient thermoelastic expansion of the molecule ultrasonic waves and thus wideband (e.g. MHz) ultrasonic emission. The generated ultrasonic waves are then detected by ultrasonic transducers to form images. Here it is known that optical absorption is closely associated with physiological properties. As a result, the magnitude of the ultrasonic emission (i.e. photoacoustic signal), which is proportional to the local energy deposition, reveals physiologically specific optical absorption contrast. 2D or 3D images of the targeted areas can then be formed.

[00252] While it is possible to administer the compounds of the present invention as described herein above directly without any formulation to a subject, in one aspect of the present invention the compounds are preferably employed in the form of a pharmaceutical or diagnostic formulation composition, comprising a pharmaceutically or diagnostically acceptable carrier, diluent or excipient and any of the compound of the present invention. Accordingly, the present invention relates to a diagnostic composition comprising any of the compounds of formula (I) comprising a label as described herein above and a pharmaceutically or diagnostically acceptable excipient. Moreover, the present invention relates to the use of a compound as disclosed herein above for the preparation of a diagnostic composition for diagnosing an inflammatory disease.

[00253] The term “diagnostic composition” when used herein refers to a composition comprising any one of the compounds of the present invention and a pharmaceutically or diagnostically acceptable carrier, diluent or excipient, which can be applied for used in diagnosis. The carrier used in combination with the compound of the present invention is water-based and forms an aqueous solution. An oil-based carrier solution containing the compound of the present invention is an alternative to the aqueous carrier solution. Either aqueous or oil-based solutions further contain thickening agents to provide the composition with the viscosity of a liniment, cream, ointment, gel, or the like. Suitable thickening agents are well known to those skilled in the art. Alternative embodiments of the present invention can also use a solid carrier containing the diagnostic compound for use in diagnosis as disclosed elsewhere herein. This enables the alternative embodiment to be applied via a stick applicator, patch, or suppository. The solid carrier further contains thickening agents to provide the composition with the consistency of wax or paraffin.

[00254] Pharmaceutically or diagnostically acceptable excipients according to the present invention include, by the way of illustration and not limitation, diluent, disintegrants, binding agents, adhesives, wetting agents, polymers, lubricants, gliands, substances added to mask or counteract a disagreeable texture, taste or odor, flavors, dyes, fragrances, and substances added to improve appearance of the composition. Acceptable excipients include lactose, sucrose, starch powder, maize starch or derivatives thereof, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinyl-pyrrolidone, and/or polyvinyl alcohol, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, and the like. Examples of suitable excipients for soft gelatin capsules include vegetable oils, waxes, fats, semisolid and liquid polyols. Suitable excipients for the preparation of solutions and syrups include, without limitation, water, polyols, sucrose, invert sugar and glucose. Suitable excipients for injectable solutions include, without limitation, water, alcohols, polyols, glycerol, and vegetable oils. The diagnostic compositions can additionally include preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, buffers, coating agents, or antioxidants. Suitable pharmaceutical and diagnostic carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. The use of the diagnostic composition of the present invention as a diagnostic kit for diagnosing inflammatory disease associated with phagocyte and/or epithelial cell activation and overexpression and accumulation of S100A9 is also encompassed by the present invention.

[00255] In a further aspect, the present invention provides a method of evaluating whether a subject may be at risk of developing an inflammatory disease associated with phagocyte and/or endothelial cell activation in a patient, comprising: (a) administering to said subject any of the compounds as disclosed herein above, (b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, and (c) comparing the imaging data received in step b) to reference imaging data. In this regard, the term “evaluating the risk” refers to any procedure or method used to assess whether or not a subject patient may develop an inflammatory disease associated with phagocyte and/or endothelial cell activation within a specific foreseeable period of time. Thus, a method of evaluating the risk of a subject of developing an inflammatory disease might be particularly useful when a subject has already suffered from any of the inflammatory diseases described herein and is of increased risk of recurrence of said disease. In this regard, the risk of the subject of developing said inflammatory disease can already be detected at an early stage and appropriate therapeutic measures and treatments can be started in time. The S100A9 level in said subject may be determined using any desired technique known to those skilled in the art and methods disclosed herein. A significant increased signal in the imaging data from the subject as compared to reference imaging data indicates that said subject is at higher risk of developing an inflammatory disease associated with phagocyte and/or epithelial cell activation. On the contrary, a signal in the imaging data at a normal level as compared to reference imaging data indicates that said subject is at lower risk of developing an inflammatory disease associated with phagocyte and/or epithelial cell activation.

[00256] According to another aspect, the present invention refers to a method of monitoring or evaluating the progression of an inflammatory disease or disorder associated with phagocyte and/or epithelial cell activation in a patient, the method comprising: (a) administering to said subject any of the compounds as disclosed herein above, (b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, and (c) comparing the imaging data received in step (b) to reference imaging data obtained from said patient at an earlier date, wherein the result of the comparison of (c) provides an evaluation of the progression of the inflammatory disease associated with phagocyte and/or epithelial cell activation in said patient. In this regards, the term “monitoring or evaluating the progression” refers to any procedure or method used in vivo to assess whether or not a patient suffering from an inflammatory disease or disorder associated with phagocyte and/or epithelial cell activation is responsive to treatment with a therapeutic compound. In this context, also tumor associated inflammation as surrogate marker for e.g. therapy response can also be assessed using any of the methods of the present invention.

[00257] In particular, a method of monitoring or evaluating the progression of an inflammatory disease or disorder relates to monitoring or evaluating the level of S100A9 in a subject at local stage prior, during and after therapy with a therapeutic compound. The term “therapeutic compound” as used herein refers to any compounds suitable to treat an inflammatory disease characterized by phagocyte and/or epithelial cell activation and overexpression and accumulation of S100A9.

[00258] As disclosed herein, a method of monitoring or evaluating the progression of an inflammatory disease or disorder might be particularly useful when treating a patient suffering from an inflammatory disease or disorder associated with phagocyte and/or epithelial cell activation with any medicament for alleviating or healing said inflammatory disease. Accordingly, the method of monitoring as described herein particularly refers to in vivo monitoring the therapeutic efficacy of a drug used in the treatment of inflammatory disorders. Hence, conclusions can be drawn during and/or after the treatment of a subject with the medicament as to whether said medicament may improve symptoms of an inflammatory disease when comparing to the physical conditions before start of treatment. Moreover, such monitoring or evaluation may help an attending physician to obtain the appropriate information to set the appropriate therapy conditions for the treatment of said inflammatory disease. A significantly increased signal in the imaging data from the subject as compared to reference imaging data obtained from said patient at an earlier date indicates a progression of the inflammatory disease associated with phagocyte and/or epithelial cell activation in said patient, whereas no change or decrease in the signal in the imaging data from the subject as compared to reference imaging data obtained from said patient at an earlier date indicates no progression or a regression of the inflammatory disease associated with phagocyte and/or epithelial cell activation in said patient.

[00259] In a further aspect, the present invention provides a method of imaging an inflammatory disease in a subject, comprising: (a) administering to said subject any of the compounds as disclosed herein above, and (b) detecting the administered compound using an in vivo non-invasive molecular imaging method, thereby collecting imaging data. The term “imaging” when used herein refers to the optical visualization of low levels of S100A9 or S100A9 accumulation at local site of inflammation under in vivo conditions, using the compounds of the invention comprising a label and any of the molecular imaging techniques described elsewhere herein. Accordingly, the term “imaging” as used herein preferably means “molecular imaging”. Molecular imaging is generally used to explore physiological processes in real-time in vivo and to diagnose or certain diseases due to molecular abnormalities by means of imaging techniques. Moreover, the method of imaging may also be applicable in recurrence diagnosis.

[00260] Although the compounds of the present invention are particularly useful to be applied under in vivo conditions, a use of said compounds in vitro is also within the scope of the present invention. Accordingly, the present application provides an in vitro method of diagnosing an inflammatory disease in a subject to whom any of the compound disclosed herein has been pre-delivered, comprising: (a) analyzing a sample taken from said subject, (b) detecting said pre-delivered compound using a non-invasive molecular imaging method, thereby collecting imaging data, (c) comparing the imaging data received in step (b) to reference imaging data. To this end, it is envisaged to compare the imaging data of a sample from a subject to whom the compound of the present invention has been pre-delivered to imaging data of a reference sample taken from a reference subject. Here, an increased signal in the imaging data from the subject as compared to reference imaging data indicates the presence of an inflammatory disease in said subject, whereas no difference in the imaging signal in the imaging data from the subject as compared to reference imaging data indicates no presence of an inflammatory disease in said subject. In this context, a sample may be analyzed that has been obtained from the subject of the present invention. The sample may be any biological sample taken from said subject and being appropriate to diagnose an inflammatory disease associated with phagocyte and/or epithelial cell activation in said subject. Non-limiting examples of useful samples may include blood samples, tissues samples, body fluid samples, skin samples or any other samples known to those skilled in the art for use in in vitro diagnosis.

[00261] The preparation of compounds according to the present invention is within the capacity of the person of ordinary skill in the art and can be carried out as described, e.g., in WO 2015/177367 A1 , which is incorporated herein by reference. For example, a compound of formula (I*) or formula (I) may be prepared in a reaction sequence as generally illustrated in Reaction Scheme 1. Thus, in a general method for preparing a compound of formula (I*) or (I) as defined herein a primary amide (X*) or (X) is first reacted with an alkyl 3, 3,3-trifluoro-2- oxopropanoate (XI), wherein R₅₀₀ is an alkyl group, e.g. a C1-C3 alkyl group, such as methyl, in the presence of an organic base, e.g. pyridine or triethyl amine, in a suitable solvent medium, e.g. DMF (N,N-dimethylformamide), DMSO (dimethylsulfoxide) or N-methyl pyrrolidine, followed by the addition of a reagent such as thionyl chloride, thionyl bromide or oxalyl chloride, to provide an "acyl imine intermediate" of the general formula XX* or XX. It is also possible to use dichloromethane, tetrahydrofuran or a mixture thereof as solvent for this step, preferably dichloromethane. The inventors have surprisingly found that using dichloromethane and/or tetra hydrofuran increases the yield of the compounds of formula (I*) or formula (I). It is also possible to omit the organic base, in particular when dichloromethane, tetrahydrofuran or a mixture thereof is used as solvent.

[00262] The acyl imine (XX*) or (XX) is then reacted with an aminobenzimidazole (XII), optionally in the presence of an organic base, e.g. pyridine or triethyl amine, in a suitable solvent medium, e.g. DMF, DMSO or N-methyl pyrrolidine, to provide the compound of formula (I) or (I*) wherein R_A, R_B, c, L, and R_L are as defined herein. It is also possible to use dichloromethane, tetrahydrofuran or a mixture thereof as solvent for this step, preferably tetrahydrofuran. The inventors have surprisingly found that using dichloromethane and/or tetrahydrofuran increases the yield of the compounds of formula (I*) or formula (I). When dichloromethane, tetra hydrofuran or a mixture thereof is used as solvent, it is preferred that the organic base, e.g. pyridine or triethyl amine, more preferably triethyl amine, is present. L* is a linker capable of forming a covalent attachment to a label R_L, or L* is a part of a linker capable of forming a covalent attachment to another part of a linker. L* may comprise a functional group which allows covalent attachment of a label or to another part of a linker in a further synthesis step. As illustrative non-limiting example, the functional group may be a leaving group, such as e.g. halogen (F, Cl, Br, I), in particular F, Cl or Br. Such leaving group, as appreciated by a person skilled in the art, can be replaced by a label R_L, another part of the linker, or another part of a linker. A person skilled in the art will readily select suitable reaction conditions, and suitable functional groups for providing a covalent attachment.

Reaction Scheme 1 : Synthesis of compounds of formula (I*) and (I). R_A, R_B, Rc, R₅₀₀, L, L* and R_L are as defined herein.

Further guidance to prepare the compounds of the invention is also given in the following and in the examples. [00263] The present invention also relates to a process for the preparation of a compound of the formula (I*) or its salts, isomers, tautomers or solvates thereof, comprising reacting a compound of the formula (X*)

and a compound of the formula (XII)

to give a compound of the formula (I*)

L* is a linker capable of forming a covalent attachment to a label R_L; or L* is a part of a linker capable of forming a covalent attachment to another part of a linker; and

R_A, R_B and R_c are as defined herein. As used herein, L* may be a linker capable of forming a covalent attachment to a label R_L. It is also possible that L* may be a part of a linker capable of forming a covalent attachment to another part of a linker. It is also possible that L* may be a part of a linker capable of forming a covalent attachment to another part of a linker bound to a label. L* may comprise a functional group capable of forming a covalent attachment. As illustrative non-limiting example, the functional group may be a leaving group, such as e.g. halogen (F, Cl, Br, I), in particular F, Cl or Br. Accordingly, in some embodiments, L* can be described as L*-FG, wherein FG is a functional group. The functional group FG may be a leaving group. The functional group may be a halogen (F, Cl, Br, I). The functional group may be F, Cl or Br. The functional group may be F or Br. The functional group may be F.

[00264] In some embodiments, the process further comprises reacting the compound of formula (I*) with a label or another part of a linker bound to a label to give a compound of formula (I):

wherein R_A, R_B, Rc, L and R_L are as defined herein.

[00265] The present invention also relates to a process for the preparation of a compound of the formula (I) or its salts, isomers, tautomers or solvates thereof, comprising reacting a compound of the formula (X)

with a compound of the formula (XI)

and a compound of the formula (XII)

to give a compound of the formula (I)

wherein R₅₀₀ is C1-C6 alkyl, preferably methyl or ethyl, more preferably ethyl; and

RA, B, RC, L and R_L are as defined herein.

[00266] In some embodiments, the compound of the formula (X) or the compound of the formula (X*) is reacted with the compound of formula (XI) in presence of a solvent. This reaction may be a first step of the reaction sequence. The solvent may be selected from the group consisting of DMF, DMSO, N-methylpyrrolidine, dichloromethane, tetrahydrofuran, and any combination thereof. Preferably, the solvent is dichloromethane, tetra hydrofuran or a mixture thereof. More preferably, the solvent is dichloromethane.

[00267] In some embodiments, after reacting the compound of the formula (X) or the compound of the formula (X*) with the compound of formula (XI), the process further comprises reacting with SOCI₂, SOBr₂ or oxalyl chloride, preferably SOCI₂ or SOBr₂, more preferably SOCI₂. Accordingly, an intermediate which may be formed in the reaction of the compound of the formula (X) or the compound of the formula (X*) with the compound of the formula (XI) may be reacted with SOCI₂, SOBr₂ or oxalyl chloride. Optionally, the solvent may be removed (e.g., in vacuo) before adding the SOCI₂, SOBr₂ or oxalyl chloride. Optionally, the reacting with the SOCI₂, SOBr₂ or oxalyl chloride can be carried out without the presence of further solvent, e.g. neat.

[00268] In some embodiments, after the reacting with SOCI₂, SOBr₂ or oxalyl chloride, the process further comprises reacting with the compound of the formula (XII) in presence of a solvent and an organic base to give the compound of the formula (I*) or the compound of the formula (I). Accordingly, an intermediate which may be formed in the reaction with SOCI₂, SOBr₂ or oxalyl chloride may be reacted with the compound of the formula (XII). Optionally, the SOCI₂, SOBr₂, oxalyl chloride and/or solvent, and or reaction gases are removed (e.g., in vacuo) before adding the compound of formula (XII). The solvent may be selected from the group consisting of DMF, DMSO, N-methylpyrrolidine, dichloromethane, tetrahydrofuran, and any combination thereof. Preferably, the solvent is dichloromethane, tetrahydrofuran or a mixture thereof. More preferably, the solvent is tetra hydrofuran. The organic base may be triethylamine or pyridine, preferably triethylamine.

[00269] In some embodiment, the process may be carried out as one-pot process. As used herein, the term “one-pot process” in particular means that all steps of forming the compound of formula (I*) or the compound of formula (I) are carried out in one (i.e. the same) reaction vessel. It is possible that during such one-pot process solvent is removed and/or exchanged, and/or that reagents are added. However, in particular, in a one-pot process no work-up (such as, e.g., an aqueous work-up) is carried out between the steps.

[00270] Optionally, after forming the compound of formula (I*) or formula (I), a work-up may be carried out. Suitable work-up procedures (e.g. aqueous work-up) are known to a person skilled in the art and can be readily selected. If desired, the compound may be further purified. Suitable purification methods (such as, e.g., crystallization or chromatography) are known to a person skilled in the art an can be readily selected.

[00271] In some embodiments, the compound of formula (X*) is

, wherein X is F, Cl or Br, preferably F or Br, more preferably F. [00272] In some embodiments, the compound of formula (X*) is o

wherein X is F, Cl or Br, preferably Cl or Br, more preferably Br; and o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5.

[00273] In some embodiments, the compound of formula (

[00274] In some embodiments, the compound of formula (XII) is

Items of the Invention

[00275] The invention is also characterized by the following items:

1. A compound of formula (I)

or a salt, isomer, or tautomer thereof; wherein R_A, R_B, and R_c are each independently selected from H, halogen, cyano, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by RTO, R₂C(O), R₃S, R₄S(O)₂, R₅OC(O), (R₆ON)C(R₇), R₈R₉NC(O), R10R11N, RI₂S(O)₂NR₁₃,

RI₄S(O)₂NR₁₅C(O), phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6- membered heterocyclyl optionally substituted by one or more moieties R₁₆; or one of R_A and R_c together with R_B forms a divalent group -(CH₂)_m- wherein m is an integer of from 3 to 5, and the other one of R_A and R_c is selected from H, halogen, cyano, R1O, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by R1O, R₂C(O), R₃S, R₄S(O)₂, R₅OC(O), (R₆ON)C(R₇), R₈R₉NC(O), R10R11N, RI₂S(O)₂NR₁₃, RI₄S(O)₂NR₁₅C(O), phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6- membered heterocyclyl optionally substituted by one or more moieties R₁₆; each R₁₆ is independently selected from halogen, cyano, nitro, RI₇O, C1-C6 alkyl optionally substituted by RI₇O, C3-C6 cycloalkyl optionally substituted by RI₇O, RI₈C(O), RI₉S, R₂₀S(O)₂, R₂IOC(O), (R₂2ON)C(R₂₃), R₂₄R₂₈NC(O), R26R27N, R₂₈S(O)₂NR₂₉, and R₃OS(0)₂NR₃₁C(0); each one of R1-R15 and RI₇-R₃I is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl;

L is a linker; and

R_L is a label.

2. The compound according to item 1 , wherein the compound is not a compound selected from the group consisting of:

3. The compound according to item 1 or 2, wherein R_L is not ¹⁹F.

4. The compound according to any one of the preceding items, wherein R_A is H.

5. The compound according to item 4, wherein R_B is H and R_c is H.

6. The compound according to any one of items 1 to 3, wherein R_A is

RI₄S(O)₂NR₁₅C(O). The compound according to claim 6, wherein

8. The compound according to claim 6 or 7, wherein R_B is H and R_c is H.

9. The compound according to any one of items 1 to 3, wherein R_A is phenyl optionally substituted by one or more moieties R₁₆.

10. The compound according to item 9, wherein R_A is phenyl optionally substituted by R17O.

11. The compound according to item 10, wherein R_A is

12. The compound according to any one of items 9 to 11 , wherein R_B is H and R_c is H.

13. The compound according to any one of items 1 to 3, wherein R_A is R₅OC(O).

14. The compound according to item 13, wherein

15. The compound according to item 13 or 14, wherein R_B is H and R_c is H or halogen; preferably wherein R_c is halogen, more preferably Cl.

16. The compound according to any one of items 1 to 3, wherein R_B is halogen, preferably Cl.

17. The compound according to item 16, wherein R_A is H.

18. The compound according to item 16 or 17, wherein R_c is halogen, preferably Cl.

19. The compound according to any one of item 1 to 3, wherein R_B is C1-C6 alkyl, preferably methyl. 20. The compound according to item 19, wherein R_A is H.

21. The compound according to item 19 or 20, wherein R_c is C1-C6 alkyl, preferably methyl.

22. The compound according to any one of the preceding items, wherein the linker L is (L1):

wherein # indicates the attachment point to the label R_L.

23. The compound according to any one of items 1 to 21, wherein the linker L is (L2):

wherein o is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 1 or 2, even more preferably o is 1; and

# indicates the attachment point to the label R_L.

24. The compound according to item 23, wherein the linker L is (L2*):

wherein # indicates the attachment point to the label R_L.

25. The compound according to any one of items 1 to 21, wherein the linker L is (L3):

(L3), wherein: o is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 1 or 2, even more preferably o is 1; p is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably p is 2 or 3, even more preferably p is 2; and

# indicates the attachment point to the label R_L.

26. The compound according to item 25, wherein the linker L is (L3*):

wherein # indicates the attachment point to the label R_L.

27. The compound according to any one of items 1 to 21, wherein the linker L is (L4):

wherein

R₂OO is H or C1-C6 alkyl; preferably R₂oo is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl; R201 is H or C1-C6 alkyl; preferably R₂OI is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;

X is an anion; preferably X is a halogenide, more preferably bromide (Br ); o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5; p is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably p is 1 or 2, even more preferably p is 1; q is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably q is 2 or 3, even more preferably q is 2; and

# indicates the attachment point to the label R_L.

28. The compound according to item 27, wherein R₂₀₀ and R₂₀I are the same; preferably wherein R₂₀₀ is methyl and R₂₀I is methyl.

29. The compound according to item 27 or 28, wherein the linker L is (L4*):

wherein # indicates the attachment point to the label R_L.

30. The compound according to any one of items 1 to 21, wherein the linker L is (L5):

wherein R_2OO is H or C1-C6 alkyl; preferably R₂₀₀ is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl; o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5; and

# indicates the attachment point to the label R_L.

31. The compound according to item 30, wherein the linker L is (L5*):

wherein # indicates the attachment point to the label R_L.

32. The compound according to any one of items 1 to 21, wherein the linker L is (L6):

(L6), wherein

R₂OO is H or C1-C6 alkyl; preferably R₂oo is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;

R₃₀I is H or C1-C6 alkyl; preferably R₃₀I is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl; o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5; p is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 2 or 3, even more preferably p is 2; and

# indicates the attachment point to the label R_L.

33. The compound according to item 32, wherein R_2Oo, R₃₀₀ and R₃₀I are the same; preferably wherein R₂oo is methyl, R₃₀₀ is methyl and R₃₀I is methyl.

34. The compound according to claim 32 or 33, wherein the linker L is (L6*):

wherein # indicates the attachment point to the label R_L.

35. The compound according to any one of items 1 to 21, wherein the linker L is (L7):

(L7), wherein

R₂₀I is H or C1-C6 alkyl; preferably R₂₀I is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl; o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5; and

# indicates the attachment point to the label R_L.

36. The compound according to item 35, wherein R_2Oo and R₂OI are the same; preferably wherein R₂₀₀ is methyl and R₂₀I is methyl.

37. The compound according to item 35 or 36, wherein the linker L is (L7*):

wherein # indicates the attachment point to the label R_L.

38. The compound according to any one of items 1 to 21, wherein the linker L is (L8):

(L8), wherein

R₂OO is H or C1-C6 alkyl; preferably R₂₀₀ is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;

R₂₀I is H or C1-C6 alkyl; preferably R₂₀I is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl; R_3OO is H or C1-C6 alkyl; preferably R₃₀₀ is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;

R301 is H or C1-C6 alkyl; preferably R₃₀I is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl; o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5; p is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 2 or 3, even more preferably p is 2; and

# indicates the attachment point to R_L.

39. The compound according to item 38, wherein R₂oo, R201, R300 and R₃₀I are the same; preferably wherein R₂oo is methyl, R₂₀I is methyl, R₃₀₀ is methyl and R₃₀I is methyl.

40. The compound according to item 38 or 39, wherein the linker L is (L8*):

wherein # indicates the attachment point to the label R_L.

41. The compound according to any one of items 1 to 21 , wherein the linker L is (L9):

wherein o is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 1 or 2, even more preferably o is 1; p is an integer ranging from 1 to 10, preferably from 1 to 8, more preferably from 2 to 5, still more preferably p is 3 or 4, even more preferably p is 3; q is an integer ranging from 1 to 5, preferably from 1 to 3; and

# indicates the attachment point to the label R_L.

42. The compound according to item 41 , wherein the linker L is (L9*):

wherein q is an integer ranging from 1 to 3; and # indicates the attachment point to the label R_L.

43. The compound according to any one of items 1 to 21, wherein the linker L is (L10):

(L10), wherein o is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 1 or 2, even more preferably o is 1; p is an integer ranging from 1 to 10, preferably from 1 to 8, more preferably from 2 to 5, still more preferably p is 3 or 4, even more preferably p is 3; and

# indicates the attachment point to the label R_L.

44. The compound according to item 43, wherein the linker L is (L10*):

(L10*), wherein # indicates the attachment point to the label R_L.

45. The compound according to any one of items 1 to 21 , wherein the linker L is (L11):

wherein o is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 1 or 2, even more preferably o is 1; p is an integer ranging from 1 to 10, preferably from 2 to 8, more preferably from 2 to 6, still more preferably p is 2 or 4, even more preferably p is 3; and

# indicates the attachment point to the label R_L.

46. The compound according to item 45, wherein the linker L is (L11*):

wherein # indicates the attachment point to the label R_L.

46a. The compound according to any one of items 1 to 21, wherein the linker L is (L12):

(L12), wherein o is an integer ranging from 1 to 20, preferably from 2 to 15, more preferably from 3 to 10, still more preferably from 4 to 6, even more preferably o is 5; R₂OO is H or C1-C6 alkyl; preferably R₂oo is H; and

# indicates the attachment point to the label R_L.

46b. The compound according to item 46a, wherein the linker L is (L12*):

(L12*), wherein # indicates the attachment point to the label R_L.

47. The compound according to any one of the preceding items, wherein the label R_L is a metal binding group for a metal selected from "^mTc, ¹⁸⁶Re, ¹⁸⁸Re, ¹¹¹ In, ⁶⁷Ga, ⁶⁸Ga, ⁶⁴Cu and/or ⁸⁹Zr.

48. The compound of item 47, wherein the metal binding group coordinates said metal together with an additional binding group.

49. The compound according to any one of the preceding items, wherein the label R_L is any one of a single photon emission tomography (SPECT) label, a positron emission tomography (PET) label, an optical imaging label, a magnetic resonance imaging (MRI) label, an ultrasound label or a photoacoustic imaging label.

50. The compound according to item 49, wherein the label R_L comprises a group selected from the group consisting of ¹⁸F, ⁶⁸Ga, ¹²³l, ¹²⁴l, ¹²⁵l, "^mTc, ¹¹¹ln, ⁶⁷Ga, ⁶⁴Cu, ¹¹C, ⁸⁹Zr, fluorescent dyes, phosphorescent dyes and photoacoustic absorbers.

51. The compound according to item 49 or 50, wherein the label R_L is a single photon emission tomography (SPECT) label or a positron emission tomography (PET) label.

52. The compound according to item 51 , wherein the label is ¹⁸F.

53. The compound according to item 52, wherein the linker L is selected from the group consisting of (L1), (L3), (L3*), (L4), (L4*), (L5), (L5*), (L6), (L6*), (L7), (L7*), (L8) and (L8*), wherein (L1), (L3), (L3*), (L4), (L4*), (L5), (L5*), (L6), (L6*), (L7), (L7*), (L8) and (L8*) are as defined in any one of the preceding claims. 54. The compound according to item 52 or 53, wherein the compound is selected from the group consisting of

55. The compound according to item 51, wherein the label R_L is selected from the group consisting of:

wherein * indicates the attachment point to the linker L.

56. The compound according to item 55, wherein the linker L is (L9) or (L9*), wherein (L9) and (L9*) are as defined in any one of the preceding claims.

57. The compound according to item 55 or 56, wherein the compound is selected from the group consisting of:

and

58. The compound according to item 49 or 50, wherein the label R_L is a single photon emission tomography (SPECT) label.

59. The compound according to item 58, wherein the label R_L is:

wherein * indicates the attachment point to the linker L.

60. The compound according to item 59, wherein the linker L is (L10) or (L10*), wherein (L10) and (L10*) are as defined in any one of the preceding claims.

61. The compound according to item 59 or 60, wherein the compound is:

62. The compound according to item 58, wherein the label R_L is:

wherein * indicates the attachment point to the linker L. 63. The compound according to item 62, wherein the linker L is (L2) or (L2*), wherein (L2) and (L2*) are as defined in any one of the preceding claims.

64. The compound according to item 62 or 63, wherein the compound is:

65. The compound according to item 49 or 50, wherein the label R_L comprises a photoacoustic imaging label.

66. The compound according to item 65, wherein the photoacoustic imaging label is a phthalocyanine, a naphthalocyanine, or a polymethine dye. 67. The compound according to item 66, wherein the photoacoustic imaging label is a polymethine dye.

68. The compound according to item 49 or 50, wherein the label R_L comprises an optical imaging label.

69. The compound according to item 68, wherein the label is a dye.

70. The compound according to item 69, wherein the dye is selected from the group consisting of fluorescein isothiocyanate (FITC), 1 ,1'-dioctadecyl-3,3,3',3'-tetramethyl indotricarbocyanine iodide (DiR), a coumarin dye, a rhodamine dye, a carbopyronin dye, an oxazine dye, a fluorescein dye, a cyanine dye, a boron-dipyrromethene (BODIPY) dye, a squaraine dye, and a squaraine rotaxane dye.

71. The compound according to item 68, wherein the optical imaging label is a fluorophore.

72. The compound according to item 71 , wherein the label is a polymethine dye.

73. The compound according to item 72, wherein the polymethine dye is a cyanine dye.

74. The compound according to item 73, wherein the cyanine dye is cyanine 3, cyanine 3.5, cyanine 5, cyanine 5.5, or cyanine 7.

75. The compound according to item 74, wherein the cyanine dye is cyanine 5.5.

76. The compound according to item 74, wherein the cyanine dye is cyanine 7.

77. The compound according to any one of items 68 to 76, wherein the label R_L is selected from the group consisting of:

wherein * indicates the attachment point to the linker L.

78. The compound according to item 77, wherein the linker L is (L11) or (L11*), wherein (L11) and (L11*) are as defined in any one of the preceding claims.

79. The compound according to item 77 or 78, wherein the compound is selected from the group consisting of:

or a salt, isomer, or tautomer thereof.

79a. The compound according to any one of items 68 to 76, wherein the label R_L is:

wherein * indicates the attachment point to the linker L.

79b. The compound according to item 79a, wherein the linker L is (L12) or (L12*), wherein (L12) and (L12*) are as defined in any one of the preceding claims.

79c. The compound according to item 79a or 79b, wherein the compound is:

or a salt, isomer or tautomer thereof.

80. The compound according to any one of items 1 to 79, wherein the compound is a diagnostic compound. 81. A diagnostic composition comprising a compound according to any one of claims 1 to 80 and a pharmaceutically or diagnostically acceptable excipient.

82. The compound according to any one of items 1 to 80 for use in a method of diagnosis.

83. The compound for use according to item 82, wherein the diagnosis is diagnosis of an inflammatory disease in a subject.

84. The compound for use according to item 83, wherein the inflammatory disease is associated with phagocyte and/or epithelial cell activation in said subject.

85. The compound for use according to item 84, wherein the inflammatory disease is further associated with an overexpression and accumulation of S100A9 in said subject.

86. The compound for use according to any one of items 82 to 85, wherein the inflammatory disease comprises dermatitis, atherosclerosis, psoriasis, autoimmune diseases, arthritis, allergies, cardiovascular processes, local and systemic infections, neuroinflammatory diseases, acute lung injury (ALI) and tumors.

87. The compound for use according to any one of items 82 to 86, wherein the method is an in vivo non-invasive molecular imaging method.

88. The compound for use according to item 87, wherein the method is any one of single photon emission tomography (SPECT), positron emission tomography (PET), optical imaging, magnetic resonance imaging (MRI), ultrasound or photoacoustic imaging.

89. The compound for use according to any one of items 82 to 88, wherein the method of diagnosis is a method of an early stage diagnosis.

90. The compound for use according to any one of items 82 to 89, wherein the inflammatory disease is at local site.

91. The compound for use according to any one of items 82 to 90, wherein said subject is a mammal. 92. The compound for use according to item 91, wherein said mammal is mouse, rat, guinea pig, rabbit, cat, dog, monkey, horse, or human.

93. The compound for use according to any one of items 82 to 92, wherein the method comprises administering said compound to the subject.

94. The compound for use according to any one of items 82 to 93, wherein said administration is carried out orally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by implantation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, transdermally, or by application to mucous membranes.

95. A method of diagnosing an inflammatory disease in a subject, comprising: a) administering to said subject a compound according to any one of items 1 to 80, b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data.

96. A non-invasive method of detecting or imaging accumulation of S100A9 in the body of a subject to whom a compound of any one of items 1 to 80 has been pre-delivered, comprising: a) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, b) comparing the imaging data received in step a) to reference imaging data.

97. The method according to item 95 or 96, wherein a significantly increased signal in the imaging data from the subject as compared to reference imaging data indicates the presence of an inflammatory disease in said subject.

98. The method according to item 95 or 96, wherein no difference in the signal in the imaging data from the subject as compared to reference imaging data indicates no presence of an inflammatory disease in said subject.

99. The method according to any one of items 95 to 98, wherein the inflammatory disease is associated with phagocyte and/or epithelial cell activation in said subject. 100. The method according to item 99, wherein the inflammatory disease is further associated with an overexpression and accumulation of S100A9 in said subject.

101. The method according to any one of items 95 to 100, wherein the inflammatory disease comprises dermatitis, atherosclerosis, psoriasis, autoimmune diseases, arthritis, allergies, cardiovascular processes, local and systemic infections, neuroinflammatory diseases, acute lung injury (ALI) and tumors.

102. The method according to any one of items 95 to 101, wherein said in vivo non- invasive molecular imaging method is any one of single photon emission tomography (SPECT), positron emission tomography (PET), optical imaging, magnetic resonance imaging (MRI), ultrasound or photoacoustic imaging.

103. The method according to any one of items 95 to 103, wherein the method of diagnosing is a method of an early stage diagnosing.

104. The method according to any one of items 95 to 102, wherein the inflammatory disease is at local site.

105. The method according to any one of items 95 to 104, wherein said subject is a mammal.

106. The method according to item 105, wherein said mammal is mouse, rat, guinea pig, rabbit, cat, dog, monkey, horse, or human.

107. Use of a compound according to any one of items 1 to 80 for the preparation of a diagnostic composition for diagnosing an inflammatory disease associated with phagocyte and/or epithelial cell activation in a subject.

108. A method for evaluating whether a subject may be at risk of developing an inflammatory disease associated with phagocyte and/or epithelial cell activation, the method comprising: a) administering to said subject a compound according to any one of items 1 to 80, b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data. 109. The method according to item 108, wherein a significantly increased signal in the imaging data from the subject as compared to reference imaging data indicates that said subject is at higher risk of developing an inflammatory disease associated with phagocyte and/or epithelial cell activation.

110. The method according to item 108, wherein a signal in the imaging data at a normal level as compared to reference imaging data indicates that said subject is at lower risk of developing an inflammatory disease associated with phagocyte and/or epithelial cell activation.

111. A method of monitoring or evaluating the progression of an inflammatory disease associated with phagocyte and/or epithelial cell activation in a patient, the method comprising: a) administering to said subject a compound according to any one of items 1 to 80, b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data obtained from said patient at an earlier date, wherein the result of the comparison of c) provides an evaluation of the progression of the inflammatory disease associated with phagocyte and/or epithelial cell activation in said patient.

112. The method according to item 111 , wherein a significantly increased signal in the imaging data from the subject as compared to reference imaging data obtained from said patient at an earlier date indicates a progression of the inflammatory disease associated with phagocyte and/or epithelial cell activation in said patient.

113. The method according to item 111, wherein no change or decrease in the signal in the imaging data from the subject as compared to reference imaging data obtained from said patient at an earlier date indicates no progression or a regression of the inflammatory disease associated with phagocyte and/or epithelial cell activation in said patient.

114. A method of imaging an inflammatory disease in a subject, comprising: a) administering to said subject a compound according to any one of items 1 to 80, b) detecting the administered compound using an in vivo non-invasive molecular imaging method, thereby collecting imaging data. 115. An in vitro method of diagnosing an inflammatory disease in a subject to whom a compound according to any one of items 1 to 80 has been pre-delivered, comprising: a) analyzing a sample taken from said subject, b) detecting said pre-delivered compound using a non-invasive molecular imaging method, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data.

116. The method according to item 115, wherein an increased signal in the imaging data from the subject as compared to reference imaging data indicates the presence of an inflammatory disease in said subject.

117. The method according to item 115, wherein no difference in the imaging signal in the imaging data from the subject as compared to reference imaging data indicates no presence of an inflammatory disease in said subject.

118. A process for the preparation of a compound of the formula (I*) or its salts, isomers, tautomers or solvates thereof, comprising reacting a compound of the formula (X*)

and a compound of the formula (XII)

to give a compound of the formula (I*)

L* is a linker capable of forming a covalent attachment to a label R_L; or

R_A, R_B and R_c are as defined in any one of items 1 to 80.

119. The process according to item 118, further comprising reacting the compound of formula (I*) with a label or another part of a linker bound to a label to give a compound of formula (I):

wherein R_A, R_B, Rc, L and R_L are as defined in any one of items 1 to 80.

120. A process for the preparation of a compound of the formula (I) or its salts, isomers, tautomers or solvates thereof, as claimed in one or more of items 1 to 80, comprising reacting a compound of the formula (X)

and a compound of the formula (XII)

to give a compound of the formula (I)

RA, B, RC, L and R_L are as defined in any one of items 1 to 80.

121. The process according to any one of items 118 to 120, wherein the compound of the formula (X) or the compound of the formula (X*) is reacted with the compound of formula (XI) in presence of a solvent. 122. The process according to item 121 , wherein the solvent is dichloromethane, tetrahydrofuran or a mixture thereof, preferably wherein the solvent is dichloromethane.

123. The process according to item 121 or 122, wherein the process, after reacting the compound of the formula (X) or the compound of the formula (X*) with the compound of formula (XI), further comprises reacting with SOCI₂, SOBr₂ or oxalyl chloride, preferably SOCI₂ or SOBr₂, more preferably SOCI₂; optionally wherein the solvent is removed before adding the SOCI₂, SOBr₂ or oxalyl chloride.

124. The process according to item 123, wherein the process, after reacting with SOCI₂, SOBr₂ or oxalyl chloride, further comprises reacting with the compound of the formula (XII) in presence of a solvent and an organic base to give the compound of the formula (I*) or the compound of the formula (I); optionally wherein the SOCI₂, SOBr₂, oxalyl chloride and/or solvent is removed before adding the compound of formula (XII).

125. The process according to item 124, wherein the solvent is dichloromethane, tetrahydrofuran or a mixture thereof, preferably wherein the solvent is tetra hydrofuran.

126. The process according to item 124 or 125, wherein the organic base is triethylamine or pyridine, preferably triethylamine.

127. The process according to any one of items 118 to 126, wherein the process is carried out as one-pot process.

128. The process according to any one of items 118 to 127, wherein the compound of formula

wherein X is F, Cl or Br, preferably F or Br, more preferably F; or the compound of formula

preferably Cl or Br, more preferably Br; and o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5. 129. The process according to any one of items 118 to 128, wherein the compound of formula (

130. The process according to any one of items 118 to 129, wherein the compound of formula (

[00276] The following examples will enable a person skilled in the art to more clearly understand and practice the present invention. These examples, however, should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.

EXAMPLES

Example 1 : Development of new diagnostic imaging tracers based on benzimidazoles

[00277] A new lead structure for S100A9-targeting for diagnostic purposes based on benzo[d]imidazo[1,2-a]imidazoles was established. Benzo[d]imidazo[1,2-a]imidazoles were so far reported in WO2015/177367 only as an inhibitor of interactions between S100A9 and interaction partners such as RAGE, TLR4 and EMMPRIN, and in WO2015/177367 these compounds have been reported only for therapeutic treatment of various disorders. In a first step, the inventors synthesized the core structure of benzo[d]imidazo[1,2-a]imidazoles with sites accessible for further modifications.

[00278] Characteristic for the lead structure is a flat tricyclic system with a sp³- hybridized carbon atom bearing an amide group and a trifluoromethyl group. The inventors surprisingly found that the moiety R1 can save as point for attaching a linker and a label for imaging, so that compounds are obtained, which are suitable for targeting S100A9, and which can be used for diagnosing an inflammatory disease in a subject.

[00279] The inventors first chose [¹⁹F]SST034 to be the first target molecule, using 6- fluoro-2-pyridine-carboxamide (1), ethyl 3,3,3-trifluoropyruvate (2) and dichloro benzimidazole derivative 4 for the preparation (Scheme 1). [¹⁹F]SST034 is not only an intermediate in the synthesis of further functionalized structures, but with its ¹⁹F-substituted pyridine it may also act as a non-radioactive reference compound.

Scheme 1 : Reaction sequence to build up the benzimidazole lead structure.

[00280] The synthetic procedures for [¹⁹F]SST034 given in WO 2015/177367 A1 use N,N-dimethylformanide (DMF) as solvent, and a yield of 25% was reported. However, upon changing the solvent to dichloromethane or tetrahydrofuran, the inventors surprisingly obtained the compound [¹⁹F]SST034 in a significantly increased isolated yield of 40-60 %. Thus, the inventors have established the following procedure (Scheme 2). Without wishing to be bound by any theory, a non-limiting reaction mechanism has been proposed (Scheme 2). The synthesis can be carried out in a one-pot procedure.

Scheme 2: Proposed non-limiting reaction mechanism when using dichloromethane and tetra hydrofuran as solvents.

[00281] Based on the precursor molecules, first optical probes and [¹⁸F]PET tracers were developed (Scheme 3). Applying X=F led to the first PET radiotracer reference compound SST034, while using SOBr₂ instead of SOCI₂ (to prevent Br-CI-exchange) and X=Br resulted in the corresponding radio precursor SST074. Additionally, in a nucleophilic aromatic substitution reaction with propargyl amine SST034 could be converted to alkine intermediate SST093. This versatile compound was coupled via Cu-catalysed [3+2]-dipolar cycloaddition to four azide-functionalized reaction partners, leading to a more hydrophilic radio tracer SST096 and three optical probes. BODIPY-TMR- and BODIPY-TR- functionalized compounds SST175 and SST176 were synthesized and used in the established fluorescence polarization assay (see below).

R= F SST096

= Cy5.5 SST110

= BODIPY-TMR SST175

= BODIPY-TR SST176

Scheme 3: Synthesis of precursors, first radio tracers and optical compounds.

[00282] Furthermore, first synthetic steps towards a labelling strategy for charged benzo[d]imidazo[1,2-a]imidazoles radio tracers were taken with the development of cationic tracer SST120 (Scheme 4). Starting with 6-bromohexanamide, as the amide part in the one- pot reaction, the resulting alkyl bromide SST108 was substituted with /V,/V-dimethyl propargylamine forming the quaternary ammonium ion SST117. This could be reacted with fluoro-ethyl azide in a Cu-catalysed [3+2]-dipolar cycloaddition to SST120, either with nonradioactive [¹⁹F]fluoroethyl azide for the radiotracer reference compound or with [¹⁸F]fluoroethyl azide for PET imaging.

Scheme 4: Synthesis of first charged PET radio tracer SST120.

Example 2a: In vitro binding assay

[00283] The equilibrium binding constant K_d of a fluorescein labelled derivative 6-FAM- SST177 was determined in fluorimetric measurements. These measurements are based on the observation, that an intramolecular quenching of the dye by the 2-amino benzimidazole lead structure in solution is reduced upon binding. This leads to a fluorescence intensity increase upon binding towards mS100A9, which is the read-out of K_d determination. The effect was neither observed using non-targeting 6-FAM-azide vs mS100A9, nor with targeting 6-FAM-SST177 in a negative control experiment towards mS100A8.

[00284] The experiments were performed in HEPES buffer (50 mM HEPES, 1 mM CaCI₂, pH 7.4), using black, flat bottom 96-well plates (THERMOFISHER, Waltham, USA, cat. no. 237108) and Flexstation 3 multi-mode microplate reader (MOLECULAR DEVICES, San Jose, USA). 6-FAM-SST177 was incubated in a fixed concentration of 25nM with increasing concentrations of mS100A9 ranging from 40 nM to 10 pM. The plate was incubated at 37°C for 30 min before measuring. Non-linear regression analysis was performed (using GraphPad PRISM 7, GRAPHPAD SOFTWARE INC.) with a one site saturation model to calculate the binding constant. The determined K_d of 217 nM confirms that the underlying 2-amino benzimidazole lead structure is eligible for imaging purposes.

Figure 8 shows three separate runs for determining the equilibrium binding constant K_d of fluorescein-labelled derivative 6-FAM-SST177 towards mS100A9 in accordance with Example 2. Depicted is the fluorescence intensity (Fl, vertical axis) depending of the concentration of mS100A9 in pM (horizontal axis).

Example 2b: K_D determination of AF488-SST193 against murine and human S100A9

[00285] The equilibrium dissociation constants (K_D) of fluorescent 2-amino benzimidazole-based compound AF488-SST193 against murine and human S100A9 were determined employing the fluorescence polarization assay technique (FP). For this, a Flexstation 3 multimodal plate reader by MolecularDevices (San Jose, USA) was utilized and experiments were performed in the 96-well plate format. Data were analyzed using GraphPad PRISM 7 by GraphPad Software Inc (San Diego, USA). Human S100A9C3S diluted from a 1.51 mM stock solution, stored at -20 °C in aliquots. mS100A9 was diluted from a 111 pM stock solution in HPS (pH 7.4), stored at -20 °C in aliquots. The protein stock solutions were diluted with ice-cooled assay buffer (Tris (50 mM Tris, 100 mM NaCI, 1 mM CaCI₂, pH 7.4) or HPS (50 mM HEPES, 1 mM CaCI₂, pH 7.4)) and treated with ZnCI₂ (5 x 0.4 eq., gentle mixing in between additions). AF488-SST193 was diluted from a 1 mM DMSO stock solution and stored at -20 °C under exclusion of light. Samples with AF488-SST193 (fixed concentration 25 nM) and increasing concentrations of human S100A9C3S or murine S100A9 ranging from 40 nM to 10 pM in a volume of 100 pL per well were prepared as triplicates and incubated at room temperature for 30, 60, 90, 120 or 150 min prior to measurement. Fluorescence polarization was measured at _ex = 485 nm and detect = 525 nm with a 515 nm cut-off filter. To calculate the net fluorescence polarization of AF488-SST193 in the presence of protein, raw values of and /_±of “protein only” samples (protein at corresponding concentration in buffer) were subtracted from the probe values (probe with protein in buffer). These protein background corrected values were used to calculate the milli-polarization according to Eq. 2. Non-linear regression analysis was performed with a “One-site specific binding” saturation model to calculate the binding constant using Eq. 1. The final estimate of K_o was given as an average over at least 3 independent experiments together with the standard error of the mean (o^), which was calculated according to Eqs 3 + 4. Equations 1 to 4 are shown in the following: nax * ^protein y = _{K + r} -

' '■'protein ~ mP = - -^ * 1000

Bmax = total number of binding sites, K_o = equilibrium dissociation constant, c_prot_ein = protein concentration, mP = milli-polarization,

= fluorescence intensity parallel to linear polarized excitation light, /_± = fluorescence intensity perpendicular to linear polarized excitation light, o* = standard error of the mean, a = standard deviation.

[00286] The experiments revealed binding of AF488-SST193 in the range of 900- nanomolar concentration against murine and in the range of 1.3 pM concentration against human S100A9 (Table 1 , Figure 9A-C). Additionally, the compound was tested for unspecific interaction with murine S100A8, which could not be observed (Figure 9D). The presented FP experiments support the above presented results of the fluorimetric measurements with 6- FAM-SST177. Thus, the two fluorescent compounds 6-FAM-SST177 and AF488-SST193 experimentally proof binding of the 2-amino benzimidazole lead structure against S100A9 and the results allow its use as a targeting entity for S100A9-targeting inflammation imaging agents.

Table 1 shows the determined K_D of AF488-SST193 towards S100-Proteins given as average over n individual experiments with standard error of the mean (o-_x). Calculations were done according to equations 05 and in a “one-site - specific binding” fitting model.

Table 1 :

AF488-SST193 vs. K_D / pM

mS100A9 in Tris buffer 0.87 0.14 3

Figure 9 shows saturation binding curves (“one-site - specific binding” model) determining the K_D of AF488-SST193 towards A) mS100A9 in HPS buffer, B) mS100A9 in Tris buffer, C) hS100A9C3S in Tris buffer and D) mS100A8 in HPS buffer as a negative control. Each curve refers to an individual experiment with date given in the legend. Example 3: In vivo imaging (Cy5.5-SST110) - ear inflammation model of irritant contact dermatitis

[00287] Balb/c mice (Harlan Laboratories) and S100A9-deficient mice (S100A9'^/_), backcrossed from C57BL/6 to Balb/c background (F10 generation) were used at the age of 10- to 14 weeks, sex and age matched for each set of experiments and housed under specific pathogen-free conditions.

[00288] Irritant contact dermatitis (ICD) was induced by the application of 20pl 1% croton oil in olive oil-acetone (1 :4) to the ventral surface of the left ear of mice for 24h (n=4), whereas the right ear served as a control. Fluorescence reflectance imaging was performed 3h after tracer application, corresponding to 27 h after croton oil treatment. The dermatitis mouse model showed significant accumulation of Cy5.5-SST 110 (i.e. a compound of formula (I) in accordance with the present invention, which is covalently linked to a label) at sites of inflammation. As shown in the results of imaging experiments depicted in Figure 1 , Cy5.5- SST110 showed significant accumulation in the inflamed ear of a dermatitis mouse model. This can be explained by binding of the compound Cy5.5-SST110 to S100A9 accumulated in the inflamed ear tissue. On the other hand, no significant accumulation of Cy5.5-SST110 was observed in in the control ear without inflammation. These results demonstrate that tracer-tagged benzimidazole-based compounds provided herein show significant accumulation at sites of inflammation and/or inflammatory active diseases, and are therefore useful for diagnostic purposes of such diseases.

Figure 1 shows in vivo imaging using the compound Cy5.5-SST110 in an ear inflammation mouse model of irritant contact dermatitis.

Example 4: Radiosyntheses

[¹⁸F]SST034

[00289] First PET radio tracer [¹⁸F]SST034 was obtained using a nucleophilic aromatic substitution reaction of bromo-precursor SST074 at 160 °C for 20 min with K¹⁸F and azacryptant K₂22- The compound was found to be stable in murine and human blood serum over a period of at least 120 min and the experimental logD- value was determined as 1.7 +/- 0.2.

• radiochem. yield: 5-10% (d. c.) n=16

• radiochem. purity: 99+%

• A_m = 7.2 GBq/pmol, A_s = 16.1 GBq/mg

• stable in serum (murine and human) over 120 min. (37°C)

• logD_eXp = 1.7 +/- 0.2

Figure 2 shows the murine and human blood serum stability of the compound [¹⁸F]SST034 over 120 min.

[¹⁸F]SST096

[00290] Second radio tracer [¹⁸F]SST096 was obtained by [3+2] dipolar cycloaddition with [¹⁸F]fluoroethyl azide as a prostetic group. This tracer was again stable in murine and human blood serum for over 120 min. The experimental logD value of 1.3 +/- 0.2 was observed to be more hydrophilic than [¹⁸F]SST034.

• radiochem. yield: 6-15% (d. c.) n=7

• radiochem. purity: 99+%

• A_m = 6.9 GBq/pmol, A_s = 12.1 GBq/mg

• stable in serum (murine and human) over 120 min. (37°C)

• logD_eXp = 1.3 +/- 0.2 Figure 3 shows the murine and human blood serum stability of the compound [¹⁸F]SST096 over 120 min.

[¹⁸F]SST120

[00291] Cationic radio tracer [¹⁸F]SST120 was obtained by the same strategy as [¹⁸F]SST096 “click-chemistry” and [¹⁸F]fluoroethyl azide as a prostetic group. The cationic tracer was stable in murine and human blood serum for 120 min and the experimental logD value was 0.1 +/- 0.09. This shows an increase of hydrophilicity compared to the previous tracers, but still its better soluble in organic solvents than in water, as the positive logD value states.

• radiochem. yield: 15-34% (d. c.) n=3

• radiochem. purity: >95%

• stable in murine and humane serum over 120 min. (37°C)

• logD_eXp = 0.1 +/- 0.09

Figure 4 shows the murine and human blood serum stability of the compound [¹⁸F]SST120 over 120 min.

Example 5: In vivo biodistribution studies with [¹⁸F]SST034

[00292] Dynamic PET studies 0-90 min p.i. [¹⁸F]SST034 were performed in adult C57BI/6 mice, followed by ex-vivo tissue radioactivity measurements.

Figure 5 shows in vivo biodistribution studies with the compound [¹⁸F]SST034. Figure 5A shows maximum intensity projections of selected time frames in vivo). Figure 5B shows an ex vivo gamma counter analysis (110 min p.i.). [00293] In vivo imaging depicts fast kinetics of [¹⁸F]SST034 after i.v. injection with predominant hepatobiliary clearance. Accumulation of radioactivity in the bones as surrogate marker for defluorination of [¹⁸F]SST034 was not observed. Furthermore, already 30 minutes after tracer injection tissues that are not involved in tracer elimination present only with low levels of radioactivity. The low background activities are favourable for diagnostic application of [¹⁸F]SST034 in vivo as they allow sensitive detection of pathological tracer accumulation with a good contrast.

Example 6: In vivo biodistribution studies with [¹⁸F]SST096

Dynamic PET studies 0-90 min p.i. [¹⁸F]SST096 were performed in adult C57BI/6 mice, followed by ex-vivo tissue radioactivity measurements.

Figure 6 shows In vivo biodistribution studies with the compound [¹⁸F]SST120. Figure 6A shows Maximum Intensity Projections of selected time frames {in vivo). Figure 6B shows an ex vivo gamma counter analysis (110 min p.i.).

[00294] In vivo imaging depicts fast kinetics of [¹⁸F]SST096 after i.v. injection with predominant hepatobiliary clearance. In comparison to [¹⁸F]SST034 the elimination pathway has slightly shifted towards renal excretion as depicted by accumulation of radioactivity in the urinary bladder and confirmed by ex vivo gamma counter analysis. Accumulation of radioactivity in the bones as surrogate marker for defluorination of [¹⁸F]SST096 was not observed. Furthermore, already 60 minutes after tracer injection tissues that are not involved in tracer elimination present only with low levels of radioactivity. The low background activities are favourable for diagnostic application of [¹⁸F]SST096 in vivo as they allow sensitive detection of pathological tracer accumulation with a good contrast.

Example 7: In vivo biodistribution studies with [¹⁸F]SST120

[00295] Dynamic PET studies 0-90 min p.i. [¹⁸F]SST120 were performed in adult C57BI/6 mice, followed by ex-vivo tissue radioactivity measurements.

Figure 7 shows in vivo biodistribution studies with the compound [¹⁸F]SST120. Figure 7A shows Maximum Intensity Projections of selected time frames in vivo). Figure 7B shows an ex vivo gamma counter analysis (110 min p.i.). [00296] In vivo imaging depicts fast kinetics of [¹⁸F]SST120 after i.v. injection with again predominant hepatobiliary clearance. However, in comparison to [¹⁸F]SST096 the elimination pathway has again slightly shifted towards renal excretion, resulting in high radioactivity concentrations in the urine as measured by gamma counting 110 min p.i.. Accumulation of radioactivity in the bones as surrogate marker for defluorination of [¹⁸F]SST120 was not observed. Furthermore, already 30 minutes after tracer injection tissues that are not involved in tracer elimination present only with low levels of radioactivity. The low background activities are favourable for diagnostic application of [¹⁸F]SST096 in vivo as they allow sensitive detection of pathological tracer accumulation with a good contrast.

Example 8: Experimental details

Chemicals, solvents and lab supply

[00297] Substrates, reagents and solvents were bought from ABCR, ABX, ACROS, Carbolutions, Fluka, Merck/Sigma-Aldrich or TCI and used without further purification, unless noted otherwise.

[00298] All air/moisture sensitive reactions were carried out under Argon (99.999 Vol.- %, Westfalen-AG) atmosphere using Schlenk technique. Unless noted otherwise, for air/moisture sensitive reactions dry solvents under inter atmosphere in septum bottles were bought in the required purity. DCM was dried over CaCI₂, distilled and stored under Argon atmosphere over 4 A molecular sieves.

[00299] Radiosynthesis was performed using Milli-Q® (Merck) purified water and dried solvents of highest purity, as well as solvents for clinical radiochemistry in septum bottles by ABX.

[00300] For thin-layer chromatography (TLC) Polygram® SIL G/UV254 plates of Macherey-Nagel coated with 0.2 mm of silica gel (normal phase or C-18 reverse phase) were used. Compounds were visualized by UV-light (A = 254 nm or 366 nm), l₂ vapors, or a suitable staining solution with heating (200-300 °C). Staining solutions used: Ceric ammonium molybdate solution, ninhydrin, potassium permanganate solution, anisaldehyde solution. [00301] Flash column chromatography was performed using silica gel Si 60 (pore size: 60 A, 40-63 pm) of Merck/Sigma-Aldrich. Detailed separation conditions are noted in the individual synthetic procedures below.

Instruments and analytics

[00302] Automatic column chromatography was performed using a Reveleris X2 system of Grace (now Buchi), with a UV compound detector and prepacked FlashPure normal and reverse phase silica cartridges. Detailed separation conditions are noted in the individual synthetic procedures below.

[00303] For analytic and semi-preparative (radio-)HPLC separations, the following reverse phase systems of Knauer with UV and y-ray detectors were utilized: analytic RP- HPLC with two Smartline 1000 pumps (Knauer), Smartline 2500 UV detector (Knauer), GabiStar y-ray detector of Raytest Isotopenmessgerate. Radio-semipreparative RP-HPLC with Knauer's K-500, K-501 pumps and K-2000 UV detector, Nal(TI) Scintibloc 51 SP51 y- ray detector of Crismatec. Non-radioactive semipreparative purification was performed on a Knauer Azura 2.1L system with two Azura pump P2.1L, two Azura assistant ASM 2.1 L, Azura control unit CU 2.1 L and a Azura UVD 2.1 L UV-detector.

Separation conditions and used columns are noted in the individual synthetic procedures below.

[00304] Melting points were determined utilizing Stuart SMP 3 of Stuart scientific. All melting points were measured three times and the mean value, as well as the solvent from which the solid was crystallized/precipitated, were noted down.

[00305] Mass spectra were measured at the mass spectrometry department in the Organisch-Chemisches Institut of the Westfalische Wilhelms-Universitat Munster, using electrospray ionization (ESI) technique on the following instruments: MicroToF of Bruker Daltonics, Orbitrap LTQ XL of Thermo Scientific. The exact masses of new compounds were determined with manual loop injection and electrospray ionization on these instruments, as well. Previously to each exact mass measurement the instrument was calibrated with sodium formiate clusters.

[00306] ¹H-NMR, ¹³C-NMR and ¹⁹F-NMR spectra were measured at the NMR department in the Organisch-Chemisches Institut of the Westfalische Wilhelms-Universitat Munster with the following instruments: DD2 600 by Agilent (¹H-NMR: 600.0 MHz, ¹³C-NMR: 151.0 MHz, ¹⁹F-NMR: 563.9 MHZ), DD2 500 by Agilent (¹H-NMR: 499.8 MHz, ¹³C-NMR: 125.7 MHz), Avance II 400 by Bruker Daltonics (¹H-NMR: 400.1 MHz, ¹³C-NMR: 100.6 MHz, ¹⁹F-NMR: 563.9 MHZ), Avance II 300 by Bruker Daltonics (¹H-NMR: 301.1 MHz, ¹³C-NMR: 75.5 MHz, ¹⁹F-NMR: 282.4 MHz). Data was analyzed with MestReNova 8.0.0 by mestrelab research S.L. Chemical shifts 5 [ppm] related to tetramethyl silane were referenced to the corresponding deuterated solvent signals: CHCI₃ (¹H-NMR: 8 = 7.26 ppm, s and ¹³C-NMR: 8 = 77.2 ppm, t) and DMSO-d₆ (¹H-NMR: 8 = 2.54 ppm, p and ¹³C-NMR: 8= 39.5 ppm, sept). Coupling constants J [Hz] are within a resolution of 0.1 Hz and multiplicities were noted down as follows: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sext = sextet, sept = septet, m = multiplet, br. = broad signal, dd = doublet of doublets, ddd = doublet of doublets od doublets, etc.). ¹³C-NMR spectra were measured with proton broadband decoupling and ¹³C-¹H multiplicities were determined using DEPT measurements. Multiplets and coupling constants in ¹³C-spectra of fluorine containing compounds refer to ¹³C-¹⁹F- couplings. Atom assignments were done using 2D-NMR experiments as well as 1 D-TOCSY and 1 D-NOESY experiments. Atom numbers of similar structures were assigned similarly due to consistency, but do not always correspond to IIIPAC numbering.

[00307] Fluorescence polarization assay was performed on a Flexstation 3 multimodal plate reader by MolecularDevices (San Jose, USA).

General procedures

[¹⁸F]-Radiolabeling

[00308] No carrier added (n.c.a.) [¹⁸F]Fluoride was generated in the RDS 111e cyclotron of Siemens via the ¹⁸O(p,n)¹⁸F nuclear reaction with isotope enriched H₂ ¹⁸O (97 %) and a 10 MeV proton beam. Unless noted otherwise, rinse activity was used in [¹⁸F]- radiochemistry. [¹⁸F]-labeling reactions were performed with a semi-automatic TRACERLab FXFDG synthesis module (GE Healthcare) and the supplied software. Radioactivity measurements were done utilizing activimeter ISOMED 2010 of Med Nuklearmedizintechnik. To retrieve H₂ ¹⁸O [¹⁸F]fluoride was fixated on a preconditioned anion exchange cartridge (Sep-Pak® QMA light cartridge, Waters). Cartridges were preconditioned with aqueous potassium carbonate solution (1 m, 5 mL) and Milli-Q® water (10 mL) or preconditioned cartridges by ABX were used. [¹⁸F]fluoride was eluted in the reactor with a solution of azacryptant K₂₂₂ (20 mg, 53 pmol) in potassium carbonate solution (1 m, 40 pl), acetonitrile (800 pL) and Milli-Q® water (200 pL) or a premixed solution by ABX was used Additionally, the anion exchange cartridge was flushed with acetonitrile (200 pl). For azeotropic drying the reactor was evacuated and solvents were evaporated at 56 °C with (2 min) and without He- stream (1 min) applied. For further drying, the reactor was heated to 84 °C under vacuum for 10 min. Dried no carried added [¹⁸F]fluoride was used in the individual labeling reactions.

[00309] [¹⁸F] rad iotracers were identified by analytical radio-HPLC and co-injection of a previously synthesized non-radioactive [¹⁹F]reference compound.

[00310] Radiochemical yields (RCY) refer to the fraction of the final radiotracer reconstituted in a physiological solution (200 pL, PBS buffer, saline, buffer/EtOH 10 %, etc) over starting activity of the applied no carrier added [¹⁸F]fluoride RCY is given including decay corrections (d.c.).

[00311] Radiochemical purity (RCP) was determined by analytical radio-HPLC and refers to the percentage of activity of the radiotracer in the semi preparative HPLC purified solution.

Experimental n-octanol/PBS partition coefficient (logD_exp)

[00312] Following the procedure of Holschbach et al. (M.H. Holschbach, R.A. Olsson, D. Bier, W. Wutz, W. Sihver, M. Schuller, B. Palm, H.H. Coenen, Synthesis and Evaluation of No-Carrier- Added 8-Cyclopentyl-3-(3-[18F]fluoropropyl)-1 -propylxanthine ([18F]CPFPX): A Potent and Selective A 1 -Adenosine Receptor Antagonist for in Vivo Imaging, Journal of Medicinal Chemistry 2002, 45 (23), 5150-5156; DOI: 10.1021/jm020905i), the experimental n-octanol/PBS buffer partition coefficient (logD_exp) was determined as a parameter for the lipophilicity of a radiotracer. All experiments were performed as triplicates and the final logD_exp was calculated as a mean value. n-Octanol (500 pL) was added to a solution of the radiotracer (20-30 kBq) in phosphate buffer (PBS, pH =7.4, 500 pL) and the two-phase system was shaken vigorously for 1 min. The layers were separated by centrifugation (2 min, 3000 rpm, MCF-2360 centrifuge, LMS consult) and the radioactivity of three aliquots (100 pL) of both phases were measured in the gamma counter in the form of decay corrected double determinations. Additionally, the partition coefficient was determined in a higher dilution by “washing” the n-octanol phase with PBS buffer. After vigorous shaking for 1 min, a mixture of the radiotracer (20-30 kBq) in PBS buffer (500 pL) and n-octanol (500 pL) was centrifuged (2 min, 3000 rpm). A fraction (400 pL) of the n-octanol layer was removed and mixed vigorously with PBS buffer (400 pL). The layers were separated by centrifugation (2 min, 3000 rpm) and three aliquots (100 pL) of both phases were measured with gamma counter Wallac Wizard 3 (PerkinElmer Life Sciences) in the form of decay corrected double determinations. The radioactivity in each layer was calculated as a mean value of corresponding aliquots. The logD_exp value was calculated as the logarithmic quotient of the measured radioactivity in both layers:

Tracerstability in humane or murine blood serum

[00313] Blood serum samples were obtained by centrifugation (5000 rpm, 10 min, centrifuge) of a blood sample and removing the serum as centrifugate. Blood serum for stability test was either freshly prepared before testing or stored at -18 °C. The radiotracer (ca. 5 MBq) in phosphate buffer (PBS, pH = 7.4, 20 pL) was added to blood serum (200 pL) and incubated at 37 °C for 120 min (PST-60 HL plus thermo shaker, Kisker biotech). These samples (20 pL) were taken at different time points (10 min, 20 min, 30 min, 60 min, 90 min, 120 min). Samples were immediately added to a ice cooled mixture of DCM/MeOH (1:1, 200 pL) to precipitate serum proteins. After shaking for 30 s the mixture was centrifugated (3000 rpm, 2 min, MCF-2360 centrifuge, LMS consult) and the organic layer was analyzed by analytical radio-HPLC for radioactive decomposition products.

Fluorescence reflectance imaging

[00314] Irritant contact dermatitis (ICD) was induced by the application of 20pl 1% croton oil in olive oil-acetone (1 :4) to the ventral surface of the left ear of mice for 24h (n=4), whereas the right ear served as a control. Fluorescence reflectance imaging was performed 3h after tracer application (i.v. injection into the tail vein), corresponding to 27 h after croton oil treatment. In vivo fluorescence reflectance imaging was performed with an I VIS Spectrum small-animal imaging system (Perkin Elmer). Images were acquired and analyzed using Living Image 4.X software (Perkin Elmer). For the measurements the Cy5.5® filter set was used. Identical excitation/emission settings were used for all experiments. Fluorescence emission was measured by Fluorescence emission radiance per incident excitation irradiance (p/sec/cm2/sr / pW/cm2).

In vivo PET/SPECT studies

[00315] Adult C57BL/6 mice (n = 6 for each tracer variant, 8 - 12 weeks) were anaesthetized by isoflurane/O₂ and one lateral tail vein was cannulated using a 27 G needle connected to 15 cm polyethylene catheter tubing. Radiotracers were prepared in buffer (PBS/EtOH 10 %), 6-9 MBq in an injection volume of 5pl/g bodyweight) and injected as a bolus via the tail vein and subsequent PET scanning was performed.

[00316] PET imaging studies were carried out using a submillimeter high resolution (0.7 mm full width at half-maximum) small animal scanner (32 module quadHIDAC, Oxford Positron Systems Ltd., Oxford, UK) with uniform spatial resolution (<1 mm) over a large cylindrical field (165 mm diameter, 280 mm axial length). List-mode data were acquired for 90 min and reconstructed into dynamic time frames using an iterative reconstruction algorithm. Subsequently, the scanning bed was transferred to the computed tomography (CT) scanner (Inveon, Siemens Medical Solutions, U.S.), and a CT acquisition with a spatial resolution of 80 pm was performed for each mouse. Reconstructed image data sets were coregistered based on extrinsic markers attached to the multimodal scanning bed and the inhouse developed image analysis software MEDgical. Three-dimensional volumes of interest (VOIs) were defined over the respective organs in CT data sets, transferred to the coregistered PET data, and analyzed quantitatively. Regional uptake was calculated as percentage of injected dose by dividing counts per milliliter in the VOI by total counts in the mouse multiplied by 100 (%ID/mL).

[00317] Ex vivo gamma counter measurements. Following the PET-CT acquisition (110 min after injection of the tracer), mice were euthanized by cervical dislocation and a necropsy was performed. Ex vivo biodistribution of radioactivity was analyzed by scintillation counting (Wizard2 gamma counter, Perkin-Elmer Life Science) and the radioactivity in respective organs decay-corrected and calculated as %ID per gram tissue (% I D/g).

Radiosyntheses

Radiosynthesis of [¹⁸F]SST034

[00318] A solution of precursor SST074 in dry DMSO (500 pL) was added to dried no carried added [¹⁸F]fluoride (1.0 - 4.9 GBq), which was generated according to general procedure XY. The reaction mixture was stirred for 20 min at 150 °C in the sealed reactor. After cooling to 40 °C the reaction mixture was diluted with Milli-Q® water (10 mL) and the crude product was fixated on a preconditioned reverse phase silica cartridge (Sep-Pak® C- 18 light cartridge, Waters, preconditioned with EtOH (10 mL) and Milli-Q® water (10 mL)). The cartridge was washed with Milli-Q® water (10 mL) and the crude product was eluted with acetonitrile (1 mL). [¹⁸F]SST034 was purified by semi preparative radio-HPLC (column: RP ACE-126-2510, 250 x 10 mm), mobile phase: Milli-Q® water (0.1 % TFA)/acetonitrile (0.1 % TFA) , flow: 5.5 mL/min, gradient see below). The product fraction was collected in previously silanized glassware (Sigmacote®, Sigma-Aldrich). Radiochemical purity was determined by analytical radio-HPLC (column: RP Eurosphere-2, 100-5, C18, 150 x 4 mm), mobile phase: Milli-Q® water (0.1 % TFA)/acetonitrile (0.1 % TFA) , flow: 1.0 mL/min, gradient see below). Solvents were evaporated under reduced pressure at 70 - 80 °C until a vacuum of ca. 5 mbar was reached. The radiotracer was dissolved in EtOH (20 pL), diluted with PBS buffer (180pL) and transferred to an eppendorf tube for further experiments.

[00319] The experimental n-octanol/PBS buffer partition coefficient (logD_exp), as well as the blood serum stability of [¹⁸F]SST034 were determined applying general procedures, respectively.

[00320] HPLC-conditions:

Semi preparative radio-HPLC gradient: isocratic 90 % water (0.1 % TFA) for 1 min, gradient to 55 % water (0.1 % TFA) within 1 min, gradient to 20 % water (0.1 % TFA) within 11 min, gradient to 90 % water (0.1 % TFA) within 1 min.

Analytical radio-HPLC gradient: isocratic 90 % water (0.1 % TFA) for 1 min, gradient to 55 % water (0.1 % TFA) within 1 min, gradient to 20 % water (0.1 % TFA) within 11 min, gradient to 90 % water (0.1 % TFA) within 1 min.

Radiosynthesis of [¹⁸F]SST096

[00321] A solution of prostetic group precursor azido-ethyl tosylate (20 mg, 82.9 pmol) in 500 pL dry ACN was added to dried no carried added [¹⁸F]fluoride (1.0 - 4.9 GBq), which was generated according to general procedure XY. The reaction mixture was stirred at 110°C for 3min and simultaneously distilled into a ice-cooled solution of precursor alkine SST084 (3 mg, 6.21 pmol in 300 pL) and the premixed Cu(l)-catalyst solution (10 mg, 62.7 pmol CuSO₄ and 16 mg, 80.8 pmol (L)-sodium ascorbate, each in 50 pL H₂O vortexed together for 3min). The reaction mixture with [¹⁸F]fluoro ethyl azide, alkine precursor SST086 and the catalyst solution was stirred at 45°C for 30min. The reaction mixture was filtered through a syringe filter (MERCK, Millex-GV, 0.22 pm, PVDF, 13 mm) and the filter was rinsed with 300 pL H₂O. [¹⁸F]SST096 was purified from the resulting filtrate by semi preparative radio-HPLC (column: RP ACE-126-2510 (10 mm x 250 mm), mobile phase: Milli-Q® water (0.1 % TFA)/acetonitrile (0.1 % TFA) , flow: 5.5 mL/min, gradient see below). The product fraction was collected in previously silanized glassware (Sigmacote®, sigma-aldrich). Radiochemical purity was determined by analytical radio-HPLC (column: RP Eurosphere-2, 100-5, C18, 150 x 4 mm), mobile phase: Milli-Q® water (0.1 % TFA)/acetonitrile (0.1 % TFA) , flow: 1.0 mL/min, gradient see below). Solvents were evaporated under reduced pressure at 70 - 80 °C until a vacuum of ca. 5 mbar was reached. The radiotracer was dissolved in EtOH (20 pL), diluted with PBS buffer (180pL) and transferred to an eppendorf tube for further (biological) experiments. [00322] The experimental n-octanol/PBS buffer partition coefficient (logD_exp), as well as the blood serum stability of [¹⁸F]SST034 were determined applying general procedures, respectively.

[00323] Semi preparative radio-HPLC gradient: isocratic 80 % water (0.1 % TFA) for 2 min, gradient to 50 % water (0.1 % TFA) within 1 min, gradient to 30 % water (0.1 % TFA) within 9 min, gradient to 80 % water (0.1 % TFA) within 2 min, isocratic 80% water (0.1 % TFA) for 1min.

[00324] Analytical radio-HPLC gradient: isocratic 80 % water (0.1 % TFA) for 2 min, gradient to 55 % water (0.1 % TFA) within 1 min, gradient to 30 % water (0.1 % TFA) within 9 min, gradient to 80 % water (0.1 % TFA) within 2 min.

Radiosynthesis of [¹⁸F]SST120

[00325] A solution of prostetic group precursor azido-ethyl tosylate (20 mg, 82.9 pmol) in 500 pL dry ACN was added to dried no carried added [¹⁸F]fluoride (1.0 - 4.9 GBq), which was generated according to general procedure XY. The reaction mixture was stirred at 110°C for 3min and simultaneously distilled into a ice-cooled solution of precursor alkine SST117 (3 mg, 5.17 pmol in 300 pL) and the premixed Cu(l)-catalyst solution (10 mg, 62.7 pmol CuSO₄ and 16 mg, 80.8 pmol (L)-sodium ascorbate, each in 50 pL H₂O vortexed together for 3min). The reaction mixture with [¹⁸F]fluoro ethyl azide, alkine precursor SST086 and the catalyst solution was stirred at 45°C for 30min. The reaction mixture was filtered through a syringe filter (MERCK, Millex-GV, 0.22 pm, PVDF, 13 mm) and the filter was rinsed with 300 pL H₂O. [¹⁸F]SST120 was purified from the resulting filtrate by semi preparative radio-HPLC (column: RP Luna C18 Semiprep 250 x 10 mm), mobile phase: Milli-Q® water (0.1 % TFA)/acetonitrile (0.1 % TFA) , flow: 5.5 mL/min, gradient see below). The product fraction was collected in previously silanized glassware (Sigmacote®, sigma-aldrich). Radiochemical purity was determined by analytical radio-HPLC (column: RP Eurosphere-2, 100-5, C18, 150 x 4 mm), mobile phase: Milli-Q® water (0.1 % TFA)/acetonitrile (0.1 % TFA) , flow: 1.0 mL/min, gradient see below). Solvents were evaporated under reduced pressure at 70 - 80 °C until a vacuum of ca. 5 mbar was reached. The radiotracer was dissolved in EtOH (20 pL), diluted with PBS buffer (180pL) and transferred to an eppendorf tube for further (biological) experiments.

[00326] The experimental n-octanol/PBS buffer partition coefficient (logD_exp), as well as the blood serum stability of [¹⁸F]SST034 were determined applying general procedures, respectively. [00327] Semi preparative radio-HPLC gradient: isocratic 90 % water (0.1 % TFA) for

I min, gradient to 75 % water (0.1 % TFA) within 1 min, gradient to 60 % water (0.1 % TFA) within 18 min, gradient to 90 % water (0.1 % TFA) within 2 min.

[00328] Analytical radio-HPLC gradient: isocratic 90 % water (0.1 % TFA) for 2 min, gradient to 65 % water (0.1 % TFA) within 1 min, gradient to 50 % water (0.1 % TFA) within

I I min, gradient to 90 % water (0.1 % TFA) within 1 min.

Synthetic procedures

SST034

[00329] In a flame-dried flask under Argon atmosphere, 6-fluoropicolinamide (3.50 g, 25.0 mmol, 1.0 eq.) was suspended in dry DCM (15 mL). Ethyl-3,3,3-trifluoro-2- oxopropanoate (5.00 g, 29.4 mmol, 1.2 eq.) was added dropwise and the reaction mixture was stirred at room temperature for 2h until the substrates were completely dissolved. Solvent was removed in vacuo and the reaction mixture was dissolved in SOCI₂ (15 mL). The reaction mixture was stirred at 60 °C for 15 h. After removing the solvent and produced gases via cooling trap and high-vacuum, the resulting white residue was dissolved in dry THF (25 mL). The reaction mixture was treated with 2-amino-5,6-dichlorobenzimidazole (3.0 g, 15.0 mmol, 0.6 eq) and dry triethylamine (5 mL, 67.6 mmoL, 2.7 eq). After stirring at room temperature for 3 h, the reaction mixture was diluted with 0.1 m HCI (50 mL) and the aqueous phase was extracted with ethyl acetate (3x 50 mL). The combined organic layers were washed with saturated NaCI solution (50 mL), dried over MgSO₄ and concentrated under reduced pressure. Flash column chromatography (CH₂CI₂/MeOH 3-5%) followed by recrystallization (toluene) yielded SST034 as white crystals (4.5 g, 10 mmol, 40 %).

¹H NMR (500 MHz, DMSO-d₆) <5[ppm] = 13.38 (s, 1 H, H-1), 10.89 (s, 1 H, H-4), 8.17 (pseudo- q, J = 8.0 Hz, 1H, ¹H {¹⁹F} NMR: dd, J= 8.3 Hz, 7.5 Hz, 1H, H-14), 7.85 (dd, J = 7.5, 2.0 Hz, 1 H, H-15), 7.82 (s, 1H, H-6/H-9), 7.80 (s, 1H, H-6/H-9), 7.53 (dd, J = 8.3, 2.0 Hz, 1 H, H-13). ¹³C NMR (126 MHz, DMSO-d₆) <5[ppm] = 168.3 (C-2), 164.8 (C-10), 161.8 (d, J = 241.0 Hz, C-12), 145.7 (d, J = 12.2 Hz, C-11), 144.0 (d, J = 8.1 Hz, C-14), 128.7 (C-4/5/7/8), 125.5 (C- 4/5/7/S), 124.9 (C-4/5/7/8), 121.7 (d, J = 3.5 Hz, C-15), 121.0 (q, J = 285.0 Hz, C-16), 119.4 (C-6/9), 114.7 (d, J = 36.4 Hz, C-13), 111.1 (C-6/9), 72.6 (q, J = 33.1 Hz, C-1).

MS-ESI(+) MicroTof exact mass: m/z = 469.9801 [M+Na⁺], calc, for Ci6H7N₅O2Cl2F₄Na 469.9806.

Melting point: 268-269 °C (toluene)

Crystallographic data:

[00330] A colorless plate-like specimen of C16H7CI2F4N5O2, approximate dimensions 0.059 mm x 0.114 mm x 0.203 mm, was used for the X-ray crystallographic analysis. The X- ray intensity data were measured.

[00331] A total of 415 frames were collected. The total exposure time was 2.31 hours. The frames were integrated with the Bruker SAINT software package using a narrow-frame algorithm. The integration of the data using a triclinic unit cell yielded a total of 12654 reflections to a maximum 0 angle of 26.79° (0.79 A resolution), of which 3592 were independent (average redundancy 3.523, completeness = 99.4%, R_int = 5.32%, R_sig = 4.92%) and 2871 (79.93%) were greater than 2o(F²). The final cell constants of a = 6.9395(3) A, b = 9.4720(5) A, c = 13.3062(7) A, a = 89.248(2)°, = 81.722(2)°, y = 78.009(2)°, volume = 846.50(7) A³, are based upon the refinement of the XYZ-centroids of 3397 reflections above 20 o(l) with 5.332° < 20 < 53.31 °. Data were corrected for absorption effects using the multiscan method (SADABS). The ratio of minimum to maximum apparent transmission was 0.880. The calculated minimum and maximum transmission coefficients (based on crystal size) are 0.9140 and 0.9740.

[00332] The structure was solved and refined using the Bruker SHELXTL Software Package, using the space group P -1 , with Z = 2 for the formula unit, C16H7CI2F4N5O2. The final anisotropic full-matrix least-squares refinement on F² with 270 variables converged at R1 = 4.15%, for the observed data and wR2 = 8.28% for all data. The goodness-of-fit was 1.056. The largest peak in the final difference electron density synthesis was 0.324 e7A³ and the largest hole was -0.405 e7A³ with an RMS deviation of 0.067 e7A³. On the basis of the final model, the calculated density was 1.758 g/cm³ and F(000), 448 e^_. SST074

[00333] In a flame-dried flask under Argon atmosphere 6-bromopicolinamide (1.00 g, 5.0 mmol, 1.0 eq.) was suspended in dry DCM (5 ml). Ethyl-3,3,3-trifluoro-2-oxopropanoate (935 mg, 5.5 mmol, 1.1 eq.) was added dropwise and the reaction mixture was stirred at room temperature for 2h until the substrates were completely dissolved. Solvent was removed in vacuo and the reaction mixture was dissolved in SOBr₂ (4 mL). The reaction mixture was stirred at 60 °C for 15 h. After removing the solvent and produced gases via cooling trap and high-vacuum, the resulting precipitate was dissolved in dry THF (7 mL). The reaction mixture was treated with 2-amino-5,6-dichlorobenzimidazole (1.00 g, 5.0 mmol, 1.0 mL) and dry triethylamine (2 mL, 33.8 mmoL, 6.7 eq). After stirring at room temperature for 3 h, he reaction mixture was diluted with 0.1 m HCI (50 mL) and the aqueous phase was extracted with ethyl acetate (3x 50 mL). The combined organic layers were washed with saturated NaCI solution (50 mL), dried over MgSO₄ and concentrated under reduced pressure. Flash column chromatography (DCM/MeOH 3-5%) followed by recrystallization (toluene) yielded benzimidazole SST074 as a white solid in yields (700 mg, 1.37 mmol, 28 %).

¹H NMR (500 MHz, DMSO-d₆) b[ppm] = 13.41 (s, 1 H, H-1), 10.78 (s, 1H, H-4), 7.95 (dd, J = 7.4, 2.0 Hz, 1 H, H-13), 7.92 (dd, J = 7.4, 7.0 Hz, 1 H, H-14), 7.89 (dd, J = 7.0, 2.0 Hz, 1 H, H- 15), 7.84 (s, 1H, H-6/H-9), 7.81 (s, 1H, H-6/H-9).

¹³C NMR (126 MHz, DMSO-d₆) b[ppm] = 168.3 (C-2) 164.9 (C-10), 148.7 (C-11), 141.0 (C- 14), 140.6 (C-12), 132.4 (C-13), 128.7 (C-4/5/7/8), 125.5 (C-4/5/7/8), 124.8 (C-4/5/7/8), 123.0 (C-15), 121.1 (q, J = 285.0 Hz, C-16), 119.4 (C-6/9), 111.2 (C-6/9), 72.2 (q, J = 33.6 Hz, C- 1).

MS-ESI(+) MicroTof exact mass: m/z = 529.8999 [M+Na⁺], calc, for Ci6H₇N₅O₂CI₂F₃BrNa 529.9004.

Melting point: 257-258 °C (lyophilized from H₂O/ACN) SST093

[00334] Benzimidazole SST034 (400 mg, 0.89 mmol, 1 eq.) was dissolved in a mixture of propargylamine/pyridine (1 :1, 0.5 mL) and stirred in a sealed tube at 100 °C for 48 h. After cooling to room temperature and releasing pressure the reaction mixture was concentrated in vacuo. The brownish residue was suspended in 0.1 m HCI (2 mL) and the aqueous phase was extracted three times with EE. The combined organic layers were dried over MgSO₄ and the solvent was removed under reduced pressure. The product was purified via flash column chromatography (DCM/MeOH 2.5-5% and additional 1% TEA), followed by washing the product fraction with 0.1 m HCI until the aqueous layer was acidic. The organic layer was dried over MgSO₄ and concentrated under reduced pressure, yielding alkyne SST093 as a white solid.

¹H-NMR (599 MHz, DMSO-d₆) 6[ppm] = 9.89 (s, 1 H, H-4), 7.82 (s, 1 H, H-6/H-9), 7.76 (s, 1 H, H-6/H-9), 7.58 (dd, J = 8.4, 7.2 Hz, 1H, H-14), 7.42 (t, J = 5.4 Hz, 1 H, H-5), 7.08 (d, J = 7.2, 1 H, H-15), 6.83 (d, J = 8.4, 1 H, H-13), 4.28 (ddd, J = 17.6, 5.4, 2.5 Hz, 1H, H-17), 4.21 (ddd, J = 17.6, 5.4, 2.5 Hz, 1H, H-17), 3.11 (t, J = 2.5 Hz, 1 H, H-19).

¹³C-NMR (151 MHz, DMSO-d₆) 5[ppm] = 165.7 (C-10), 157.1 (C-12), 144.8 (C-11), 138.1 (C-14), 128.7 (C-4/C-5/C-7, C-8), 125.7 (C-4/C-5/C-7, C-8), 125.0 (C-4/C-5/C-7, C-8), 121.3 (q, J = 285.0 Hz, 1C, C-16), 119.5 (C-6/C-9), 113.8 (C-13), 111.6 (C-15), 110.9 (C-6/C-9), 81.9 (C-18), 72.8 (C-19), 72.5 (q, J = 33.8 Hz, 1C, C-1), 30.3 (C-17).

¹⁹F-NMR (564 MHz, DMSO-d₆) 5[ppm] = -75.7 (CF₃).

MS-ESI(+) MicroTof exact mass: m/z = 505.0151 [M+Na⁺], calc, for CigHnC FsNeNaC^ 505.0165. SST096

[00335] Behind additional protective shields fluoro ethyl tosylate (218 mg, 1.0 mmol, 5.0 eq) was reacted with sodium azide (64 mg, 1.0 mmol, 5.0 eq) in DMF (2 ml) at room temperature for 16h. The reaction mixture was filtered and the filtrate was added to a solution of alkyne SST074 (100 mg, 0.20 mmol, 1.0 eq.) in DMF (0.5 ml). A catalyst solution was prepared by vigorously mixing CuSO₄ 5 H₂O (16 mg, 0.1 mmol, 0.5 eq.) and sodium ascorbate (44 mg, 0.22 mmol, 1.1 eq.) in water (1 ml) for 5 min until the solution turned cloudy orange. After addition of the catalyst solution to the reaction mixture, it was stirred at room temperature for 2h. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with NH₃-solution (10%, neutralized with NH₄CI to pH 7-8, 50 ml). The aqueous phase was extracted with ethyl acetate (2x50 ml). The combined organic layers were washed with sat. sodium chloride solution (50 ml), dried over MgSO₄ and the solvent was removed under reduced pressure. The product was purified by flash column chromatography (DCM/MeOH 6-9%) using deactivated silica (stirred over night in DCM/TEA 2%). The product was obtained as a white solid (77 mg, 0.134 mmol, 67 %).

¹H-NMR (599 MHz, DMSO-d₆) 6[ppm] = 9.45 (s, 1 H, H-4), 8.15 (s, 1H, H-19), 7.68 (s, 1H, H-6/H-9), 7.63 (t, J = 5.7 Hz, 1 H, H-5), 7.54 (dd, J = 8.4, 7.2 Hz, 1H, H-14), 7.40 (s, 1H, H-6/H-9), 7.13 (d, J = 7.2 Hz, 1H, H-15), 6.78 (d, J = 8.4 Hz, 1 H, H-13), 4.89 - 4.78 (m, 1 H, H-21), 4.74 - 4.66 (m, 1H, H-20), 4.60 (dd, J = 15.1, 5.7 Hz, 1 H, H-17), 4.49 (dd, J = 15.1, 5.7 Hz, 1H, H-17).

¹³C-NMR (151 MHz, DMSO-d₆) b[ppm] = 177.6 (C-2), 172.9 (C-3), 163.7 (C-10), 157.0 (C-12), 147.0 (C-5), 145.6 (C-11) 145.5 (C-18), 137.9 (C-14), 131.3 (C-4), 123.4 (C-19), 122.8 (C-7/C-8), 122.6 (q, J = 285.0 Hz, 1C, C-16), 120.8 (C-7/C-8), 116.9 (C-6/C-9), 113.2 (C-13), 110.3 (C-15), 110.2 (C-6/C-9), 81.8 (d, J = 168.3 Hz, 1C, C-21), 71.7 (q, J = 31.8 Hz, 1C, C-1), 49.9 (d, J = 19.8 Hz, 1C, C-20), 36.0 (C-17).

¹⁹F-NMR (564 MHz, DMSO-d₆) b[ppm] = -74.1 (CF₃), -222.1 (CH₂F). MS-ESI(+) Orbitrap XL exact mass: m/z = 572.0737 [M+H⁺], calc, for C2iH₁₆Cl2F₄N₄O2H 572.0735.

SST108: 6-Bromo-A/-(6,7-dichloro-2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H-benzo[c/l- imidazo[1,2-a]imidazol-3-yl)hexanamide

[00336] In a flame-dried flask 6-bromohexamide (2.00 g, 10.3 mmol, 1.0 eq.) was suspended in dry DCM (10 mL) and treated dropwise with 3,3,3-trifluoropyruvate (xxx, 1.63 ml, 12.3 mmol, 1.2 eq.) at room temperature. After stirring for 30 min, completion was observed by full solubility. SOCI₂ (1.45 ml, 20.6 mmol, 2.0 eq.) was added under ice bath cooling and the reaction mixture was stirred at room temperature for 48 h. It was concentrated under reduced pressure, using high vacuum and liquid nitrogen cooling traps. The residue was suspended in dry DCM (10 mL) and treated with a solution of 2-amino-5,6- dichlorobenzimidazole hydrochloride (2.456 g, 10.3 mmol, 1.0 eq.) and dry TEA (4.3 mL, 30.9 mmol, 3 eq.) in dry DCM (10 mL) under ice bath cooling. The reaction mixture was stirred at room temperature for 30 min, diluted with sat. sodium chloride (50 ml) and neutralized to pH 6 with 0.1 M HCI. The aqueous phase was extracted with ethyl acetate (3x 50ml), the combined organic layers were dried over MgSO₄ and the solvent was removed under reduced pressure. The product was obtained by flash column chromatography (DCM/MeOH 4-6%) as a white solid (2.35 g, 4.68 mmol, 46 %).

¹H-NMR (599 MHz, DMSO-d₆) 6[ppm] = 10.32 (s, 1 H, H-4), 7.83 (s, 1 H, H-6/H-9), 7.42 (s, 1 H, H-6/H-9), 3.36 (t, J = 6.7 Hz, 2H, H-11), 2.33 - 2.22 (m, 2H, H-15), 1.71 - 1.63 (m, 2H, H-14), 1.42 - 1.34 (m, 2H, H-12), 1.21 - 1.08 (m, 2H, H-13).

¹³C-NMR (151 MHz, DMSO-d₆) 6[ppm] = 174.1 (C-10), 128.7 (C-4/C-5/C-7/C-8), 125.5 (C-4/C-5/C-7/C-8), 124.7 (C-4/C-5/C-7/C-8), 120.9 (q, J = 285.0 Hz, 1C, C-16), 119.9 (C-6/C-9), 110.2 (C-6/C-9), 72.2 (q, J = 31.9 Hz ,C-1) 34.5 (C-11), 33.8 (C-15), 31.7 (C-14), 26.7 (C-13), 23.7 (C-12). ¹⁹F-NMR (564 MHz, DMSO-d₆) b[ppm] = -75.8 (CF₃).

MS-ESI(+) Orbitrap XL exact mass: m/z = 522.9524 [M+Na⁺], calc, for CieH^C FsN^Na 522.9522.

Melting point: 176 °C melting, 210 °C decomposition (toluene).

R_f (CHCh/MeOH 10 %): 0.52.

SST110

[00337] Reaction, purification and storage of all fluorescent compounds were performed protected from direct light. Alkyine SST093 (1.00 mg, 2.07 pmol, 1.0 eq.) was reacted in DMF (500 pL) with sulfo-Cyanine5.5-azide (2.28 mg, 2.07 pmol, 1.0 eq., LUMIPROBE), Cu"(TBTA)SO₄-Solution (103 pL, 1.03 pmol, 0.5 eq., 10 mM in 55% DMSO in water) and (L-) sodium ascorbate (0.49 mg, 2.48 pmol, 1.2 eq.) for 16h at room temperature in a black Eppendorf tube. The reaction mixture was directly purified via semipreparative RP- HPLC in 5-8 separate runs (column: Knauer Eurosphere 100-5 C18 250 x 8 mm, mobile phase: Milli-Q® water (0.1 % TFA)/acetonitrile (0.1 % TFA) , flow: 5.5 mL/min, gradient see below)). The combined product fractions were lyophilized, after removing organic solvent via roto-evaporation. The product was obtained as a dark-blue solid (0.37 mg, 0.23 pmol, 11 %). For further in vivo and in vitro experiments the compound was stored in an aqueous stock solution at -30°C protected from light. Structure and purity of the compound were confirmed by HR-ESI(-)-MS and RP-HPLC.

Semipreparative HPLC gradient: gradient 90 % water (0.1 % TFA) to 60 % water (0.1 % TFA) within 14 min, isocratic 60 % water (0.1 % TFA) for 1 min, gradient to 40 % water (0.1 % TFA) within 1 min, isocratic 40 % water (0.1 % TFA) for 1 min, gradient to 90 % water (0.1 % TFA) within 3 min.

MS-ESI(-) VelosPro exact mass: mlz = 365.55360 [M-K₄-H]⁴', calc, for C62H5₅Cl2F3N₁₂Oi5 365.55359, 487.74020 [M-K₄]³’, calc, for CezHseChFsN^Ois 365.55359.

[00338] Bromide SST108 (500 mg, 0.996 mmol, 1.0 eq.) and /V,/V-dimethyl propargylamine (415 mg, 4.99 mmol, 5.0 eq.) were dissolved in dry THF (1 ml) and reacted for 30 min at 75 °C at 150 W. The resulting sticky oil was completely dissolved in MeOH. The crude product was precipitated by dropwise addition to ice cold to Et₂O. The product was obtained by silica column filtration (DCM/MeOH 9:1 to MeOH) and reverse phase column chromatograph (H₂O/MeOH 40 % to 70 % over 10 column volumes) as a white solid (210 mg, 0.36 mmol, 36 %).

¹H-NMR (600 MHz, DMSO-d₆) b[ppm] = 9.24 (s, 1H, H-4), 7.33 (s, 1 H, H-6/H-9), 7.17 (s, 1 H, H-6/H-9), 4.34 (s, 2H, H-17), 4.01 (s, 1 H, H-19), 3.29 - 3.19 (m, 2H, H-15), 3.05 (s, 6H, H-20, H-21), 2.23 (t, J = 7.1 Hz, 2H, H-11), 1.68 - 1.54 (m, 2H, H-14), 1.48 - 1.41 (m, 2H, H-12), 1.23 - 1.09 (m, 2H, H-13).

¹³C-NMR (151 MHz, DMSO-d₆) b[ppm] = 177.9 (C-2), 173.5 (C-3), 172.2 (C-10), 147.3 (C-5), 130.9 (C-4), 122.8 (q, J = 285.0 Hz, 1C, C-16), 122.3 (C-7/C-8), 120.1 (C-7/C-8), 116.6 (C-6/C-9), 108.2 (C-6/C-9), 82.9 (C-18), 72.4 (C-19), 72.1 (q, J = 32.0 Hz, 1C, C-1), 63.1 (C-15), 53.1 (C-17), 49.8 (C-20/C-21), 49.8 (C-20/C-21), 34.2 (C-11), 25.1 (C-13), 24.2 (C-12), 21.5 (C-14).

¹⁹F-NMR (564 MHz, DMSO-d₆) b[ppm] = -74.7 (CF₃). MS-ESI(+) Velos Pro exact mass: m/z = 504.1178 [M-Br‘], calc, for C₂IH₂₃CI₂F₃N₅O₂ 504.1175, m!z = 526.0994 [M-Br’-H’+Na⁺], calc, for C₂iH₂₂CI₂F₃N₅NaO₂ 526.0995.

[00339] Behind additional protective shields fluoro ethyl tosylate (371 mg, 1.7 mmol, 5.0 eq) was reacted with sodium azide (110 mg, 1.7 mmol, 5.0 eq) in DMF (3 ml) at room temperature for 16h. The reaction mixture was filtered and the filtrate was added to a solution of alkyne (SST117, 200 mg, 0.34 mmol, 1.0 eq.) in DMF (1 ml). A catalyst solution was prepared by vigorously mixing CuSO₄ 5 H₂O (42 mg, 0.17 mmol, 0.5 eq.) and sodium ascorbate (67 mg, 0.34 mmol, 1.0 eq.) in water (2 ml) for 5 min until the solution turned cloudy orange. After addition of the catalyst solution to the reaction mixture, it was stirred at room temperature for 16h. The solvent was removed under reduced pressure. The crude product was obtained by filtration over a short silica plug (DCM -> DCM/MeOH 1 :1 -> MeOH). Applying automated reverse phase column chromatography (H₂O/MeOH 40 % to 70 % over 10 column volumes) and lyophilization, tracer reference compound SST120 was obtained as a white solid (70 mg, 0.1 mmol, 30%).

¹H NMR (600 MHz, DMSO-d₆) b[ppm] = 9.34 (s, 1 H, H-4), 8.52 (s, 1H, H-19), 7.34 (s, 1H, H-6/H-9), 7.18 (s, 1 H, H-6/H-9), 4.90 (t, J = 4.6 Hz, 1 H, H-21), 4.85 - 4.81 (m, 2H, H-20, H-21), 4.80 - 4.77 (m, 1 H, H-20), 4.66 (s, 2H, H-17), 3.15 - 3.09 (m, 2H, H-15), 3.00 (s, 6H, H-22, H-23), 2.29 - 2.21 (m, 2H, H-11), 1.78 - 1.66 (m, 2H, H-14), 1.48 - 1.41 (m, 2H, H-12), 1.20 - 1.07 (m, 2H, H-13).

¹³C NMR (151 MHz, DMSO-d₆) b[ppm] = 177.9 (C-2), 173.5 (C-3), 172.3 (C-10), 147.3 (C-5), 135.5 (C-18), 130.9 (C-4), 128.7 (C-19), 122.7 (q, J = 284.9 Hz, C-16), 122.3 (C-7/C-8), 120.2 (C-7/C-8), 116.6 (C-6/C-9), 108.2 (C-6/C-9), 81.8 (d, J = 168.3 Hz, C-21), 72.1 (q, J = 30.9 Hz, C-1), 62.8 (C-15), 57.0 (C-17), 50.3 (d, J = 19.6 Hz, C-20), 49.6 (C-22/C-23), 49.6 (C-22/C-23), 34.2 (C-11), 25.1 (C-13), 24.2 (C-12), 21.4 (C-14). ¹⁹F-NMR (564 MHz, DMSO-d₆) b[ppm] = -74.8 (CF₃), -222.0 (CH₂F).

MS-ESI(+) Orbitrap XL exact mass: m/z = 593.1571 [M-Br‘], calc, for C23H₂7Cl2F₄N₈O2⁺

593.1565, m!z = 615.1387 [M-Br’-H’+Na⁺], calc, for C₂3H26CI₂F₄N₈NaO2 615.1384.

SST175

[00340] Reaction, purification and storage of all fluorescent compounds were performed protected from direct light. Alkyine SST093 (3.60 mg, 7.45 pmol, 1.2 eq.) was reacted in DMF (470 pL) with BODIPY-TMR-azide (3.0 mg, 6.21 pmol, 1.0 eq., LUMIPROBE), Cu"(TBTA)SO₄-Solution (622 pL, 6.21 pmol, 1.0 eq., 10 mM in 55% DMSO in water) and (L-) sodium ascorbate (1.50 mg, 7.45 pmol, 1.2 eq.) for 36h at room temperature in a black Eppendorf tube. The reaction mixture was directly purified via semipreparative RP-HPLC in 10-12 separate runs (column: Knauer Eurosphere 100-5 C18 250 x 8 mm, mobile phase: Milli-Q® water / acetonitrile, flow: 5.5 mL/min, gradient see below). The combined product fractions were lyophilized, after removing organic solvent via roto-evaporation. The product was obtained as a reddish/pink solid (1.14 mg, 1.15 pmol, 15 %). For further in vivo and in vitro experiments the compound was stored in an DMSO stock solution at -30°C protected from light. Structure and purity of the compound were confirmed by HR-ESI(-)-MS and RP- HPLC.

Semipreparative HPLC gradient: gradient 60 % water to 10 % water within 14 min, isocratic 10 % water for 4 min, gradient to 60 % water within 2 min. SST176

[00341] Reaction, purification and storage of all fluorescent compounds were performed protected from direct light. Alkyine SST093 (3.60 mg, 7.45 pmol, 1.2 eq.) was reacted in DMF (470 pL) with BODIPY-TR-azide (3.14 mg, 6.21 pmol, 1.0 eq., LUMIPROBE), Cu"(TBTA)SO₄-Solution (622 pL, 6.21 pmol, 1.0 eq., 10 mM in 55% DMSO in water) and (L-) sodium ascorbate (1.50 mg, 7.45 pmol, 1.2 eq.) for 36h at room temperature in a black Eppendorf tube. The reaction mixture was directly purified via semipreparative RP-HPLC in 10-12 separate runs (column: Knauer Eurosphere 100-5 C18 250 x 8 mm, mobile phase: Milli-Q® water / acetonitrile, flow: 5.5 mL/min, gradient see below). The combined product fractions were lyophilized, after removing organic solvent via roto-evaporation. The product was obtained as a reddish/pink solid (1.25 mg, 1.30 pmol, 17 %). For further in vivo and in vitro experiments the compound was stored in an DMSO stock solution at -30°C protected from light. Structure and purity of the compound were confirmed by HR-ESI(-)-MS and RP- HPLC.

Semipreparative HPLC gradient: gradient 60 % water to 10 % water within 14 min, isocratic 10 % water for 4 min, gradient to 60 % water within 2 min.

SST177

[00342] Reaction, purification and storage of all fluorescent compounds were performed protected from direct light. Alkyine SST093 (3.60 mg, 7.45 pmol, 1.2 eq.) was reacted in DMF (470 pL) with 6-FAM-azide (3.41 mg, 6.21 pmol, 1.0 eq., CARL-ROTH), Cu"(TBTA)SO₄-Solution (622 pL, 6.21 pmol, 1.0 eq., 10 mM in 55% DMSO in water) and (L-) sodium ascorbate (1.50 mg, 7.45 pmol, 1.2 eq.) for 48h at room temperature in a black Eppendorf tube. The reaction mixture was directly purified via semipreparative RP-HPLC in 5-8 separate runs (column: Knauer Eurosphere 100-5 C18 250 x 8 mm, mobile phase: MilliCi® water / acetonitrile, flow: 5.5 mL/min, gradient see below). The combined product fractions were lyophilized, after removing organic solvent via roto-evaporation. The product was obtained as a light green solid (1.97 mg, 2.09 pmol, 33.6 %). For further in vivo and in vitro experiments the compound was stored in an DMSO stock solution or solid at -30°C protected from light. Structure and purity of the compound were confirmed by HR-ESI(-)-MS and RP-HPLC.

Semipreparative HPLC gradient: gradient 80 % water to 20 % water within 10 min, isocratic 20 % water for 3 min, gradient to 80 % water within 2 min.

MS-ESI(-) Orbitrap Velos Pro exact mass: m/z = 939.14262 [M-H]’, calc. for C₄3H28Cl2F3N₁₀O₈-: 939.14262. SST189: 6-Azido-A/-(6,7-dichloro-2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H- benzo[c/]imidazo[1,2-a]imidazol-3-yl)hexanamide

[00343] The reaction was performed behind an additional protection shield. Bromide SST108 (200 mg, 398 pmol, 1.0 eq.) was reacted in ACN/H₂O (4:1 , 5 mL) with sodium azide (78 mg, 1.19 mmol, 3.0 eq.) and catalytic amounts of potassium iodide (6.6 mg, 39.8 pmol, 0.1 eq.) at 80 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with saturated NaCI solution (50 mL) and extracted with ethyl acetate (3x 50 mL). The combined organic layers were dried over MgSO₄ and the solvent was removed under reduced pressure. The product was obtained by solid phase extraction over a short silica plug, eluting with DCM/MeOH 5 % as a white solid (150 mg, 323 pmol, 81 %).

¹H NMR (600 MHz, DMSO-d₆): 5 [ppm] = 10.30 (s, 1 H, NH, H-4), 7.83 (s, 1 H, H-6/H-9), 7.41 (s, 1H, H-9/H-6), 3.16 (td, J = 7.0, 1.6 Hz, 2H, H-11), 2.32 - 2.22 (m, 2H, H-15), 1.43 - 1.34 (m, 4H, H-12, H-14), 1.11 - 1.01 (m, 2H, H-13).

¹³C NMR (151 MHz, DMSO-d₆): 6 [ppm] = 174.1 (C-10), 128.7 (C-5/C-4), 125.4 (C-4/C-5), 124.6 (C-7, C-8), 121.3 (CF₃), 119.8 (C-6/C-9), 110.2 (C-9/C-6), 72.2 (C-1), 50.4 (C-11), 33.8 (C-15), 27.8 (C-12), 25.3 (C-13), 24.1 (C-14).

¹⁹F-NMR (564 MHz, DMSO-d₆): 5 [ppm] = -75.8 (CF₃).

MS-ESI(-) Orbitrap XL exact mass: m/z = 462.04571 [M-H]', calc, for Ci6H₁₃CI₂F₃N₇O2 = 462.04277.

Melting point: 187 °C, 210 °C (decomposition, DCM/MeOH).

R_f (CH/EA 1 :1): 0.36; R_f (CHCI₃/MeOH 10 %): 0.44. SST191 : 6-Amino-A/-(6,7-dichloro-2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H- benzo[c/]imidazo[1,2-a]imidazol-3-yl)hexanamide

[00344] Azide SST189 (50.0 mg, 108 pmol, 1.0 eq.) was reduced with Pd/C (catalytic amounts) under H₂-atmosphere (1 bar) in MeOH (2 mL). The reaction mixture was vigorously stirred for 16 h until the corresponding ammonium hydrochloride was formed by addition of HCI (4M in dioxane, 100 pL). The crude product was precipitated with Et₂O (5 mL) and solvents were removed under reduced pressure. The product was purified by means of semipreparative RP-HPLC at R_t = 6.2 min in separate 15 runs (column: Knauer Eurosphere 100-5 C18 250 x 8 mm, mobile phase: Milli-Q® H₂O / ACN, flow: 5.5 mL/min, gradient see below). The combined product fractions were lyophilized, after removing organic solvent under reduced pressure, which yielded SST191 as a white powder (6 mg, 12.6 pmol, 12 %). NMR revealed that after HPLC purification with 0.1 % TFA in the eluent at least partially chloride was exchanged for TFA as counter-anion.

Semipreparative HPLC gradient: gradient 90 % H₂O to 30 % H₂O within 10 min, isocratic 30 % H₂O for 3 min, gradient to 90 % H₂O within 2 min.

¹H-NMR (500 MHz, DMSO-d₆): 5 [ppm] = 10.38 (s, 1 H, H-4), 7.85 (s, 1 H, H-6/H-9), 7.62 (s, 3H, NH₃X), 7.44 (s, 1H, H-6/H-9), 2.72 - 2.60 (m, 2H, H-15), 2.28 (td, J = 7.4, 1.5 Hz, 2H, H- 11), 1.47 - 1.39 (m, 2H, H-14), 1.40 - 1.33 (m, 2H, H-12), 1.19 - 1.05 (m, J = 7.6, 7.1 Hz, 2H, H-13).

¹³C-NMR (126 MHz, DMSO-d₆): 5 [ppm] = 174.0 (2C, C-2, C-10), 157.9 (TFA), 125.4 (C-4/C- 5/C-7/C-8), 124.6 (C-4/C-5/C-7/C-8), 121.2 (C-16 (CF₃)), 117.0 (C-6/C-9), 110.2 (C-6/C-9), 109.5 (TFA), 72.2 (C-1), 38.5 (C-15), 33.8 (C-11), 26.6 (C-14), 25.0 (C-13), 24.0 (C-12). Not all carbon atoms were detected, including quarternary C-3 and two peaks of C-4/C-5/C-7/C- 8.

¹⁹F-NMR (470 MHz, DMSO-d₆): 5 [ppm] = -78.8 (CF₃), -73.8 (TFA). MS-ESI(+) MicroTof exact mass: m/z = 505.0151 [M+Na]⁺, calc, for CigHnC FsNeNaC^ = 505.0165.

Melting point: 198 °C (decomposition, lyophilized from ACN/H₂O).

R_f (CHCh/MeOH 10 %): 0.37.

AF488-SST193: Bis(triethylammonium) 2-(6-amino-3-iminio-4,5-disulfonato-3H- xanthen-9-yl)-5-((6-((6,7-dichloro-2-oxo-3-(trifluoromethyl)-2,3-dihydro-1H- benzo[c/]imidazo[1,2-a]imidazol-3-yl)amino)-6-oxohexyl)carbamoyl)benzoate

[00345] Reaction, purification and storage of all fluorescent compounds were performed protected from direct light. Amine hydrochloride SST191 (1.1 mg, 2.11 pmol, 1.5 eq.) was reacted with AF488-NHS (1.17 mg, 1.40 pmol, 1.0 eq., Lumiprobe) in DMF (500 pL) in the presence of triethylamine (1 pL, 4.20 pmol, 3 eq.). The reaction mixture was shaken in a black reaction tube for 16 h and directly purified by means of semipreparative RP-HPLC in 5-8 separate runs (column: Knauer Eurosphere 100-5 C18 250 x 8 mm, mobile phase: Milli-Q® H₂O / ACN, flow: 5.5 mL/min, gradient see below). The product fractions were combined and the organic solvent was evaporated under reduced pressure. Subsequently, the product was obtained by lyophilization as a light green solid (0.51 mg, 0.441 pmol, 32 %). For further experiments the compound was stored in a DMSO stock solution or solid at -30°C protected from light. The structure of the compound was confirmed by HR-ESI(-)-MS and purity was determined as 97.5 % using semipreparative RP-HPLC with the separation gradient (Chromatogram is given at the end of this subchapter 4.5.2).

Semipreparative HPLC gradient: gradient 95 % H₂O to 40 % H₂O within 10 min, gradient to 10 % H₂O over 3 min, isocratic 10 % H₂O for 2 min, gradient to 95 % H₂O within 2 min, isocratic 95 % H₂O for 1 min. MS-ESI(-) Orbitrap Velos Pro exact mass: mlz = 475.52091 [M-2Et₃H]²', calc. for

C37H26 I2F3N7O12²" = 475.52105 and 316.67820 [M-2Et₃H-H]³', calc, for C37H25CI2F3N7O12 = 316.67827.

[00346] It will be clear that the invention may be practiced otherwise than as particularly described in the foregoing description and examples. Numerous modifications and variations of the present invention are possible in light of the above teachings and, therefore, are within the scope of the appended claims.

Claims

CLAIMS What is claimed is:

1. A compound of formula (I)

or a salt, isomer, or tautomer thereof; wherein

R_A, R_B, and R_c are each independently selected from H, halogen, cyano, RTO, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by RTO, R₂C(O), R₃S, R₄S(O)₂, R₅OC(O), (R₆ON)C(R₇), R₈R₉NC(O), R10R11N, RI₂S(O)₂NR₁₃,

RI₄S(O)₂NR₁₅C(O), phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6- membered heterocyclyl optionally substituted by one or more moieties R₁₆; or one of R_A and R_c together with R_B forms a divalent group -(CH₂)_m- wherein m is an integer of from 3 to 5, and the other one of R_A and R_c is selected from H, halogen, cyano, R1O, C1-C6 alkyl optionally substituted by RTO, C3-C6 cycloalkyl optionally substituted by R1O, R₂C(O), R₃S, R₄S(O)₂, R₅OC(O), (R₆ON)C(R₇), R₈R₉NC(O), R10R11N, RI₂S(O)₂NR₁₃, RI₄S(O)₂NR₁₅C(O), phenyl optionally substituted by one or more moieties R₁₆, and 5- or 6- membered heterocyclyl optionally substituted by one or more moieties R₁₆; each R₁₆ is independently selected from halogen, cyano, nitro, RI₇O, C1-C6 alkyl optionally substituted by RI₇O, C3-C6 cycloalkyl optionally substituted by RI₇O, RI₈C(O), RI₉S, R₂₀S(O)₂, R₂IOC(O), (R₂2ON)C(R₂₃), R₂₄R₂₈NC(O), R26R27N, R₂₈S(O)₂NR₂₉, and R₃OS(0)₂NR₃₁C(0); each one of RTR₁₅ and R17-R31 is independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl;

L is a linker; and

R_L is a label.

2. The compound according to claim 1 , wherein R_A is H, R_B is halogen, and R_c is halogen.

3. The compound according to claim 2, wherein R_A is H, R_B is Cl, and R_c is Cl.

4. The compound according to any one of the preceding claims,

(a) wherein the linker L is (L1):

wherein # indicates the attachment point to the label R_L;

(b) wherein the linker L is (L2):

wherein o is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 1 or 2, even more preferably o is 1 ; and

# indicates the attachment point to the label R_L;

(c) wherein the linker L is (L3):

wherein: o is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 1 or 2, even more preferably o is 1; p is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably p is 2 or 3, even more preferably p is 2; and

# indicates the attachment point to the label R_L:

(d) wherein the linker L is (L4):

wherein

X“ is an anion; preferably X“ is a halogenide, more preferably bromide (Br“); o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5; p is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably p is 1 or 2, even more preferably p is 1; q is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably q is 2 or 3, even more preferably q is 2; and

# indicates the attachment point to the label R_L;

(e) wherein the linker L is (L5):

(L5), wherein

R200 is H or C1-C6 alkyl; preferably R₂oo is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl; o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5; and

# indicates the attachment point to the label R_L;

(f) wherein the linker L is (L6):

(L6), wherein

R200 is H or C1-C6 alkyl; preferably R₂oo is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl; R_3OO is H or C1-C6 alkyl; preferably R₃₀₀ is C1-C6 alkyl, more preferably C1-C3 alkyl, still more preferably methyl or ethyl, even more preferably methyl;

# indicates the attachment point to the label R_L;

(g) wherein the linker L is (L7):

(L7), wherein

# indicates the attachment point to the label R_L:

(h) wherein the linker L is (L8):

wherein

# indicates the attachment point to R_L;

(i) wherein the linker L is (L9):

# indicates the attachment point to the label R_L;

(j) wherein the linker L is (L10):

# indicates the attachment point to the label R_L;

(k) wherein the linker L is (L11):

(L11), wherein o is an integer ranging from 1 to 6, preferably from 1 to 4, more preferably from 1 to 3, still more preferably o is 1 or 2, even more preferably o is 1; p is an integer ranging from 1 to 10, preferably from 2 to 8, more preferably from 2 to 6, still more preferably p is 2 or 4, even more preferably p is 3; and

# indicates the attachment point to the label R_L; or

(I) wherein the linker L is (L12):

R₂OO is H or C1-C6 alkyl; preferably R₂oo is H; and # indicates the attachment point to the label R_L.

5. The compound according to any one of the preceding claims, wherein the label R_L is any one of a single photon emission tomography (SPECT) label, a positron emission tomography (PET) label, an optical imaging label, a magnetic resonance imaging (MRI) label, an ultrasound label or a photoacoustic imaging label.

6. The compound according to claim 5, wherein the label R_L comprises a group selected from the group consisting of ¹⁸F, ⁶⁸Ga, ¹²³l, ¹²⁴l, ¹²⁵l, "^mTc, ¹¹¹ln, ⁶⁷Ga, ⁶⁴Cu, ¹¹C, ⁸⁹Zr, fluorescent dyes, phosphorescent dyes and photoacoustic absorbers.

7. The compound according to claim 5 or 6, wherein the label R_L is a single photon emission tomography (SPECT) label or a positron emission tomography (PET) label.

8. The compound according to claim 7, wherein the label is ¹⁸F.

9. The compound according to claim 8, wherein the compound is selected from the group consisting of

10. The compound according to claim 7, wherein the label R_L is selected from the group consisting of:

wherein * indicates the attachment point to the linker L.

11. The compound according to claim 5 or 6, wherein the label R_L is a single photon emission tomography (SPECT) label.

12. The compound according to claim 11 , wherein the label R_L is:

wherein * indicates the attachment point to the linker L.

13. The compound according to claim 5 or 6, wherein the label R_L comprises a photoacoustic imaging label.

14. The compound according to claim 13, wherein the photoacoustic imaging label is a phthalocyanine, a naphthalocyanine, or a polymethine dye.

15. The compound according to claim 5 or 6, wherein the label R_L comprises an optical imaging label.

16. The compound according to claim 15, wherein the label is a dye.

17. The compound according to claim 16, wherein the dye is selected from the group consisting of fluorescein isothiocyanate (FITC), 1 ,1'-dioctadecyl-3,3,3',3'-tetramethyl indotricarbocyanine iodide (DiR), a coumarin dye, a rhodamine dye, a carbopyronin dye, an oxazine dye, a fluorescein dye, a cyanine dye, a boron-dipyrromethene (BODIPY) dye, a squaraine dye, and a squaraine rotaxane dye.

18. The compound according to any one of claims 15 to 17, wherein the label R_L is selected from the group consisting of:

wherein * indicates the attachment point to the linker L.

19. The compound according to claim 18, wherein the compound is selected from the group consisting of:

or a salt, isomer, or tautomer thereof.

20. A diagnostic composition comprising a compound according to any one of claims 1 to 19 and a pharmaceutically or diagnostically acceptable excipient.

21. The compound according to any one of claims 1 to 19 for use in a method of diagnosis.

22. The compound for use according to claim 21 , wherein the diagnosis is diagnosis of an inflammatory disease in a subject.

23. The compound for use according to any one of claims 21 to 22, wherein the inflammatory disease comprises dermatitis, atherosclerosis, psoriasis, autoimmune diseases, arthritis, allergies, cardiovascular processes, local and systemic infections, neuroinflammatory diseases, acute lung injury (ALI) and tumors.

24. The compound for use according to any one of claims 21 to 23, wherein the method is an in vivo non-invasive molecular imaging method.

25. The compound for use according to claim 24, wherein the method is any one of single photon emission tomography (SPECT), positron emission tomography (PET), optical imaging, magnetic resonance imaging (MRI), ultrasound or photoacoustic imaging.

26. A method of diagnosing an inflammatory disease in a subject, comprising: a) administering to said subject a compound according to any one of claims 1 to 19, b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data.

27. A non-invasive method of detecting or imaging accumulation of S100A9 in the body of a subject to whom a compound of any one of claims 1 to 19 has been pre-delivered, comprising: a) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, b) comparing the imaging data received in step a) to reference imaging data.

28. Use of a compound according to any one of claims 1 to 19 for the preparation of a diagnostic composition for diagnosing an inflammatory disease associated with phagocyte and/or epithelial cell activation in a subject.

29. A method for evaluating whether a subject may be at risk of developing an inflammatory disease associated with phagocyte and/or epithelial cell activation, the method comprising: a) administering to said subject a compound according to any one of claims 1 to 19, b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data.

30. A method of monitoring or evaluating the progression of an inflammatory disease associated with phagocyte and/or epithelial cell activation in a patient, the method comprising: a) administering to said subject a compound according to any one of claims 1 to 19, b) detecting the administered compound using an in vivo non-invasive molecular imaging technique, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data obtained from said patient at an earlier date, wherein the result of the comparison of c) provides an evaluation of the progression of the inflammatory disease associated with phagocyte and/or epithelial cell activation in said patient.

31. A method of imaging an inflammatory disease in a subject, comprising: a) administering to said subject a compound according to any one of claims 1 to 19, b) detecting the administered compound using an in vivo non-invasive molecular imaging method, thereby collecting imaging data.

32. An in vitro method of diagnosing an inflammatory disease in a subject to whom a compound according to any one of claims 1 to 19 has been pre-delivered, comprising: a) analyzing a sample taken from said subject, b) detecting said pre-delivered compound using a non-invasive molecular imaging method, thereby collecting imaging data, c) comparing the imaging data received in step b) to reference imaging data.

33. A process for the preparation of a compound of the formula (I*) or its salts, isomers, tautomers or solvates thereof, comprising reacting a compound of the formula (X*)

and a compound of the formula (XII)

to give a compound of the formula (I*)

L* is a linker capable of forming a covalent attachment to a label R_L; or

R_A, R_B and R_c are as defined in any one of claims 1 to 19.

34. The process according to claim 33, further comprising reacting the compound of formula (I*) with a label or another part of a linker bound to a label to give a compound of formula (I):

(I), wherein R_A, R_B, Rc, L and R_L are as defined in any one of claims 1 to 19.

35. A process for the preparation of a compound of the formula (I) or its salts, isomers, tautomers or solvates thereof, as claimed in one or more of claims 1 to 19, comprising reacting a compound of the formula (X)

with a compound of the formula (XI)

and a compound of the formula (XII)

to give a compound of the formula (I)

RA, B, RC, L and R_L are as defined in any one of claims 1 to 19.

36. The process according to any one of claims 33 to 35, wherein the compound of the formula (X) or the compound of the formula (X*) is reacted with the compound of formula (XI) in presence of a solvent.

37. The process according to claim 36, wherein the solvent is dichloromethane, tetrahydrofuran or a mixture thereof, preferably wherein the solvent is dichloromethane.

38. The process according to claim 36 or 37, wherein the process, after reacting the compound of the formula (X) or the compound of the formula (X*) with the compound of formula (XI), further comprises reacting with SOCI₂, SOBr₂ or oxalyl chloride, preferably SOCI₂ or SOBr₂, more preferably SOCI₂; optionally wherein the solvent is removed before adding the SOCI₂, SOBr₂ or oxalyl chloride.

39. The process according to claim 38, wherein the process, after reacting with SOCI₂, SOBr₂ or oxalyl chloride, further comprises reacting with the compound of the formula (XII) in presence of a solvent and an organic base to give the compound of the formula (I*) or the compound of the formula (I); optionally wherein the SOCI₂, SOBr₂, oxalyl chloride and/or solvent is removed before adding the compound of formula (XII).

40. The process according to claim 39, wherein the solvent is dichloromethane, tetrahydrofuran or a mixture thereof, preferably wherein the solvent is tetra hydrofuran.

41 . The process according to claim 39 or 40, wherein the organic base is triethylamine or pyridine, preferably triethylamine.

42. The process according to any one of claims 33 to 41 , wherein the process is carried out as one-pot process.

43. The process according to any one of claims 33 to 42, wherein the compound of formula

preferably

Cl or Br, more preferably Br; and o is an integer ranging from 1 to 15, preferably from 2 to 10, more preferably from 3 to 8, still more preferably from 4 to 6, even more preferably o is 5.

44. The process according to any one of claims 33 to 43, wherein the compound of formula (

45. The process according to any one of claims 33 to 44, wherein the compound of formula (