RU2819907C2 - Imaging means for radiolabeled exogenous and endogenous albumin - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention relates to albumin-binding radioactive metal complexes, specifically to a metal complex of Formula (I) or a pharmaceutically acceptable salt thereof. In Formula (I): M is ¹¹¹In³⁺; X is absent; R¹ is C₁-C₁₈ alkyl; Y is absent or selected from -NH-C(O)- and -C(O)-NH-; R² is C₁-C₁₈ alkyl; and TBG is a maleimide group. Also disclosed is a pharmaceutical composition, methods for diagnosing and treating cancer, a method for assessing sensitivity of a subject with cancer to an albumin-binding chemotherapeutic agent, method for assessing cancer susceptibility in a subject to an albumin-binding chemotherapeutic agent, method for assessing the ability of an albumin-binding chemotherapeutic agent to treat cancer in a subject, a diagnostic kit, use of said metal complex.

EFFECT: disclosed metal complexes are used as imaging agents for radiolabeled endogenous and exogenous albumin in position cysteine-34, which in combination with adequate imaging techniques enable to detect albumin in the body and determine the degree of albumin absorption and its distribution in pathological areas of the patient.

32 cl, 12 dwg, 5 ex

Description

CROSS REFERENCE TO PREVIOUS APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 62/702,081, filed July 23, 2018, which is incorporated herein by reference in its entirety.

BACKGROUND OF THE ART

[0002]Delivery drug in oncology has the potential to expand the narrow therapeutic index of cytotoxic agents. Suitable macromolecular carriers include antibodies, synthetic polymers and Withwhey proteins (F. Kratz et al. (2008): ChemMedChem, 3:20-53).

[0003] A promising approach is to develop dosage forms of cytotoxic agents that, when administered, covalently bind to circulating serum albumin as a macromolecular carrier. Albumin or its drug conjugate exhibits a significantly longer half-life (up to 19 days) in the systemic circulation. This is due to 1) increased permeability of the vessel walls of malignant, infected or inflamed tissue for macromolecules in combination with a violation of the lymphatic drainage system; and 2) expression of albumin-binding proteins on the tumor endothelium and within the tumor interstitium, then the drug-albumin conjugate transports the therapeutically effective substance to the target site, where the cytotoxic agent is released via a pH-dependent or enzymatic pathway (F. Kratz (2008): J. Control. Release, 132:171-183, F. Kratz, U. Beyer (1998): Drug Delivery, 5: 281-299).

[0004] The macromolecular form of the drug targets the cysteine-34 position of albumin, which is located in subdomain IA of human serum albumin (HSA). This cysteine residue is highly conserved in all mammalian species studied, with the exception of salmonid albumin (DC Carter, JX Ho, (1994): Adv. Protein. Chem. 45: 153-203; T. Jr. Peters (1985): Adv. Protein Chem. 37:161-245).

[0005] The free HS group of cysteine-34 is an atypical feature of an extracellular protein. X-ray diffraction analysis of the defatted protein structure demonstrates that cysteine-34 is located in a recess approximately 10-12 Å to the protein surface (pdb-entry 1ao6, Crystal structure of human serum albumin, DOI: 10.2210/pdblA06/pdb; Protein Data Bank at Brookhaven ; version 1.2 (2011-7-13)). When HSA is complexed with long-chain fatty acids, as in the X-ray structure, when five molecules of myristic acid are bound, the cavity remains open for interaction with the HS group of cysteine-34 (pdb-entry 1bj5, Human serum albumin complexed with myristic acid, DOI: 10.2210 /pdblBJ5/pdb; Protein Data Bank at Brookhaven; version 1.2 (2011-7-13)).

[0006] In the bloodstream, albumin is typically complexed with one to three molecules of long-chain fatty acids (DC Carter, JX Ho, (1994): Adv. Protein. Chem. 45:153-203). Approximately 70% of circulating albumin is mercaptoalbumin, containing available cysteine-34, which is not blocked by endogenous sulfhydryl compounds such as cysteine or glutathione (i.e., non-mercaptoalbumins) (M. Sogami et al. (1985): J. Chromatogr. 332:19-27; T. Etoh et al. (1992): J. Chromatogr. 578:292-296;

[0007] Whereas free thiol groups are not found on most circulating whey proteins with the exception of albumin, endogenous protein cysteine-34 is a unique amino acid on the surface of circulating protein (reviewed by F. Kratz (2007): Expert Opin. Investig Drugs 16:855-866).

[0008] In addition, the blood concentration of low molecular weight sulfhydryl compounds in reduced form, such as cysteine, homocysteine, cysteine glycine or glutathione is very low, on the order of 0.15-12 μM (MA Mansoor, et al. (1992): Anal. Biochemistry 200 :218-229; L. Hagenfeldt, et al. (1978): Clin. Chim. Acta 85:167-173), since they are present either as disulfides or bound at the cysteine-34 position of albumin. Therefore, the free thiol group at the cysteine-34 position of serum albumin is the major contributor to the total thiol content in the blood.

[0009] Finally, the HS group of cysteine-34 of HSA is the most reactive thiol group in human plasma due to the low pK _SH of cysteine -34 in HSA, which is approximately 7.0 compared to 8.5 and 8.9 for cysteine and glutathione , respectively (A. Pedersen, J. Jacobsen, (1980): Eur. J. Biochem. 106:291-295).

[0010] In summary, the HS group of cysteine-34 of HSA is a unique and accessible plasma protein functional group that can be used to covalently link a thiol-reactive drug derivative to circulating albumin after parenteral administration.

[0011] Kratz and co-workers investigated and developed a prodrug therapeutic concept that used endogenous albumin as a drug carrier. In this therapeutic strategy, a prodrug was designed to rapidly and selectively bind the cysteine at position 34 to circulating serum albumin after intravenous administration, thereby forming a macromolecular drug transport form in the blood in situ .

[0012]Demonstrated,What (6-maleimidocaproyl)hydrazone as a doxorubicin derivative (DOXO-EMCH or aldoxorubicin) rapidly and selectively bound to circulating albumin within minutes (F. Kratz et al. (2002): J. Med. Chem. 45:5523-5533) . DOHO-EMCH therapy dramatically increased the efficacy of doxorubicin in preclinical tumor models. Kratz and coworkers have also developed other dosage forms that bind to albumin (reviewed in F. Kratz (2008): J. Controlled Release, 132:171-183).

These dosage forms consist of an antitumor drug, a maleimide group as a thiol-binding functionality, and an enzymatically cleavable peptide linker.

Examples include doxorubicin dosage forms that are cleaved by matrix metalloproteases 2 and 9, cathepsin B, urokinase, or prostate specific antigen (PSA) methotrexate dosage forms that are cleaved by cathepsin B and plasmin, camptozecin dosage forms that are cleaved by cathepsin B, or unidentified proteases. In addition, maleamide derivatives with 5-fluorouracil analogues and platinum(II) complexes have been developed.

[0013] DOXO-EMCH (also called aldoxorubicin) was evaluated in Phase 1-3 clinical trials in several forms of cancer, demonstrating a 3.5-fold increase in maximum tolerated dose (MTD) compared to conventional doxorubicin, a modified pharmacokinetic profile including an increase AUC, small volume of distribution and low clearance compared with doxorubicin, reduced cardiotoxicity, and significant benefits for first- and second-line treatment of soft tissue sarcoma (M. Seetharam, et al. (2018): Future Oncology, Epub ahead of print, Published Online : 5 Jun 2018).

[0014] To achieve more effective and personalized use of albumin-related drugs, there is an unmet clinical need to diagnose patients regarding increased albumin uptake in pathological sites, especially in the tumor and metastatic sites of cancer patients. To date, there are no clinically relevant diagnostic and/or imaging tools that identify and quantify albumin uptake at pathological sites in patients.

[0015] Therefore, the purpose of the present invention is to provide new imaging agents for radiolabeled endogenous and exogenous albumin at the cysteine-34 position, which, in combination with adequate imaging techniques, allow the detection of albumin in the body and the determination of the extent of albumin uptake and distribution in pathological sites of the patient .

[0016] This objective is achieved through the embodiments of the present invention, as presented and characterized in the claims, as well as in the description and examples.

DISCLOSURE OF INVENTION

[0017] The present invention provides imaging agents for endogenous or exogenous albumin labeled at cysteine at position 34 followed by imaging of the isotope, preferably using single photon emission computed tomography (SPECT).

[0018] The present invention relates to imaging agents that include a thiol-linking group, an aliphatic and/or oligoethylene glycol linker containing an optional aromatic functional group, diethylenetriamine pentaacetic acid as a chelating agent, and a radionuclide (e.g.

^lll indium, ⁶⁷ gallium or ^99m technetium).

[0019] In the embodiments presented herein, a metal complex having the structure of Formula (I) or (II) or (III) is disclosed:

their conjugate acids, or their pharmaceutically acceptable salts, or their hydrates; wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺

X is absent or selected from -NH-, and -O-;

R ¹ is absent or or optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl, each optionally independently substituted with -OCH ₂ CH ₂ -;

Y is absent or selected from -O-C(O)-, -C(O)-O-, -NH-C(O)-, -C(O)-NH-, -NH-C(O)-NH-, -O-C(O)-O-, -NH-C(O)-O-, and -O-C(O)-NH-;

R ² is optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl each optionally independently substituted with -OCH ₂ CH ₂ -; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

[0020] In some embodiments, the metal complex has the structure of Formula (I):

Formula (I),

or its conjugate acid base, or a pharmaceutically acceptable salt, or a hydrate thereof;

wherein:

M is ¹¹¹ In ^{3 +} , ⁶⁷ Ga ^3+99m , Tc ⁴⁺ or ^99m Tc ^{3 +} ;

X is absent or selected from -NH-, and -O-;

R ¹ is absent or optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl each optionally independently substituted with -OCH ₂ CH ₂ -;

Y is absent or selected from -O-C(O), -C(O)-O-, -NH-C(O)-, -C(O)-NH-, -NH-C(O)-NH-, - O-C(O)-O-, -NH-C(O)-O-, and -O-C(O)-NH-;

R ² is optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl each optionally independently substituted with -OCH ₂ CH ₂ -; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

[0021] In some embodiments, the metal complex has the structure of Formula (II):

Formula (II),

or its conjugate acid base, or a pharmaceutically acceptable salt, or a hydrate thereof;

wherein

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺ ;

R ¹ is absent or optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl, each optionally independently substituted with -OCH ₂ CH ₂ -

Y is absent or selected from -O-C(O), -C(O)-O-, -NH-C(O)-, -C(O)-NH-, -NH-C(O)- NH-, - O-C(O)-O-, -NH-C(O)-O-, and -O-C(O)-NH-;

R ² is optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl each optionally independently substituted with -OCH ₂ CH ₂ - ; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

[0022] In some embodiments, the metal complex has the structure of Formula (III):

Formula (III),

or its conjugate acid base, or a pharmaceutically acceptable salt, or a hydrate thereof; wherein

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺ ;

R ¹ is absent or optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl each optionally independently substituted with -OCH ₂ CH ₂ -;

Y is absent or selected from -O-C(O)-, -C(O)-O-, -NH-C(O)-, -C(O)-NH-, -NH-C(O)- NH-, -O-C(O)-O-, -NH-C(O)-O-, and -O-C(O)-NH-;

R ² is optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl each optionally independently substituted with -OCH ₂ CH ₂ -; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

[0023] In some embodiments, the metal complex has a structure of Formula (IV), (V) or (VI):

their conjugate acids, or their pharmaceutically acceptable salts, or their hydrates; wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺

m=1 or 2;

n=1-5;

o=1-12; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

[0024] In some embodiments, the metal complex has the structure of Formula (IV):

Formula (IV),

or its conjugate acid, or a pharmaceutically acceptable salt, or a hydrate thereof,

wherein

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ , or ^99m Tc ³⁺

m=1 or 2;

n=1-5;

o=1-12; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

[0025] In some embodiments, the metal complex has the structure of Formula (V):

Formula (V),

or its conjugate acid base, or a pharmaceutically acceptable salt, or a hydrate thereof;

wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺

n=1-5;

o=1-12; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

[0026] In some embodiments, the metal complex has the structure of Formula (VI):

Formula (VI),

or its conjugate acid base, or a pharmaceutically acceptable salt, or a hydrate thereof;

wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺ ;

n=1-5;

o=1-12; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

[0027] In some embodiments, the metal complex has a structure of Formula (VII), (VIII) or (IX):

their conjugate acids, or their pharmaceutically acceptable salts, or their hydrates;

wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺

m=1 or 2;

n=1-5; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

[0028] In some embodiments, the metal complex has the structure of Formula (VII):

Formula (VII),

or its conjugate acid base, or a pharmaceutically acceptable salt, or a hydrate thereof;

wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ , or ^99m Tc ³⁺

m=1 or 2;

n=1-5; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

[0029] In some embodiments, the metal complex has the structure of Formula (VIII):

Formula (VIII),

or its conjugate acid base, or a pharmaceutically acceptable salt, or a hydrate thereof;

wherein:

M is ¹¹¹ In ^{3 +} , ⁶⁷ Ga ^{3 +} , ^99m Tc ^{4 +} , or ^99m Tc ^{3 +} ;

n=1-5; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

[0030] In some embodiments, the metal complex has the structure of Formula (IX):

Formula (IX),

or its conjugate acid base, or a pharmaceutically acceptable salt, or a hydrate thereof;

wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ , or ^99m Tc ³⁺ ;

n=1-5; And

thiol-linking group (TBG) selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and an optionally substituted acetylene group.

[0031] In some embodiments, the metal complex has the structure of Formula (X), (XI), or (XII):

their conjugate acids, or their pharmaceutically acceptable salts, or their hydrates;

wherein:

M is ¹¹¹ In ^{3 +} , ⁶⁷ Ga ^{3 +} , ^99m Tc ^{4 +} , or ^99m Tc ^{3 +} ;

p=1-12; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

[0032] In some embodiments, the metal complex has the structure of Formula (X):

Formula (X),

or its conjugate acid base, or a pharmaceutically acceptable salt, or a hydrate thereof;

wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ , or ^99m Tc ³⁺ ;

p=1-12; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

[0033] In some embodiments, the metal complex has the structure of Formula (XI):

Formula (XI),

or its conjugate acid base, or a pharmaceutically acceptable salt, or a hydrate thereof;

wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ , or ^99m Tc ³⁺ ;

p=1-12; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

[0034] In some embodiments, the metal complex has the structure of Formula (XII):

Formula (XII),

or its conjugate acid base, or a pharmaceutically acceptable salt, or a hydrate thereof; wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺ ;

p=1-12; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

[0035] In some embodiments, TBG is an optionally substituted maleimide group. In some embodiments, the TBG is:

[0036] In some embodiments, M is ¹¹¹ In ³⁺ .

[0037] In some embodiments, the metal complex is selected from:

or their conjugate acids, or pharmaceutically acceptable salts or hydrates thereof.

[0038] In some embodiments, the metal complex is selected from:

or their conjugate acids, or pharmaceutically acceptable salts or hydrates thereof.

[0039] In some embodiments, the metal complex is selected from:

or their conjugate acids, or pharmaceutically acceptable salts or hydrates thereof.

[0040] In some embodiments, the metal complex is selected from:

or their conjugate acids, or pharmaceutically acceptable salts or hydrates thereof.

[0041] In some embodiments, the pharmaceutically acceptable salt countercation is selected from: one or two Na ⁺ , K ⁺ , or NH ₄ ⁺ ; or one Ca ^2+- or Mg ²⁺ .

[0042] In some embodiments, the invention provides a pharmaceutical composition comprising a metal complex as provided herein. In some embodiments, the invention provides a pharmaceutical composition comprising a metal complex as provided herein and a pharmaceutically acceptable carrier.

[0043] In some embodiments, the metal complex is covalently linked to a cysteine-34 thiol group from endogenous or exogenous albumin. In some embodiments, the metal complex is linked to the thiol group of cysteine-34 in vivo. In some embodiments, the metal complex binds to the thiol group of cysteine-34 ex vivo. In some embodiments, the bond of the metal complex to the albumin is covalent. In other embodiments, the bond of the metal complex to the albumin is not covalent.

[0044] In some embodiments, the invention provides a method for diagnosing a disease in a subject, wherein the disease is selected from cancer, viral, autoimmune, acute or chronic inflammatory entities, and diseases caused by bacteria, fungi, or other microorganisms, including administering to the subject a diagnostically effective amount of a metal complex or a pharmaceutical composition disclosed herein, and then subjecting the subject to imaging using SPECT (single photon emission computed tomography). In some embodiments, the disease is cancer.

[0045] In some embodiments, the invention provides a method for diagnosing cancer in a subject, comprising:

administering to a subject a detectable amount of a metal complex or pharmaceutical composition disclosed herein; And

imaging the subject after administration of the metal complex or pharmaceutical composition to detect a signal from the labeled metal complex, wherein detection of the signal from the isotope in the tissue indicates that the tissue is malignant, thereby diagnosing cancer in the subject.

[0046] In some embodiments, the invention provides a method for diagnosing cancer in a subject, comprising:

administering to the subject a detectable amount of a metal complex or pharmaceutical composition disclosed herein; And

imaging the subject after administration of a metal complex or pharmaceutical composition to detect a signal from the labeled metal complex, wherein the presence of a higher cumulative signal from the isotope in the tissue compared to normal tissue of the same type indicates that the tissue is malignant, thereby diagnosing cancer in the subject.

[0047] A method for diagnosing cancer in a subject, comprising:

administering to a subject a metal complex or pharmaceutical composition as described herein, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate that accumulates in malignant tissue; And

imaging the subject after administration of a metal complex or pharmaceutical composition to detect a signal from the labeled metal complex, wherein detection of a signal from the isotope in tissue indicates that the tissue is malignant, thereby diagnosing cancer in the subject.

[0048] In some embodiments, the invention provides a method of treating cancer in a subject, comprising:

administering to a subject a metal complex or pharmaceutical composition disclosed herein, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate that accumulates in malignant tissue;

imaging the subject after administration of the metal complex or pharmaceutical composition to detect a signal from the labeled metal complex, wherein detection of the signal from the isotope in the tissue indicates that the tissue is malignant, diagnosing the subject with a tumor in the tissue; And

administering to the subject a therapeutically effective amount of a chemotherapeutic agent.

[0049] In some embodiments, the invention provides a method for diagnosing and treating a cancer subject that is sensitive to an albumin-bound chemotherapeutic agent, comprising:

administering to a subject a metal complex or pharmaceutical composition disclosed herein, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate that accumulates in malignant tissue;

imaging a subject after administration of a metal complex or pharmaceutical composition to detect a signal from the labeled metal complex, wherein detection of a signal from the isotope in tissue indicates that the tissue is malignant;

diagnosing a cancer subject that is sensitive to therapy with an albumin-related chemotherapeutic agent; and administering to the subject a therapeutically effective amount of an albumin-bound chemotherapeutic agent.

[0050] In some embodiments, the invention provides a method for diagnosing a cancer subject that is sensitive to an albumin-bound chemotherapeutic agent, comprising:

administering to a subject a metal complex or pharmaceutical composition disclosed herein, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate that accumulates in malignant tissue;

performing imaging on a subject following administration of a metal complex or pharmaceutical composition to detect a signal from the labeled metal complex, wherein detection of a signal from the isotope in tissue indicates that the tissue is malignant; and diagnosing a cancer subject that is sensitive to treatment with an albumin-bound chemotherapeutic agent.

[0051] In some embodiments, the invention provides a method of treating cancer in a subject that is sensitive to an albumin-bound chemotherapeutic agent, comprising:

administering to a subject a metal complex or pharmaceutical composition disclosed herein, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate that accumulates in malignant tissue;

performing imaging on a subject following administration of a metal complex or pharmaceutical composition to detect a signal from the labeled metal complex, wherein detection of a signal from the isotope in the tissue indicates that the tissue is malignant;

diagnosing a cancer subject that is sensitive to therapy with an albumin-related chemotherapeutic agent; And

administering to the subject a therapeutically effective amount of an albumin-bound chemotherapeutic agent.

[0052] In some embodiments, the invention provides a method including:

administering to a subject a metal complex or pharmaceutical composition disclosed herein, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate that accumulates in malignant tissue;

performing imaging of the subject following administration of a metal complex or pharmaceutical composition to detect a signal from the labeled metal complex, wherein detection of a signal from the isotope in the tissue indicates that the tissue is malignant;

diagnosing this subject with malignant tissue,

and administering to the subject a therapeutically effective amount of an albumin-bound chemotherapeutic agent .

[0053] In some embodiments, the invention provides a method including:

administering to a subject a metal complex or pharmaceutical composition disclosed herein, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate, which metal complex-albumin conjugate accumulates in the malignant tissue;

performing imaging of a subject following administration of a metal complex or pharmaceutical composition to detect a signal from the labeled metal complex, wherein detecting the presence of a signal from the isotope in that tissue indicates that the tissue is malignant;

diagnosing this tissue lesion in a cancer subject;

classification of the subject's sensitivity to the albumin-bound chemotherapeutic agent; And

administering to a subject a therapeutically effective amount of the albumin-bound chemotherapeutic agent .

[0054] In some embodiments, the invention provides a method for assessing the sensitivity of a cancer subject to an albumin-bound chemotherapeutic agent, comprising:

administering to a subject a metal complex or pharmaceutical composition as disclosed herein, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate, wherein the metal complex-albumin conjugate accumulates in the malignant tissue;

performing imaging of the subject following administration of a metal complex or pharmaceutical composition to detect a signal from the labeled metal complex, wherein detection of the presence of a signal from the isotope in the tissue indicates that the tissue is malignant;

diagnosing tissue damage in an oncological subject; And

classifying the subject as sensitive to this albumin-bound chemotherapeutic agent.

[0055] In some embodiments, the invention provides a method for assessing the susceptibility of a cancer subject to an albumin-bound chemotherapeutic agent, comprising:

administering to the subject a metal complex or pharmaceutical composition disclosed herein, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate, which metal complex-albumin conjugate accumulates in the malignant tissue;

performing imaging of the subject following administration of the metal complex or pharmaceutical composition to detect a signal from the labeled metal complex, wherein detecting the presence of a signal from the isotope in the tissue indicates that the tissue is malignant;

diagnosing this affected tissue in a cancer subject; and classifying the subject's cancer as susceptible to the albumin-bound chemotherapeutic agent.

[0056] In some embodiments, the invention provides a method for evaluating the use of an albumin-bound chemotherapeutic agent in cancer therapy in susceptible subjects, comprising:

administering to a subject a metal complex or pharmaceutical composition disclosed herein, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate, wherein the metal complex-albumin conjugate accumulates in the malignant tissue;

imaging the subject after administration of the metal complex or pharmaceutical composition to detect the signal from the labeled metal complex, wherein detecting the presence of the signal from the isotope in the malignant tissue indicates that the albumin-bound chemotherapeutic agent is capable of treating the cancer in the subject.

[0057] In some embodiments, the metal complex is administered as a metal complex-albumin conjugate formed ex vivo. In some embodiments, the metal complex-albumin conjugate is formed by conjugation of albumin to the corresponding TBG functional group of the metal complex; followed by metal chelation (M). In some embodiments, this metal complex-albumin conjugate is formed by chelation of M to form the metal complex; followed by conjugation of albumin with the TBG of the metal complex to form a metal complex-albumin conjugate.

[0058] In some embodiments, the malignancy is selected from the following: adenocarcinoma, uveal melanoma, acute leukemia, acoustic neuroma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, connective tissue tumors, bladder cancer, bronchial carcinoma, non-small cell bronchial carcinoma, breast cancer, Burkitt's lymphoma, uterine corpus cancer, CUP syndrome, colon cancer, small intestine cancer, ovarian cancer, endometrial carcinoma, gallbladder cancer, gallbladder carcinomas, uterine corpus cancer , cervical cancer, neck, nose and ear tumors, hematological neoplasia, hairy cell leukemia, urethral cancer, skin cancer, gliomas, testicular cancer, Kaposi's sarcoma, laryngeal cancer, bone cancer, colorectal carcinoma, head/neck tumors, colon carcinoma, craniopharyngeoma , liver cancer, leukemia, lung cancer, non-small cell lung carcinoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, gastric cancer, colon cancer, meduloblastoma, melanoma, meningioma, renal cancer, renal cell carcinomas, oligodendroglioma, esophageal carcinoma, osteoplastic carcinomas and osteolytic carcinomas, osteosarcoma, ovarian carcinoma, pancreatic carcinoma, penile cancer, prostate cancer, tongue cancer, ovarian carcinoma and lymph node cancer.

[0059] In some embodiments, the invention provides a kit for assessing the susceptibility of a cancer subject to an albumin-bound chemotherapeutic agent, the kit comprising a metal complex or pharmaceutical composition disclosed herein. In some embodiments, the invention provides a kit for diagnosing susceptibility

cancer subject to an albumin-bound chemotherapeutic agent, wherein the kit includes the metal complex disclosed herein. In some embodiments, the invention provides a kit for assessing the susceptibility of a cancer subject to an albumin-bound chemotherapeutic agent, the kit comprising a pharmaceutical composition disclosed herein.

[0060] In some embodiments, the invention provides for the use of a metal complex disclosed herein for the production of a drug for diagnosing cancer in a subject.

[0061] In some embodiments, the invention provides the use of a metal complex disclosed herein for the production of a drug used for diagnosing cancer in a cancer subject that is sensitive to an albumin-bound chemotherapeutic agent.

[0062] In some embodiments, the invention provides for the use of a metal complex disclosed herein to produce a formulation for assessing the sensitivity of a subject to an albumin-bound chemotherapeutic agent.

[0063] In some embodiments, the invention provides the use of a metal complex disclosed herein for the production of a drug for assessing the susceptibility of a cancer subject to an albumin-bound chemotherapeutic agent.

[0064] In some embodiments, the invention provides for the use of a metal complex disclosed herein in diagnosing cancer in a subject.

[0065] In some embodiments, the invention provides the use of a metal complex disclosed herein in diagnosing cancer in a subject that is sensitive to an albumin-bound chemotherapeutic agent.

[0066] In some embodiments, the invention provides for the use of a metal complex disclosed herein to assess the sensitivity of a subject to an albumin-bound chemotherapeutic agent.

[0067] In some embodiments, the invention provides the use of a metal complex disclosed herein to assess the susceptibility of a cancer subject to an albumin-bound chemotherapeutic agent.

[0068] In some embodiments, the invention provides the use of a metal complex disclosed herein to evaluate the therapeutic potential of an albumin-bound chemotherapeutic agent in treating cancer in a subject.

BRIEF DESCRIPTION OF THE DRAWINGS

[0069] Figure 1 shows radiographs for free ¹¹¹ In ³⁺ , ¹¹¹ In-C4-DTPA and albumin-conjugated ¹¹¹ In-C4-DTPA in mouse serum. Block A: Radiogram of free ¹¹¹ In ^{3 +} ; Block B: Radiogram for ¹¹¹ In-C4-DTPA. Block C: Radiogram for ¹¹¹ In-C4-DTPA-albumin conjugate in mouse serum.

[0070] Figure 2 presents the results of a study of the binding and stability of the ¹¹¹ In-C4-DTPA complex to albumin in mouse and human serum. Box A: Level of conjugation of ¹¹¹ In-C4-DTPA to albumin and stability of the complex in mouse serum. Box B: Level of conjugation ^{of 111} In-C4-DTPA to albumin in human serum.

[0071] Figure 3 shows the diagram and radiograms for labeled C4-DTPA 3b with ¹¹¹ In ⁺³ . Block A: Scheme for the synthesis of ¹¹¹ In-C4-DTPA with C4-DTPA 3b; Block B: Radiogram of free ¹¹¹ In ^{3 +} ; Block C: Radiogram for ¹¹¹ In-C4-DTPA.

[0072] Figure 4 presents results for ¹¹¹ In-C4-DTPA-labeled albumin concentrations in blood and plasma after 48 hours in healthy nude mice. Box A: Concentration of albumin-bound ¹¹¹ In-C4-DTPA over time in the blood of mice; Box B: Concentration of albumin-bound ¹¹¹ In-C4-DTPA over time in mouse plasma. Concentrations were determined on a gamma counter.

[0073] Figures 5A and 5B represent in vivo SPECT/CT imaging of patient-derived LXFL529 lung xenografts inoculated into tumor-bearing mice subcutaneously bilaterally and treated with ¹¹¹ In-C4-labeled DTPA. Figure 5A shows a rendering of mouse #22 and mouse #23. Figure 5B shows a rendering of mouse #27 and mouse #29. The circles represent the original tumors and the tumor areas are highlighted.

[0074] Figure 6 shows representative 3D SPECT/CT images of one tumor-bearing mouse (mouse #22) (LXFL model 529). The circles represent the original tumors and the tumor areas are highlighted.

[0075] Figure 7 presents gamma counter results for various tissues in the LXFL 529 model 72 hours after administration of ¹¹¹ In-C4-DTPA.

[0076] Figures 8A and 8B show SPECT/CT imaging of patient-derived ovarian xenograft OVXF 899 grafted into tumor-bearing mice subcutaneously bilaterally and treated with ¹¹¹ In-C4-labeled DTPA. Figure 8A shows visualizations for mouse #1 and mouse #7. Figure 8B shows a rendering of mouse #11 and mouse #14. The circles represent the original tumors and the tumor areas are highlighted.

[0077] Figure 9 shows representative 3D SPECT/CT images of one tumor-bearing mouse (mouse #11) (OVXF model 899). The circles represent the original tumors and the tumor areas are highlighted.

[0078] Figure 10 presents gamma counter results for various tissues in the OVXF 899 model 72 hours after administration of ¹¹¹ In-C4-DTPA.

DETAILED DESCRIPTION OF THE INVENTION

[0079] In order to fully understand the invention presented herein, the following detailed description is set forth. Although the invention will be presented in combination with the listed embodiments, it is intended that they are not intended to limit the invention to these embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents that may be included within the scope of the existing invention as defined in the claims. Those skilled in the art will recognize that there are many methods and materials similar or equivalent to those presented herein that may be used in the practice of the present invention.

[0080] Unless terms are otherwise defined herein, scientific and technical terms used in this application are intended to have meanings that are readily apparent to those skilled in the art. In general, the definitions relating to the methods of chemistry, molecular biology, cancer cell biology, immunology, microbiology, pharmacology and protein chemistry presented herein are known and widely used in modern scientific practice. Chemical terms used herein are stated in accordance with generally accepted definitions as evidenced by the McGraw-Hill Dictionary of Chemical Terms, Parker S., Ed., McGraw-Hill, San Francisco, CA (1985).

[0081] All publications, patents and published patent applications mentioned in this application are incorporated herein by reference. In the event of a conflict, the present specification, including its definitions, will control. Unless otherwise indicated, it should be understood that each embodiment disclosed herein may be used alone or in combination with any of the other embodiments disclosed herein.

[0082] The term “herein” refers to the entirety of this document.

[0083]Along the way description of the invention the word “includes” or variations thereof such as “contains” or “comprising” should be understood to include the entire composition (or components) or groups of entire compositions (or components), but not to exclude any other complete composition (or components) or full groups (or components).

[0084]Along the way applications where a compound, metal complex or composition is presented as “has”, “includes” or “contains” specific components, it is contemplated that such compounds, metal complex or composition may also consist essentially of, or consist of, the presented components. Likewise, where methods or processes are described as having, including, or containing specific process steps, the processes may also consist essentially of, or consist of, the presented processing steps. In addition, it should be understood that the order of steps or the order in which certain actions are performed is immaterial as long as the compounds, metal complex compositions, and methods presented herein are in effect. In addition, two or more steps or actions can be performed simultaneously.

[0085] The English singular forms "a", "an" and "the" also include plural forms unless the context clearly states otherwise.

[0086] The term "including" as used herein means "including but not limiting." The terms "including" and "including but not limited to" are used interchangeably.

[0087] The term “or” as used in this document should be understood to mean “and/or” unless the context clearly indicates otherwise.

[0088] As used herein, the terms “about” or “approximately” mean within an acceptable range of errors for specific values, according to the state of the art, which will depend in part on how the value is measured or determined, that is, limited by the measurement system.

[0089] The reading of the value ranges set forth herein is intended to serve as a shorthand way of individually referring to each individual value within the range unless otherwise stated herein, and each individual value included in the specification is presented as such , as if it were read separately herein. All methods described herein may be performed in any suitable order, unless otherwise indicated herein or as otherwise required by context. The use of any and all examples, or exemplary expressions (such as "such as") presented herein is intended only to better illuminate the embodiments and does not create a limitation on the scope of the claims unless otherwise stated. No language in the specification of the application should be construed as indicating any element required that is not claimed.

[0090] The terms " metal complex", "agent", "imaging agent", or "diagnostically effective substance" are used interchangeably and are intended to include any metal complex that has a diagnostic effect either alone or after its transformation in the organism in question, and thus also includes derivatives of these transformations. The term "metal complex" may include the metal complex of Formulas I-XII, or its conjugate acid, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0091] The term "base conjugate acid" of a metal complex disclosed herein refers to a metal complex of Formulas I-XII in which one or more carboxyl groups accept a proton to form a carboxylic acid.

[0092]Terms "connections""metal complex", "agent", "imaging agent", or "diagnostically effective substance" are intended to include compounds, metal complexes, agents, imaging agents and/or substances for which the structure or formula, or any derivative thereof, has been disclosed in the present invention, or the structure or formula, or any derivative thereof, is incorporated herein by reference. The terms also include isomers, stereoisomers, geometric isomers, enantiomers, tautomers, solvates, metabolites, conjugate acids and salts (eg, pharmaceutically acceptable salts) of a compound, metal complex, agent, imaging agent, and/or substance of all formulas disclosed herein. The terms also include any preceding solvates, hydrates and polymorphs. Specific inclusion of the terms "isomers", "stereoisomers", "geometric isomers", "enantiomers", "tautomers", "solvates", "metabolites", "salt", "conjugates", "conjugated acid", "conjugated salt", "solvate", "hydrate" or "polymorph" in the specific aspects of the invention presented in this application should not be interpreted as deliberate omission of those forms in other aspects of the invention where the terms "compound", "metal complex", "agent", "imaging agent" or "substance" are used without including these other forms.

[0093] The terms "patient", "subject", or "human" are used interchangeably and refer to either a human or an experimental animal. These terms include mammals such as humans, primates, domestic animals (eg, cattle, pigs), pets (eg, dogs, cats), and rodents (eg, mice and rats). In some embodiments, the patient or subject is a human patient or subject that requires diagnosis.

[0094] The term "pharmaceutical composition" refers to a composition suitable for diagnostic use in an experimental animal, including, but not limited to, a mammal, such as a human, in combination with one or more pharmaceutically acceptable carriers, excipients or diluents. Such a composition may also contain diluents, fillers, salts, buffers, stabilizers, solubilizers, protectors and other materials known in the art. In some embodiments, a pharmaceutical composition includes a composition containing active ingredient(s) and inert component(s), which include an excipient, carrier or diluent, as well as any product that inhibits, directly or indirectly, the combination, complexation or aggregation of any two or more components, or from the dissociation of one or more components, or from other types of reactions or interactions of one or more components. Accordingly, the pharmaceutical compositions of the present disclosure include any composition prepared by mixing a compound, conjugate or metal complex of the invention with one or more pharmaceutically acceptable excipients, carriers and/or diluents.

[0095] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier that can be administered to a patient in conjunction with a diagnostically effective agent of the present invention and that does not interfere with the diagnostic activity of the imaging agent. The term "excipient" refers to an additive in a composition or formulation that is not a pharmaceutically active ingredient.

In some embodiments, a "pharmaceutically acceptable" substance is a formulation that can be used in contact with cells, tissues or organs of animals or humans without undue toxicity, irritation, allergic reaction, immunogenicity or other adverse reactions, in the amount used in the dosage form according to dosing regimen, and in proportion to a reasonable benefit/risk ratio. In some embodiments, the “pharmaceutically acceptable” substance is a component of a pharmaceutical composition, and is also compatible with other component(s) of the composition. In some embodiments, the terms "pharmaceutically acceptable excipient", "pharmaceutically acceptable carrier" and "pharmaceutically acceptable solvent" include, but are not limited to, pharmaceutically acceptable inactive components, materials, compositions and carriers, such as liquid excipients, solid excipients, solvents , fillers, carriers, solvents and encapsulated materials.

Carriers, solvents and excipients also include all pharmaceutically acceptable dispersing media, coatings, buffers, isotonic agents, stabilizers, anti-absorption agents, antimicrobial agents, antibacterial agents, antifungal agents, adjuvants, etc. In addition, since any conventional excipient, carrier or diluent is incompatible with the active ingredient, the present disclosure includes the use of conventional excipients, carriers and diluents in pharmaceutical compositions. See, for example, Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (Philadelphia, Pennsylvania, 2005); Handbook of Pharmaceutical Excipients, 5th Ed., Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association (2005); Handbook of Pharmaceutical Additives, 3rd Ed., Ash and Ash, Eds., Gower Publishing Co. (2007); and Pharmaceutical Preformulation and Formulation, Gibson, Ed., CRC Press LLC (BOCa Raton, Florida, 2004).

[0096] The terms “diagnostically effective amount” or “diagnostically effective dose” refer to an amount capable of diagnosing a disease in a patient, eg, providing useful and/or desirable identification of pathological sites in a patient suffering from a disease (eg, cancer). The exact effective amount required for a subject may depend, for example, on the subject's constitution, health and age, the nature and extent of the disease, the imaging agent selected for administration, and the route of administration. One skilled in the art can readily determine the effective amount for a given situation by routine experimentation.

[0097] The term “therapeutically effective amount” refers to an amount of a compound, agent, or composition that is capable of treating a disease or symptoms of a disease, reducing the severity of symptoms of a disease, ameliorating a disease, and inducing remission to stop the progression of a disease or prevent the complication of a disease or symptoms.

[0098] As used herein, the terms "diagnosis", "diagnosis" and variations thereof refer to the identification of a molecular or pathological condition, disease or condition, such as the identification of a malignant process or cancer patient who may benefit from the details of a treatment protocol. In one embodiment of the invention, diagnosis refers to the identification of a specific tumor type.

[0099] As used herein, the terms “imaging,” “labeled,” and “molecular imaging” refer to an approach that produces qualitative, semiquantitative, and/or quantitative images of pathological sites, such as tumors and metastatic lesions, that engulf and accumulate labeled albumin. An example of such an imaging modality includes, but is not limited to, single photon emission computed tomography (SPECT).

[0100] " Use" or "administration" of a metal complex, imaging agent, or pharmaceutical composition or chemotherapeutic agent to a subject may be accomplished using one of a variety of methods known to those skilled in the art. For example, the metal complex, imaging agent, or pharmaceutical composition may be administered intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (swallowing), intranasally (inhalation), intraspinal, intracerebral, and transdermally (by absorption, e.g., through ducts). skin). The compound, metal complex or composition may also be administered by rechargeable or biodegradable polymer devices or other devices, such as patches and pumps, or compounds that allow for extended, slow or controlled administration of the compound, metal complex or agent. Administration may also be performed, for example, once, multiple times over time, and/or in one or more extended periods. Appropriate administration of a metal complex, imaging agent, or pharmaceutical composition will also depend, for example, on the age of the subject, whether the subject is active or inactive at the time of administration, cognitive impairment at the time of administration, deterioration, chemical and biological properties of the compound, metal complex, or agent (eg, solubility, digestibility, bioavailability, stability and toxicity).

[0101] The term “substituted” refers to components having substituents that replace hydrogen on one or more carbon atoms in a chemical or complexed with a metal. It will be understood that "substitution" or "is replaced by" includes the mandatory condition that such substitution corresponds to the allowed valence of the substituted atom and substituent, and that the substitution results in the formation of a stable compound or metal complex, for example, which does not spontaneously undergo changes such as rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is intended to include all valid substituents for organic compounds. In broad terms, acceptable substituents include non-cyclic and cyclic, branched and straight-chain, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. An acceptable substituent may be one or more of the same or different appropriate organic compounds. To achieve the objectives of the invention, heteroatoms such as nitrogen may have hydrogen substituents, and/or any permissible substituents of the organic compounds presented herein that satisfy the valency of the heteroatoms. Substituents may include any of the substituents presented herein, for example, halogen, hydroxyl, carbonyls (such as carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyls (such as thioether, thioacetate or thioformate), acoxyl, alkylthio, acyloxy, phosphoryl, phosphate, phosphonate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic group.

[0102] " Optional" or "optional" means that the circumstances described may or may not subsequently occur, so the application includes cases in which the circumstance occurs and cases in which it does not. For example, the phrase "optionally substituted" means that a non-hydrogen substituent may or may not be present on a given atom, and thus the application includes structures in which a non-hydrogen substituent is present and structures in which there is no non-hydrogen substituent.

[0103] Unless specifically stated as “unsubstituted,” reference to chemical groups herein is intended to include substituted variants. For example, reference to an "alkyl" group or moiety is intended to include both substituted and unsubstituted variants. Examples of chemical group substituents include, but are not limited to, halogen, hydroxyl, carbonyls (such as carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyls (such as thioether, thioacetate or thioformate), acoxyl, alkylthio, acyloxy, phosphoryl, phosphate, phosphonate , amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aryl, or heteroaryl group.

[0104] The term "alkyl" refers to radicals of saturated aliphatic groups, including straight and branched chain alkyl groups. In some embodiments, straight chains or alkylated branched chains have 30 or fewer carbon atoms in their molecule (e.g., C ₁ -C ₃₀ for straight chain, C ₄ -C ₃₀ for branched chains), but more preferably 20 carbon atoms or less. In some embodiments, the alkyl groups are lower alkyl groups, for example, methyl, ethyl, n -propyl, i -propyl, n -butyl and n -pentyl. In addition, the term "alkyl" is used throughout the specification of this invention, examples and claims include both "unsubstituted alkyls" and "substituted alkyls", the latter referring to alkyl molecules having substituents replacing hydrogen on one or more carbons. In certain embodiments, the straight chain or branched alkyl chain has 30 or fewer carbon atoms in its molecule (eg, C ₁ -C ₃₀ for straight chains, C ₃ -C ₃₀ for branched chains). In some embodiments, the chain contains ten or fewer carbon atoms (C ₁ -C ₁₀ ) in its molecule. In other embodiments, the chains include six or fewer carbon atoms (C ₁ -C ₆ ) in their molecule.

[0105] Such substituents may include, for example, halogen, hydroxyl, carbonyls (such as carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyls (such as thioether, thioacetate or thioformate), acoxyl, alkylthio, acyloxy, phosphoryl, phosphate, phosphonate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl or aryl, or a heteroaryl group.

[0106] "Conjugate metal complex with albumin" refers to the compound obtained by combining the metal complex provided herein with albumin. The bond of albumin to the metal complex can be covalent or non-covalent. The covalent bond may be through the thiol-linking groups disclosed herein, binding to the cysteine molecule of albumin. In some embodiments, the albumin is covalently linked to the metal complex via cysteine-34.

[0107] "Maleimide" refers to the optionally substituted chemical structure:

When used as a substituent or thiol-binding group (TBG), the maleimide may have a conjugation point with the molecule for which it is a substituent, with a corresponding coupling site at the maleimide's N-H or C-H bonds.

[0108] " Haloacetamide" refers to the structure:

where X is a halogen atom (eg I, Br, F or Cl).

[0109] "Haloacetate" refers to the structure:

where X is a halogen atom (eg, I, Br, F, or Cl).

[0110] "Pyridyldithio" refers to the group or optionally substituted structure:

preferably

[0111] "Isothiocyanate" refers to the structure:

[0112] "Vinylcarbonyl" refers to an optionally substituted functional group, with the formula -CH= _CH2 , in which the carbonyl group is a covalently attached structure:

[0113] "Aziridine" refers to a group which, when used as a substituent or TBG, has an optionally substituted structure:

[0114] "Acetylene" refers to a group which, when used as a substituent or TBG, has an optionally substituted structure:

[0115] At various places in the description of the present invention, substituents of the compounds and metal complexes of the application are disclosed in groups or ranges. The disclosure is intended to include each distinct subcombination of members of such groups and ranges. For example, the term "C ₁ - C ₆ alkyl" is specifically intended to separately disclose methyl, ethyl, propyl, isopropyl, n -butyl, sec -butyl, isobutyl, etc.

[0116] A " pharmaceutically acceptable salt" is a salt of a compound or metal complex that is suitable for pharmaceutical use, including, but not limited to, metal salts (e.g., sodium, potassium, magnesium, calcium, etc.), salts prepared by the addition of an acid (eg mineral acids, carboxylic acids, etc.), and salts obtained by adding a base (eg ammonia, organic amines, etc.). The salts obtained by adding an acid form a compound which occurs in the free form, since the base can be obtained by treating the above free base forms with an appropriate acid, for example an inorganic acid, for example hydrohalic acids such as hydrochloric acid or hydrobromic acid, sulfuric, nitrogen, phosphorus, etc.; or organic acids, for example, acetic, hydroxyacetic, methylacetic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, metasulfonic, ethanosulfonic, benzosuulfonic, p -toluenesulfonic, cyclic, salicylic, p- aminosalicylic, pamoic and etc. (See, for example, WO 01/062726. Several pharmaceutically acceptable salts are listed by Berge et al, Journal of Pharmaceutical Sciences, 66: 1-19 (1977) and are incorporated herein by reference in their entirety).

Compounds containing acid protons can be converted to their therapeutically active, non-toxic salt form by the addition of a base, such as metal or amine salts, by treatment with appropriate organic and inorganic bases. Suitable forms of base salts include, for example, ammonium salts, alkali salts and alkaline earth metal salts or ions, for example lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, for example N -methyl-D -glucamine, hydrabamine salts and salts with amino acids such as, for example, arginine, lysine, etc. Conversely, the salt forms listed above can be converted to free forms by treatment with an appropriate base or acid. The compounds or metal complexes and their salts may be in solvate form, which is included within the scope of the present invention. Such solvates include, for example, hydrates, alcoholates, and the like. (see for example WO 01/062726).

[0117] The term "hydrate" refers to salts containing water molecules combined in a specific ratio as an integral part of a crystal, which are either associated with a metal center (M) or crystallized with a metal complex.

[0118] " Chemotherapeutic agent" refers to an agent that is used in chemotherapy to treat cancer. Non-limiting examples include alkylating agents, antimetabolites, antimicrotubulin agents, topoisomerase inhibitors and cytotoxic antibiotics.

[0119]Stereochemical and generally accepted definitions used herein are set forth in accordance with: S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds, metal complexes, agents, imaging agents and/or substances of the invention may contain asymmetric or chiral centers and therefore exist in different stoichiometric forms. All stoichiometric forms, which include, but are not limited to, isomers, diastereomers, enantiomers and atropisomers, as well as mixtures thereof, such as racemated mixtures, are intended to be part of the present invention. Many organic molecules exist in optically active forms, that is, they have the ability to rotate the plane of linearly polarized light. When describing an optically active molecule, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule around its chiral center(s). The prefixes D and L or (+) and (-) are used to indicate the direction of rotation of the joint in polarized light, with the designation (-) or 1 implying that the joint is left-handed. A molecule prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can occur in the absence of stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers without optical activity.

[0120] The term "isomer" as used herein includes, but is not limited to, tautomers, cis and trans isomers (E (counter-), Z (co-)), R- and S -enantiomers (prefixes R and S are used in accordance with the rules presented in Pure Appl. Chem. (1976), 45, 11-30), diastereomers, (D) isomers, (L) isomers, stereoisomers, racemic and other mixtures thereof. All of the above isomers, as well as their mixtures, are intended to be included in the claimed invention. Although tautomers are not specified in the formulas presented herein, they are intended to be included in the present invention.

[0121] The term "stereoisomer" refers to molecules with identical chemical structures and bonds, but differing atomic orientations in space, which cannot be interconverted by rotation of single bonds.

[0122] The term "diastereomer" refers to stereoisomers with two or more centers of chirality and whose molecules are not mirror images. Diastereomers are characterized by different physical properties, such as melting point, boiling point, spectral properties and reactivity. Mixtures of diastereomers are separated using high-resolution analytical procedures such as crystallization, electrophoresis and chromatography.

[0123] The term "enantiomers" refers to two stereoisomers of a molecule that are not the same when superimposed as a mirror image.

[0124] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are equivalent due to a low energy barrier. For example, protic tautomers (also known as prototropic tautomers) involve interconversions via proton migration, such as keto-enol and imine-enamine isomerization. The valence of tautomers involves interconversions through the conversion of some electron bonds.

Metal complexes

[0125] One aspect of the present invention is provided by a metal complex with the structure represented by formulas (I) or (II) or (III):

their conjugate acids, or their pharmaceutically acceptable salts, or their hydrates;

wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺

X is missing or selected from -NH-, and -O-;

R ¹ is absent or optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl each optionally independently substituted with -OCH ₂ CH ₂ -;

Y is absent or selected from -O-C(O)-, -C(O)-O-, -NH-C(O)-, -C(O)-NH-, -NH-C(O)- NH-, -O-C(O)-O-, -NH-C(O)-O-, and -O-C(O)-NH-;

R ² is optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl each optionally independently substituted with -OCH ₂ CH ₂ -; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

[0126] In some embodiments, the metal complex is the structure represented by formula (I):

Formula (I)

its conjugate acid, or a pharmaceutically acceptable salt, or a hydrate thereof;

wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺ ;

X is missing or selected from -NH-, and -O-;

R ¹ is optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl each optionally independently substituted with -OCH ₂ CH ₂ -; And

Y is absent or selected from -O-C(O)-, -C(O)-O-, -NH-C(O)-, -C(O)-NH-, -NH-C(O)-NH-, -O-C(O)-O-, -NH-C(O)-O-, and -O-C(O)-NH-;

R ² is optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl each optionally independently substituted with -OCH ₂ CH ₂ -; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

[0127] In some embodiments, X is omitted. In some embodiments, X and R ¹ are omitted. In some embodiments, X, Y, and R ¹ are absent. In some embodiments, R ² is optionally substituted with C ₂ -C ₅ alkyl. In some embodiments, R ² is C ₂ -C ₅ alkyl. In some embodiments, X is absent, R ¹ is absent, Y is absent, and R ² is optionally substituted with C ₂ -C ₅ alkyl. In some embodiments, X is absent, R ¹ is absent, Y is absent, and R ² is C ₂ -C ₅ alkyl. In some embodiments, X is absent, R ¹ is absent, Y is absent, R ² is optionally substituted with C ₂ -C ₅ alkyl, and TBG is an optionally substituted maleimide group. In some embodiments, X is absent, R ¹ is absent, Y is absent, R ² is C ₂ -C ₅ alkyl, and TBG is a maleimide group. In some embodiments, M is ¹¹¹ In ³⁺ . In some embodiments, M is ⁶⁷ Ga ³⁺ . In some embodiments, M is ^99m Tc ^{4 +} ; in some embodiments, M is ^99m Tc ^{3 +} . In some embodiments, X is absent, R ¹ is absent, Y is absent, R ² is optionally substituted with C ₂ -C ₅ alkyl, M is ¹¹¹ In ³⁺ and TBG is an optionally substituted maleimide group. In some embodiments, X is absent, R ¹ is absent, Y is absent, R ² is C ₂ -C ₅ alkyl, M is ¹¹¹ In ³⁺ and TBG is a maleimide group. In some embodiments, X is absent, R ¹ is absent, Y is absent, R ² is optionally substituted with C ₂ -C ₅ alkyl, M is ⁶⁷ Ga ³⁺ and TBG is an optionally substituted maleimide group. In some embodiments, X is absent, R ¹ is absent, Y is absent, R ² is C ₂ -C ₅ alkyl, M is ⁶⁷ Ga ³⁺ and TBG is a maleimide group. In some embodiments, X is absent, R ¹ is absent, Y is absent, R ² is optionally substituted with C ₂ -C ₅ alkyl, M is ^99m Tc ⁴⁺ , and TBG is an optionally substituted maleimide group. In some embodiments, X is absent, R ¹ is absent, Y is absent, R ² is C ₂ -C ₅ alkyl, M is ^99m Tc ⁴⁺ and TBG is a maleimide group. In some embodiments, X is absent, R ¹ is absent, Y is absent, R ² is optionally substituted with C ₂ -C ₅ alkyl, M is ^99m Tc ³⁺ , and TBG is an optionally substituted maleimide group. In some embodiments, X is absent, R ¹ is absent, Y is absent, R ² is C ₂ -C ₅ alkyl, M is ^99m Tc ³⁺ and TBG is a maleimide group.

[0128] In some embodiments, R ¹ is optionally substituted with C ₁ -C ₂ alkyl. In some embodiments, R ¹ is C ₁ -C ₂ alkyl. In some embodiments, Y is NH-C(O)-. In some embodiments, X is absent, R ¹ is optionally substituted with C ₁ -C ₂ alkyl, Y is NH-C(O)-, and R ² is optionally substituted with C ₁ -C ₂ alkyl. In some embodiments, X is absent, R ¹ is C ₁ -C ₂ alkyl, Y is NH-C(O)-, and R ² is C ₁ -C ₂ alkyl. In some embodiments, X is absent, R ¹ is optionally substituted with C ₁ -C ₂ alkyl, Y is NH-C(O)-, R ² is optionally substituted with C ₁ -C ₂ alkyl, and TBG is an optionally substituted maleimide group. In some embodiments, X is absent, R ¹ is C ₁ -C ₂ alkyl, Y is NH-C(O)-, R ² is C ₁ -C ₂ alkyl, and TBG is a maleimide group. In some embodiments, X is absent, R ¹ is optionally substituted with C ₁ -C ₂ alkyl, Y is NH-C(O)-, R ² is optionally substituted with C ₁ -C ₂ alkyl, TBG is an optionally substituted maleimide group, and M is ¹¹¹ In ³⁺ . In some embodiments, X is absent, R ¹ is a C ₁ -C ₂ alkyl, Y is NH-C(O)-, R ² is a C ₁ -C ₂ alkyl, TBG is a maleimide group, and M is ¹¹¹ In ³⁺ . In some embodiments, X is absent, R ¹ is optionally substituted with C ₁ -C ₂ alkyl, Y is NH-C(O)-, R ² is optionally substituted with C ₁ -C ₂ alkyl, TBG is an optionally substituted maleimide group, and M is ⁶⁷ Ga ^{3 +} . In some embodiments, X is absent, R ¹ is a C ₁ -C ₂ alkyl, Y is NH-C(O)-, R ² is a C ₁ -C ₂ alkyl, TBG is a maleimide group, and M is ⁶⁷ Ga ³⁺ . In some embodiments, X is absent, R ¹ is optionally substituted with C ₁ -C ₂ alkyl, Y is NH-C(O)-, R ² is optionally substituted with C ₁ -C ₂ alkyl, TBG is an optionally substituted maleimide group, and M is ^99m Tc ⁴⁺ . In some embodiments, X is absent, R ¹ is a C ₁ -C ₂ alkyl, Y is -NH-C(O)-, R ² is a C ₁ -C ₂ alkyl, TBG is a maleimide group, and M is ^99m Tc ^{4 +} . In some embodiments, X is absent, R ¹ is optionally substituted with C ₁ -C ₂ alkyl, Y is -NH-C(O)-, R ² is optionally substituted with C ₁ -C ₂ alkyl, TBG is an optionally substituted maleimide group, and M is ^99m Tc ³⁺ . In some embodiments, X is absent, R ¹ is C ₁ -C ₂ alkyl, Y is -NH-C(O)-, R ² is C ₁ -C ₂ alkyl, TBG is a maleimide group, and M is ^99m Tc ³⁺ .

[0129] In some embodiments, the metal complex has the structure of Formula (II):

Formula (II),

its conjugate acid, or a pharmaceutically acceptable salt, or a hydrate thereof; wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺ ;

R ¹ is absent or optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl each optionally independently substituted with -OCH ₂ CH ₂ -;

Y is absent or selected from -O-C(O)-, -C(O)-O-, -NH-C(O)-, -C(O)-NH-, -NH-C(O)-NH-, -O-C(O)-O-, -NH-C(O)-O-, and -O-C(O)-NH-;

R ² is optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl each optionally independently substituted with -OCH ₂ CH ₂ -; and a thiol-binding group (TBG) selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group groups and an optionally substituted acetylene group.

[0130] In some embodiments, M is ¹¹¹ In ³⁺ . In some embodiments, M is ⁶⁷ Ga ³⁺ . In some embodiments, M is ^199m Tc ⁴⁺ . In some embodiments, M is ^99m Tc ³⁺ . In some embodiments, R ¹ is absent. In some embodiments, Y is absent. In some embodiments, R ¹ and Y are absent. In some embodiments, R ² is optionally substituted C ₁ -C ₁₈ alkyl. In some embodiments, R ² is C ₁ -C ₁₈ alkyl. In some embodiments, R ¹ and Y are absent, and R ² is optionally substituted C ₁ -C ₁₈ alkyl. In some embodiments, R ¹ and Y are absent and R ² is C ₁ -C ₁₈ alkyl. In some embodiments, R ¹ and Y are absent and R ² is C ₂ -C ₆ alkyl.

[0131] In some embodiments, TBG is an optionally substituted maleimide group. In some embodiments, TBG is a maleimide group. In some embodiments, TBG is this maleimide group:

[0132] In some embodiments, R ¹ and Y are absent, R ² is C ₂ -C ₆ alkyl, and TBG is a maleimide group:

[0133] In some embodiments, the metal complex has the structure of Formula (III):

Formula (III),

its conjugate acid, or a pharmaceutically acceptable salt, or a hydrate thereof; wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺ ;

R ¹ is absent or optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl each optionally independently substituted with -OCH ₂ CH ₂ -;

Y is absent or selected from -O-C(O)-, -C(O)-O-, -NH-C(O)-, -C(O)-NH-, -NH-C(O)-NH-, -O-C(O)-O-, -NH-C (O)-O-, and -O-C (O)-NH-;

R ² is optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl each optionally independently substituted with -OCH ₂ CH ₂ -; And

a thiol-linking group (TBG) selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and an optionally substituted acetylene group.

[0134] In some embodiments, M is ¹¹¹ In ^{3 +} . In some embodiments, M is ⁶⁷ Ga ³⁺ . In some embodiments, M is ^199m Tc ⁴⁺ . In some embodiments, M is ^99m Tc ³⁺ . In some embodiments, R ¹ is absent. In some embodiments, Y is absent. In some embodiments, R ¹ and Y are absent. In some embodiments, R ² is optionally substituted with C ₁ -C ₁₈ alkyl. In some embodiments, R ² is C ₁ -C ₁₈ alkyl. In some embodiments of the invention, R ² is optionally substituted with C ₂ -C ₆ alkyl. In some embodiments, R ² is C ₂ -C ₆ alkyl. In some embodiments, R ¹ and Y are absent and R ² is optionally substituted with C ₁ -C ₁₈ alkyl. In some embodiments, R ¹ and Y are absent and R ² is C ₁ -C ₁₈ alkyl. In some embodiments, R ¹ and Y are absent and R ² is optionally substituted with C ₂ -C ₆ alkyl. In some embodiments, R ¹ and Y are absent and R ² is C ₂ -C ₆ alkyl.

[0135] In some embodiments, TBG is an optionally substituted maleimide group. In some embodiments, TBG is a maleimide group. In some embodiments, TBG is a maleimide group, in which TBG is linked to the rest of the metal complex through the maleimide nitrogen. In some embodiments, TBG is a maleimide group:

[0136] In some embodiments, R ¹ and Y are absent, R ² is C ₂ -C ₆ alkyl, and TBG is a maleimide group:

[0137] In some embodiments, the metal complex has the structure of Formula (IV), (V), or (VI):

their conjugate acids, or their pharmaceutically acceptable salts, or their hydrates, wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺

m=1 or 2;

n=1-5;

o=1-12; And

thiol-linking group (TBG) selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and an optionally substituted acetylene group.

[0138] In some embodiments, the metal complex has the structure of Formula (IV):

Formula (IV),

its conjugate acid, or a pharmaceutically acceptable salt, or a hydrate thereof;

wherein

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺ ;

m=1 or 2;

n=1-5;

o=1-12; And

thiol-linking group (TBG) selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and an optionally substituted acetylene group.

[0139] In some embodiments, M is ¹¹¹ In ^{3 +} . In some embodiments, M is ⁶⁷ Ga ^{3 +} . In some embodiments, M is ^99m Tc ⁴⁺ . In some embodiments, M is ^99m Tc ^{3 +} .

[0140] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4. In some embodiments, o is equal to 5. In some embodiments, o is equal to 6. In some embodiments, o is equal to 7. In some embodiments, o is equal to 8. In some embodiments, o is equal to 9. In some embodiments, In some embodiments, o is equal to 10. In some embodiments, o is equal to 11. In some embodiments, o is equal to 12.

[0141] In some embodiments, TBG is an optionally substituted maleimide group. In some embodiments, TBG is a maleimide group. In some embodiments, TBG is this maleimide group:

[0142] In some embodiments, the metal complex has the structure of Formula (V):

Formula (V),

its conjugate acid, or a pharmaceutically acceptable salt, or a hydrate thereof, wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺ ;

n=1-5;

o=1-12; And

thiol-linking group (TBG) selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and an optionally substituted acetylene group.

[0143] In some embodiments, M is ¹¹¹ In ^{3 +} . In some embodiments, M is ⁶⁷ Ga ^{3 +} . In some embodiments

invention M is ^99m Tc ⁴⁺ . In some embodiments, M is ^99m Tc ³⁺ .

[0144] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some In some embodiments, o is equal to 1. In some embodiments, o is equal to 2. In some embodiments, o is equal to 3. In some embodiments, o is equal to 4. In some embodiments, o is equal to 5. In some embodiments, o is equal to 6. In some embodiments, o is equal to 7. In some embodiments, o is equal to 8. In some embodiments, o is equal to 9. In some embodiments, o is equal to 10. In some embodiments, o is equal to 11. In some embodiments, embodiment of the invention o is equal to 12.

[0145] In some embodiments, TBG is an optionally substituted maleimide group. In some embodiments, TBG is a maleimide group. In some embodiments, TBG is this maleimide group:

[0146] In some embodiments, the metal complex has the structure of Formula (VI):

Formula (VI)

its conjugate acid, or a pharmaceutically acceptable salt, or a hydrate thereof, wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺ ;

n=1-5;

o=1-12; And

thiol-linking group (TBG) selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and an optionally substituted acetylene group.

(0147) In some embodiments, M is ¹¹¹ In ^{3 +} . In some embodiments, M is ⁶⁷ Ga ³⁺ . In some embodiments, M is ^199m Tc ⁴⁺ . In some embodiments, M is ^99m Tc ^{3 +} .

[0148] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some In some embodiments, o is equal to 1. In some embodiments, o is equal to 2. In some embodiments, o is equal to 3. In some embodiments, o is equal to 4. In some embodiments, o is equal to 5. In some embodiments, o is equal to 6. In some embodiments, o is equal to 7. In some embodiments, o is equal to 8. In some embodiments, o is equal to 9. In some embodiments, o is equal to 10. In some embodiments, o is equal to 11. In some embodiments, embodiment of the invention o is equal to 12.

[0149] In some embodiments, TBG is an optionally substituted maleimide group. In some embodiments, TBG is a maleimide group. In some embodiments, TBG is this maleimide group:

[0150] In some embodiments, the metal complex has a structure of Formula (VII), (VIII), or (IX):

their conjugate acids, or their pharmaceutically acceptable salts, or their hydrates, wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺

m=1 or 2;

n=1-5; And

thiol-linking group (TBG) selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and an optionally substituted acetylene group.

[0151] In some embodiments, the metal complex has the structure of Formula (VII):

Formula (VII),

its conjugate acid, or a pharmaceutically acceptable salt, or a hydrate thereof, wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ , or ^99m Tc ³⁺ ;

m=1 or 2;

n=1-5; And

thiol-linking group (TBG) selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and an optionally substituted acetylene group.

[0152] In some embodiments, M is ¹¹¹ In ³⁺ . In some embodiments, M is ⁶⁷ Ga ^{3 +} . In some embodiments, M is ^199m Tc ⁴⁺ . In some embodiments, M is ^99m Tc ^{3 +} .

[0153] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some In embodiments, n is 4. In some embodiments, n is 5.

[0154] In some embodiments, TBG is an optionally substituted maleimide group. In some embodiments, TBG is a maleimide group. In some embodiments, TBG is this maleimide group:

[0155] In some embodiments, the metal complex has the structure of Formula (VIII):

Formula (VIII)

its conjugate acid or pharmaceutically acceptable salt or hydrate thereof, wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ , or ^99m Tc ³⁺ ;

n=1-5; And

thiol-linking group (TBG) selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and an optionally substituted acetylene group.

[0156] In some embodiments, M is ¹¹¹ In ³⁺ . In some embodiments, M is ⁶⁷ Ga ^{3 +} . In some embodiments, M is ^199m Tc ^{4 +} . In some embodiments, M is ^99m Tc ³⁺ . In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0157] In some embodiments, TBG is an optionally substituted maleimide group. In some embodiments, TBG is a maleimide group. In some embodiments, TBG is this maleimide group:

[0158] In some embodiments, the metal complex has the structure of Formula (IX):

Formula (IX)

its conjugate acid, or a pharmaceutically acceptable salt, or a hydrate thereof, wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ , or ^99m Tc ³⁺ ;

n=1-5; And

thiol-linking group (TBG) selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and an optionally substituted acetylene group.

[0159] In some embodiments, M is ¹¹¹ In ³⁺ . In some embodiments, M is ⁶⁷ Ga ^{3 +} . In some embodiments, M is ^199m Tc ⁴⁺ . In some embodiments, M is ^99m Tc ³⁺ . In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0160] In some embodiments, TBG is an optionally substituted maleimide group. In some embodiments, TBG is a maleimide group. In some embodiments, TBG is this maleimide group:

[0161] In some embodiments, the metal complex has the structure of Formula (X), (XI), or (XII):

their conjugate acids, or their pharmaceutically acceptable salts, or their hydrates, wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ , or ^99m Tc ³⁺ ;

p=1-12; And

thiol-linking group (TBG) selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and an optionally substituted acetylene group.

[0162] In some embodiments, TBG is an optionally replaceable maleimide group. In some embodiments, TBG is this maleimide group:

In some embodiments, M is ¹¹¹ In ³⁺ . In some embodiments, M is ⁶⁷ Ga ³⁺ . In some embodiments, M is ^199m Tc ⁴⁺ . In some embodiments, M is ^99m Tc ^{3 +} .

[0163] In some embodiments, the metal complex has the structure of Formula (X):

Formula (X),

its conjugate acid, or a pharmaceutically acceptable salt, or a hydrate thereof, wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ , or ^99m Tc ³⁺ ;

p=1-12; And

thiol-linking group (TBG) selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and an optionally substituted acetylene group.

[0164] In some embodiments, M is ¹¹¹ In ³⁺ . In some embodiments, M is ⁶⁷ Ga ^{3 +} . In some embodiments, M is ^199m Tc ⁴⁺ . In some embodiments, M is ^99m Tc ^{3 +} .

[0165] In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is 9. In some embodiments, p is 10. In some embodiments, p is 11. In some embodiments, p is equal to 12.

[0166] In some embodiments, TBG is an optionally substituted maleimide group. In some embodiments, TBG is a maleimide group. In some embodiments, TBG is this maleimide group:

[0167] In some embodiments, the metal complex has the structure of Formula (XI):

Formula (XI),

its conjugate acid, or a pharmaceutically acceptable salt, or a hydrate thereof, wherein

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺ ;

p=1-12; And

thiol-binding group (TBG) selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted

a haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and an optionally substituted acetylene group.

[0168] In some embodiments, M is ¹¹¹ In ^{3 +} . In some embodiments, M is ⁶⁷ Ga ^{3 +} . In some embodiments, M is ^199m Tc ⁴⁺ . In some embodiments, M is ^99m Tc ³⁺ . In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is 9. In some embodiments, p is 10. In some embodiments, p is 11. In some In embodiments of the invention, p is equal to 12.

[0169] In some embodiments, TBG is an optionally substituted maleimide group. In some embodiments, TBG is a maleimide group. In some embodiments, TBG is this maleimide group:

[0170] In some embodiments, the metal complex has the structure of Formula (XII):

Formula (XII)

its conjugate acid, or a pharmaceutically acceptable salt, or a hydrate thereof, wherein

M is ¹¹¹ In ^{3 +} , ⁶⁷ Ga ^{3 +} , ^99m Tc ^{4 +} , or ^99m Tc ^{3 +} ;

p=1-12; And

thiol-linking group (TBG) selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and an optionally substituted acetylene group.

[0171] In some embodiments, M is ¹¹¹ In ³⁺ . In some embodiments, M is ⁶⁷ Ga ^{3 +} . In some embodiments, M is ^199m Tc ⁴⁺ . In some embodiments, M is ^99m Tc ³⁺ . In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is 9. In some embodiments, p is 10. In some embodiments, p is 11. In In some embodiments, p is equal to 12.

[0172] In some embodiments, TBG is an optionally substituted maleimide group. In some embodiments, TBG is a maleimide group. In some embodiments, TBG is a maleimide group in which TBG is linked to the rest of the metal complex through the maleimide nitrogen and p is 2-6. In some embodiments, TBG is a maleimide group:

[0173] In some embodiments, the metal complex is selected from:

or their conjugate acids, or pharmaceutically acceptable salts, or hydrates thereof.

[0174] In some embodiments, the metal complex is selected from:

or their conjugate acids, or pharmaceutically acceptable salts, or hydrates thereof.

[0175] In some embodiments, the metal complex is:

or its conjugate acid, or a pharmaceutically acceptable salt, or a hydrate thereof.

[0176] In some embodiments, the metal complex is selected from:

or their conjugate acids, or pharmaceutically acceptable salts, or hydrates thereof.

[0177] In some embodiments, the metal complex is selected from:

or their conjugate acids, or pharmaceutically acceptable salts, or hydrates thereof.

[0178] In some embodiments, the pharmaceutically acceptable metal complex salt or its conjugate acid provided herein includes a countercation selected from one or two Na ⁺ , K ⁺ , or NH4 ⁺ ; or one Ca ²⁺ or Mg ²⁺ .

[0179] Albumin can be derivatized with any metal complex disclosed herein (eg, forming a metal complex-albumin conjugate). In some embodiments, the albumin derivative is a base-conjugate acid of a metal complex. Derivatization of albumin with different protein amino acid sites has a significant impact on the pharmacokinetic characteristics of albumin. The first albumin-drug conjugate to enter clinical trials was an ex vivo synthesized albumin-methotrexate conjugate in which the glutamate residue of methotrexate is covalently linked to the epsilon amino group of the lysine residues of human serum albumin with a methotrexate:albumin ratio of approximately 1.0.

The half-life of this albumin-methotrexate conjugate is estimated to be up to 3 weeks in humans (G. Hartung et al. (1999): Clin. Cancer Res. 5:753-759). In comparison, the half-life of the (6-maleimidocaproyl) hydrazone derivative of doxorubicin (DOXO-EMCH, renamed aldoxorubicin), which selectively and specifically binds to cysteine-34 of endogenous albumin after intravenous administration, was significantly lower, with a human t _1/2 of 20 -21 hours (MM Mita et al. (2015): Invest. New Drugs 33: 341 -348). The thiol-linked pharmaceutical form, aldoxorubicin, is believed to have demonstrated a favorable toxicity profile and increased efficacy in the first and second line treatment of soft tissue sarcoma compared with doxorubicin (M. Seetharam et al. (2018): Future Oncology, Epub ahead of print published online: 5 Jun 2018). Therefore, an appropriate imaging agent must specifically and selectively bind to cysteine at position 34 of endogenous or exogenous albumin to enable the diagnosis of uptake of serum albumin modified by this amino acid at pathological sites, especially tumor or metastatic sites. In some embodiments, the bond of the albumin to the imaging agent is covalent. In other embodiments, the association of the albumin with the imaging agent is non-covalent.

[0180] Modern molecular imaging has been established for the diagnosis of diseases and for tracking carrier molecules and determining their absorption and distribution at pathological sites. Molecular imaging is provided by magnetic resonance imaging (MRI), positron emission tomography (PET), computed tomography (CT), and single photon emission computed tomography (SPECT).

[0181] Radiolabeling of carrier molecules such as peptides or proteins with gamma-emitting metal radionuclides such as ¹¹¹ indium, ⁶⁷ gallium or ^99m technetium is a suitable method for subsequent imaging in the patient using SPECT. DTPA (Diethylene Thiamine Penta Acetic Acid) is the chelating agent of choice for complexation, which forms stable complexes with ¹¹¹ indium, complexes with ⁶⁷ gallium and with ^99m technetium with stable labeled metal complex kinetics.

[0182] In the context of the present invention, new radioactive ¹¹¹ indium complexes and ⁶⁷ gallium complexes have been developed that include a bifunctional chelating agent consisting of a DTPA derivative as a chelating agent associated with a linker comprising a thiol-binding group (TBG) and a metal radionuclide , selected from ¹¹¹ indium or ⁶⁷ gallium.

[0183] The thiol-binding group (TBG) is selected from a maleimide group, a haloacetamide group, a haloacetate group, a pyridyl dithio group, a disulfide group, a vinyl carbonyl group, an aziridine group and/or an acetylene group and its bonds selectively and/or covalently react with the thiol (- SH) cysteine groups on the surface of proteins in a physiological environment. In some embodiments, the thiol-binding group is this maleimide group:

which, after intravenous administration, quickly binds to cysteine - 34 of endogenous or exogenous albumin, preferably to endogenous albumin in the bloodstream.

[0184] In some embodiments, the metal complex of the invention, abbreviated as ¹¹¹ In-C4-DTPA, is represented by the following chemical structure as an acid or salt conjugate:

[0185] The binding of ¹¹¹ In-C4-DTPA and its non-radioactive analogue, In-C4-DTPA, to cysteine - 34 endogenous and exogenous albumin and representative examples of SPECT/CT scans in tumor-bearing athymic mice are demonstrated in the corresponding figures.

[0186] Synthetic routes for the formation of metal complexes according to the above embodiments are presented in the Examples and illustrated in the following 4 synthesis schemes:

[0187] The synthesis procedure and characterization of certain bifunctional chelating agents and metal complexes according to the present invention are presented in the Examples section.

Pharmaceutical compositions

[0188] Another aspect of the present invention provides a pharmaceutical composition comprising the metal complex of this invention together with a pharmaceutically acceptable carrier or excipient. The metal complexes or pharmaceutical compositions of this invention can be used in vitro or in vivo.

[0189] The total amount of metal complex in the composition that will be administered to the subject is that which is appropriate for the subject. Those skilled in the art will appreciate that different subjects may require different amounts of a diagnostically effective agent. In some embodiments, the amount of the metal complex is a diagnostically effective amount. A skilled artisan would determine the amount of metal complex in the composition needed for diagnostic imaging of a subject based on factors such as, for example, the age, body weight, and physical condition of the subject. The concentration of the metal complex depends on its solubility in the solution for intravenous administration and the permissible volume of the liquid composition used. For example, the concentration of the metal complex may be from about 0.001 mg/ml to about 8 mg/ml in an injectable composition.

[0190] The pharmaceutical compositions of the present invention may also contain diluents, excipients, salts, buffers, stabilizers, solubilizers, protectors and other materials known in the art. The term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the diagnostic effectiveness of the active component(s). The characteristics of the vehicle will depend on the route of administration.

[0191] In some embodiments, one or more excipients may be included in the composition. Those skilled in the art will recognize that the selection of any excipient may influence the selection of any other excipient. For example, the choice of excipient may eliminate the use of one or more additional excipients because the combination of excipients may have undesirable effects. Based on experience, one skilled in the art will be able to empirically determine which excipients, if any, may be acceptable to include in the compositions. Excipients may include, but are not limited to, co-solvents, solubilizers, buffers, pH adjusters, bulking agents, surfactants, encapsulating agents, tonicity regulators, stabilizers, protectants and viscosity modifiers. In some embodiments, it may be useful to include a pharmaceutically acceptable carrier in the compositions.

[0192] In some embodiments, solubilizers may be included in the pharmaceutical composition, which can be used to increase the solubility of any of the components of the composition, including a compound or excipient. This document does not provide a definitive list of solubilizers, but provides examples of solubilizing agents that may be used in these formulations. In some embodiments, solubilizers include, but are not limited to, gentisic acid, myo-inositol, sodium citrate, citric acid, and combinations thereof, and any pharmaceutically acceptable salts and/or combinations thereof.

[0193]pH value in compositions can be anything that provides the desired properties for the composition or composition. Desirable properties may include, for example, stability of the compound or metal complex, increased retention of the compound relative to compounds at other pH values, and improved filtration efficiency. In some embodiments, the pH of the compositions may be from about 3.0 to about 8.0, such as from about 3.0 to about 5.0. In some embodiments, the pH values of the compositions may be 3.0 ± 0.1; 3.5±0.1; 4.0±0.1; 4.5±0.1; 5.0±0.1.

[0194] In some embodiments, it may be useful to buffer solutions by including one or more buffers in the composition. In some embodiments, the buffer may have a pKa of, for example, about 3.0, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6.0, or about 6.5. One skilled in the art can evaluate and select an adequate buffer to include in the compositions based on its pKa and other properties. Buffers are known in the art. Accordingly, the buffers presented herein are not intended to constitute a comprehensive list and are presented merely as examples of buffers that may be used in the compositions or claims. In some embodiments, the buffer includes, but is not limited to, Tris, Tris-HCl, potassium phosphate, sodium phosphate, sodium citrate, sodium ascorbate, combinations of sodium and potassium phosphate, Tris/Tris-HCl, sodium bicarbonate, arginine phosphate, arginine hydrochloride , histidine hydrochloride, cocadylate, succinate, 2-( N- morpholino)ethanosulfonic acid (MES), maleate, bi-Tris, phosphate, carbonate and any pharmaceutically acceptable salts and/or combinations thereof.

[0195] In some embodiments, pH balancing agents may be included in the compositions. Modification of the pH of the composition may have a beneficial effect on, for example, the stability or solubility of the metal complex, or may be useful in forming a composition suitable for parenteral administration. pH adjusting agents are known in the art. Accordingly, the pH adjusting agents presented herein are not intended to constitute an exhaustive list, but are provided as exemplary pH adjusting agents that may be used in the compositions. pH adjusting agents may include, for example, acids and bases. In some embodiments, the pH adjusting agent includes, but is not limited to, acetic acid, hydrochloric acid, phosphoric acid, sodium hydroxide, sodium carbonate, and combinations thereof.

[0196] In some embodiments, the invention may include a bulking agent in the composition. Bulking agents are typically used in lyophilized compositions to provide additional volume to the composition and its visualization, especially in cases where the lyophilized granules are difficult to see. Bulking agents may also help prevent the release of the active component(s) of the pharmaceutical composition and/or promote cryoprotection of the composition. Volume-forming agents are known in the art. Accordingly, the volume enhancers presented herein are not intended to constitute an exhaustive list, but rather provide examples of those that may be used in the compositions.

[0197] Examples of the bulking agent may include carbohydrates, monosaccharides, disaccharides, polysaccharides, carbohydrate alcohols, amino acids, carbohydrate acids, and combinations thereof. Bulking agent carbohydrates include, but are not limited to, mono-, di-, or poly-carbohydrates, starch, aldoses, ketoses, amino sugars, glyceraldehyde, arabinose, lyxose, pentose, ribose, xylose, galactose, glucose, hexose, idose, mannose, talose, heptose, glucose, fructose, methyl - D - glucopyranoside, maltose, lactone, sorbose, erythrose, tereose, arabinose, allose, altrose, gulose, idose, talose, erythrulose, ribulose, xylulose, psicose, tagatose, glucosamine, galactosamine, arabinans, fructans, fucans, galactans, galacturonans, glucans, mannans, xylans, inulin, levan, fucoidan, carrageenan, galactocarolose, pectins, amylose, pullulan, glycogen, amylopectin, cellulose, pustulan, chitin, agarose, keratin, chondroitin , dermatan, hyaluronic acid, xanthine gum, sucrose, tresalose, dextran and lactose. Bulking agent carbohydrate alcohols include, but are not limited to, alditols, inositols, sorbitol and mannitol.

Bulking agent carbohydrate acids include, but are not limited to, aldonic acids, uronic acids, aldaric acids, gluconic acid, isoascorbic acid, ascorbic acid, glucaric acid, glucuronic acid, gluconic acid, galacturonic acid, mannuronic acid, neuraminic acid, pectic acids and alginic acid. Bulking agent amino acids include, but are not limited to, glycine, histidine and proline.

[0198] In some embodiments, a surfactant may be included in the composition. Surfactants generally reduce the surface tension of a liquid composition. They may provide beneficial properties such as improved filtration capacity. Surfactants can also act as emulsifying agents and/or solubility enhancing agents. Surfactants are known in the art. Accordingly, the surfactants presented herein are not intended to provide a complete list, but are provided merely as examples of surfactants that may be used in the formulations or compositions of the invention. Surfactants used include, but are not limited to, sorbitan esters such as polysorbates (eg, polysorbate 20 and polysorbate 80), lipopolysaccharides, polyethylene glycols (eg, PEG 400 and PEG 3000), poloxamers (eg, Pluronics), ethylene oxides, and polyethylene oxides. (eg Triton X-100), saponins, phospholipids (eg lecithin) and combinations thereof.

[0199] In some embodiments, agents that control the tonicity of the solution may be included in the composition. The tonicity of a liquid composition is an important characteristic when administering the composition to a subject, for example, during parenteral administration. Therefore, tonicity adjusting agents can be used to optimize the composition for administration. Agents that regulate tonicity are known in the art. Therefore, the tonicity adjusting agents presented herein are not intended to be an exhaustive list, but merely provide examples of tonicity adjusting agents that may be used in the compositions. Tonicity adjusting agents may be ionic or non-ionic and include, but are not limited to, inorganic salts, amino acids, carbohydrates, sugars, sugar alcohols and carbohydrates. Examples of inorganic salts may include sodium chloride, potassium chloride, sodium sulfate and potassium sulfate. An example of an amino acid is glycine. Examples of sugars may include sugar alcohols such as glycerin, propylene glycol, glucose, sucrose, lactose and mannitol.

[0200] In some embodiments, stabilizers may be included in the composition. Stabilizers help to increase the stability of the metal complex in compositions, for example, to reduce degradation or prevent aggregation of the metal complex. Without committing the mechanism of action to bond theory, stability enhancing agents may act as isolating reagents for the metal complex from the solvent or as inhibitors of free radical oxidation of a therapeutically effective substance. Stabilizers are known in the art. Therefore, the stabilizers set forth herein are not intended to constitute an exhaustive list, but are provided merely as examples of stabilizers that may be used in the compositions. Stabilizers may include, but are not limited to, emulsifiers and surfactants.

[0201] In some embodiments, a protectant may be included in the composition. Protectants are substances that protect a diagnostically active component (eg, a diagnostically effective substance or composition, eg, an imaging agent) from an undesirable condition (eg, instability caused by freezing or lyophilization or oxidation). Protective agents may include, for example, cryoprotectants, lyoprotectants and antioxidants. For example, the cryoprotectant may be included in the resuspended lyophilized composition by freezing the composition prior to dilution for intravenous administration. Cryoprotectants are known in the art. Therefore, the cryoprotectants presented herein are not intended to constitute an exhaustive list, but are provided to provide examples of cryoprotectants that may be used in the compositions. Cryoprotectants include, but are not limited to, solvents, surfactants, encapsulation agents, stabilizers, viscosity modifiers, and combinations thereof. Cryoprotectants may include, for example, disaccharides (eg, sucrose, lactose, maltose and trehalose), polyols (eg, glycerol, mannitol, sorbitol and dulcitol), glycols (eg, ethylene glycol, polyethylene glycol and propylene glycol).

[0202]Lyoprotectors useful for stabilizing the components of the composition. For example, a diagnostically effective substance may be lyophilized with a lyoprotectant prior to reconstitution. Lyoprotectors are known in the art. Therefore, the lyoprotectants presented herein are not intended to constitute an exhaustive list, but provide examples of lyoprotectants that may be used in the compositions. Lyoprotectants include, but are not limited to, solvents, surfactants, encapsulation agents, stabilizers, viscosity modifiers, and combinations thereof. Examples of lyoprotectants include, for example, sugars and polyols. Trehalose, sucrose, dextran and hydroxypropyl-beta-cyclodextrin are non-limiting examples of lyoprotectants.

[0203] Antioxidants are used to prevent oxidation of the components of the composition. Oxidation may lead to aggregation of imaging agents or other undesirable effects on the purity of the imaging agent. Antioxidants are known in the art. Therefore, the antioxidants presented herein are not intended to constitute an exhaustive list, but provide examples of antioxidants that may be used in the compositions. Antioxidants can be, for example, gentisic acid, sodium ascorbate, citrate, thiols, metabisulfite and combinations thereof.

[0204] In some embodiments, viscosity modifying agents may be included in the composition. Viscosity modifiers change the viscosity of liquid compositions, which can be beneficial since viscosity plays an important role in the filtration ability of a liquid composition. The composition may be filtered before lyophilization and reconstitution or after reconstitution. Viscosity modifiers are known in the art. Therefore, the modifiers presented herein are not intended to constitute an exhaustive list, but are provided to provide examples of viscosity modifiers that may be used in the compositions. Viscosity modifiers include solvents, solubilizers, surfactants, and encapsulating agents. Examples of viscosity modifiers that may be included in the compositions include, but are not limited to, N-acetyl-DL-tryptophan and N-acetylcysteine.

[0205] The compositions can be administered in many conventional ways. Examples of routes of administration used include oral, parenteral, intravenous, intraarterial, cutaneous, subcutaneous, intramuscular, cutaneous, intracranial, intraorbital, ophthalmic, intravitreal, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intranasal for aerosol forms, central nervous system administration ( CNS), or administration using suppositories. In some embodiments, the compositions may be administered parenterally, for example, intraperitoneally, intravenously, or intrathecally. In some embodiments, the compositions are administered intravenously. In some embodiments, the resuspended composition can be prepared by dissolving the lyophilized metal complex conjugate composition in a solvent, for example, alcohol, DMSO and/or polyethylene glycol and water and/or saline. Such reconstitution may involve adding a diluent and mixing, for example, by rotating or vigorously stirring the mixture. The resuspended composition can then be prepared for administration, for example, by mixing it with lactated Ringer's solution, 5% glucose solution, isotonic saline or a suitable saline buffer for the composition to form a composition for administration. Those skilled in the art will fully appreciate that the method of administration of a diagnostically effective composition of substance or formula will depend on factors such as the age, body weight and physical condition of the subject being treated, as well as depending on the disease or condition thereof. Therefore, the skilled artisan can select the optimal route of administration for the subject depending on the clinical situation.

[0206] In some embodiments, the invention provides metal complexes and compositions that are used in the imaging of a labeled agent to evaluate a cancer process, a viral disease, an autoimmune disease, an acute or chronic inflammatory process, and/or a disease caused by bacteria, fungi, or other microorganisms.

[0207] In some embodiments, the compositions, compounds or metal complex disclosed herein can be used in the preparation of a drug for radioimaging of diseases selected from malignancy, viral disease, autoimmune disease, acute or chronic inflammatory process and disease caused by bacteria, fungi or other microorganisms.

[0208] In some embodiments, the malignancy is a blood cancer or a solid tumor. In some embodiments, the malignancy is selected from carcinoma, sarcoma, leukemia, lymphoma, multiple myeloma, or melanoma.

[0209] In some embodiments, the malignancy is adenocarcinoma, uveal melanoma, acute leukemia, acoustic neuroma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, connective tissue tumor, bladder cancer, bronchial carcinoma, non-small cell bronchial carcinoma, breast cancer, Burkitt's lymphoma, uterine body carcinoma, cancer of unknown primary site, colon cancer, small bowel cancer, ovarian cancer, endometrial carcinoma, gallbladder cancer, gallbladder carcinomas, uterine body cancer, cervical cancer, neck, nose tumors and ear, hematologic neoplasia, hairy cell leukemia, urethral cancer, skin cancer, gliomas, testicular cancer, Kaposi's sarcoma, laryngeal cancer, bone cancer, colorectal cancer, head/neck tumors, colon carcinoma, craniopharyngeoma, liver cancer, leukemia, lung cancer , non-small cell lung cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, stomach cancer, colon cancer, medulloblastoma, melanoma, meningioma, kidney cancer, renal cell carcinomas, oligodendroglioma, esophageal carcinoma, osteolytic carcinomas and osteoplastic carcinomas, osteogenic sarcoma, ovarian carcinoma ohm , pancreatic carcinoma, penile cancer, prostate cancer, tongue cancer, ovarian cancer or lymph node cancer.

Diagnostic/imaging and treatment modalities

[0210] The metal complexes and compositions presented herein are used for numerous clinical applications. Therefore, another aspect of the invention provides methods for diagnosing, imaging and/or treating a subject.

[0211] In some embodiments, the metal complexes and compositions of this invention may be administered intravenously and selectively and rapidly covalently bind to endogenous albumin in the bloodstream for radioimaging purposes (eg, single photon emission computed tomography (SPECT)).

[0212] In some embodiments, the invention provides a method of imaging a malignancy comprising administering to a subject in need thereof a diagnostically effective amount of a metal complex or pharmaceutical composition comprising a metal complex as provided herein.

[0213] The invention also provides a method of imaging a condition or disease in a subject, when such condition or disease is selected from malignant diseases, viral disease, autoimmune disease, acute or chronic inflammatory disease and disease caused by bacteria, fungi or other microorganisms, including administering to the subject, presented herein, a metal complex or pharmaceutical composition.

[0214] In some embodiments, the invention provides a method for diagnosing a disease selected from a malignant disease, a viral disease, an autoimmune disease, an acute or chronic inflammatory disease, and a disease caused by bacteria, fungi, or other microorganisms, including administering to a subject in need thereof the present in this document the metal complex and subsequent visualization. In some embodiments, the disease is a malignancy.

[0215] In some embodiments, the invention provides a method for diagnosing cancer in a subject, which includes: administering to the subject a detectable amount of a metal complex or pharmaceutical composition comprising a metal complex disclosed herein (including, for example, a metal complex containing a radioactive label); imaging the subject following administration of a metal complex or pharmaceutical composition comprising the metal complex to detect a signal from the labeled metal complex, wherein the presence of the labeled isotope in the tissue indicates that the tissue is malignant, thereby diagnosing cancer in the subject. In some embodiments, the invention provides a method for diagnosing cancer in a subject, which includes administering to the subject a detectable amount of a metal complex or pharmaceutical composition comprising a metal complex disclosed herein (comprising, for example, a metal complex containing a radioactive label); imaging the subject following administration of a metal complex or pharmaceutical composition comprising the metal complex to detect a signal from the labeled metal complex in tissue of said subject, wherein the presence of the labeled isotope in the tissue indicates that the tissue is malignant, thereby diagnosing cancer in the subject. In some embodiments, the invention provides a method for diagnosing cancer in a subject, which includes administering to the subject a detectable amount of a metal complex or pharmaceutical composition containing a metal complex disclosed herein (including, for example, a metal complex containing a radioactive tracer) and imaging the subject after administration of the metal complex or a pharmaceutical composition containing a metal complex for detecting a signal from a labeled metal complex in tissue of a specified subject, wherein detection of a signal from an isotope in that tissue indicates that the tissue is malignant, thereby diagnosing cancer in the subject.

[0216] In some embodiments, the invention provides a method for diagnosing cancer in a subject, the method comprising administering to the subject a detectable amount of a metal complex or pharmaceutical composition comprising a metal complex disclosed herein (comprising, for example, a metal complex containing an isotope); imaging the subject following administration of a labeled metal complex or a pharmaceutical composition comprising a metal complex to detect a signal from the labeled metal complex, wherein detection of a signal with higher accumulation in tissue compared to similar unaffected tissue indicates that the tissue is malignant, thereby diagnosing cancer in the subject. In some embodiments, the invention provides a method for diagnosing cancer in a subject, which includes administering to the subject a detectable amount of a metal complex or pharmaceutical composition comprising a metal complex disclosed herein (comprising, for example, a metal complex containing a radioactive label); performing imaging of a subject after administration of a radiolabeled metal complex or a pharmaceutical composition comprising a metal complex to detect a signal from the radiolabeled metal complex, wherein detecting the presence of a more intense signal from the isotope in the subject's tissue compared to similar non-cancerous tissue indicates that the tissue is malignant, thereby making a diagnosis of cancer in that subject.

[0217] In some embodiments, the invention provides a method for diagnosing cancer in a subject, which includes administering to the subject a metal complex or pharmaceutical composition containing a metal complex disclosed herein (including, for example, a metal complex containing a radiolabel), wherein the metal complex binds to albumin to form metal-complex-albumin conjugate, after accumulation of the metal-complex-albumin conjugate in malignant tissue; a subject is imaged after administration of a metal complex or pharmaceutical composition comprising a metal complex disclosed herein to detect a signal from an isotope of the metal complex in tissue of the subject, wherein detection of a signal from a labeled agent in that tissue indicates that the tissue is malignant, thus The subject is diagnosed with cancer. In some embodiments, the invention provides a method for diagnosing cancer in a subject, which includes administering to the subject a metal complex or a pharmaceutical composition comprising a metal complex disclosed herein (containing, for example, a metal complex containing a radioactive label), wherein the metal complex binds to albumin to form a metal complex conjugate - albumin, while the conjugate of the metal complex - albumin accumulates in malignant tissue; imaging of a subject is performed upon administration of a metal complex or a pharmaceutical composition comprising a metal complex disclosed herein to detect the metal complex in tissue of said subject (or an isotope of the metal complex), wherein detection of the metal complex (or isotope of the metal complex) in that tissue indicates that the tissue is malignant, thus The subject is diagnosed with cancer.

[0218] In some embodiments, the invention provides a method of treating cancer in a subject, which includes administering to the subject a metal complex or pharmaceutical composition containing a metal complex disclosed herein (including, for example, a metal complex containing a radioactive label), wherein the metal complex binds to albumin to form metal complex-albumin conjugate, wherein the metal complex-albumin conjugate accumulates in malignant tissue, imaging of the subject is performed after administration of the metal complex or pharmaceutical composition including the metal complex to detect the signal from the labeled metal complex in the tissue of the above-mentioned subject, while recording the signal from the isotope in the tissue, indicates that this tissue is malignant; diagnosing the subject as having a malignant tissue lesion; and administering a therapeutically effective amount of a chemotherapeutic agent to the subject. In some embodiments, the invention provides a method of treating cancer in a subject, comprising: administering to the subject a metal complex or a pharmaceutical composition comprising a metal complex disclosed herein (comprising, for example, a metal complex with an isotope), wherein the metal complex binds to albumin to form a metal complex-albumin conjugate, in this case, the conjugate of the metal complex with albumin accumulates in malignant tissue; imaging the subject after administration of a metal complex or a pharmaceutical composition containing a metal complex to detect the metal complex (or labeled metal complex) in tissue of the above subject, wherein the presence of a label in the tissue indicates that the tissue is malignant; diagnosing the subject as having a malignant tissue lesion; and administering a therapeutically effective amount of a chemotherapeutic agent to the subject.

[0219] In some embodiments, the invention provides a method for diagnosing and treating a cancer subject sensitive to an albumin-bound chemotherapeutic agent, the method comprising: administering to the subject a metal complex or pharmaceutical composition containing a metal complex disclosed herein (comprising, for example, a metal complex containing an isotope ), while the metal complex binds to albumin to form a metal complex - albumin conjugate, while the metal complex - albumin conjugate accumulates in malignant tissue; imaging the subject after administration of the metal complex or a pharmaceutical composition comprising the metal complex to detect a signal from the labeled metal complex in tissue of said subject, wherein recording the signal from the isotope in the tissue indicates that the tissue is malignant; diagnosing a cancer subject that is sensitive to therapy with an albumin-bound chemotherapeutic agent; and administering a therapeutically effective amount of an albumin-bound chemotherapeutic agent to the subject. In some embodiments, the invention provides a method for diagnosing and treating a cancer subject sensitive to an albumin-bound chemotherapeutic agent, the method comprising: administering to the subject a metal complex or pharmaceutical composition containing a metal complex disclosed herein (comprising, for example, a metal complex containing an isotope), at in this case, the metal complex binds to albumin to form a metal complex albumin conjugate, while the metal complex albumin conjugate accumulates in malignant tissue; imaging a subject after administration of a metal complex or a pharmaceutical composition comprising a metal complex to detect the presence of a metal complex (or an isotope of a metal complex) in tissue of said subject, wherein detection of the metal complex (or an isotope of a metal complex) in the tissue indicates that the tissue is malignant; diagnosing a cancer subject that is sensitive to therapy with an albumin-bound chemotherapeutic agent; and administering a therapeutically effective amount of an albumin-bound chemotherapeutic agent to the subject.

[0220] In some embodiments, the invention provides a method comprising: administering to a subject a metal complex or pharmaceutical composition comprising a metal complex disclosed herein (including, for example, a metal complex containing a radioactive label), wherein the metal complex binds to albumin to form a metal complex-albumin conjugate, in this case, the metal complex-albumin conjugate accumulates in malignant tissue; performing imaging of a subject after administration of a metal complex or a pharmaceutical composition comprising a metal complex to detect a signal from the labeled metal complex in tissue of said subject, wherein detecting the presence of a signal from the label in the tissue indicates that the tissue is malignant; diagnosing the affected tissue of an oncological subject; and administering a therapeutically effective amount of an albumin-bound chemotherapeutic agent to the subject. In some embodiments, the invention provides a method comprising: administering to a subject a metal complex or pharmaceutical composition comprising a metal complex disclosed herein (comprising, for example, an isotope-containing metal complex), wherein the metal complex binds to albumin to form a metal complex-albumin conjugate, wherein metal complex-albumin conjugate accumulates in malignant tissue; performing imaging of a subject after administration of a metal complex or a pharmaceutical composition comprising a metal complex and detecting the metal complex (or an isotope from the metal complex) in the tissue of said subject, wherein detecting the presence of the metal complex (or an isotope from the metal complex) in the tissue indicates that the tissue is malignant; diagnosing the affected tissue of an oncological subject; and administering a therapeutically effective amount of an albumin-bound chemotherapeutic agent to the subject.

[0221] In some embodiments, the invention provides a method comprising: administering to a subject a metal complex or pharmaceutical composition comprising a metal complex disclosed herein (including, for example, a metal complex containing a radioactive label), wherein the metal complex binds to albumin to form a metal complex--conjugate. albumin, while the metal complex-albumin conjugate accumulates in malignant tissue; performing imaging of a subject after administration of a metal complex or a pharmaceutical composition comprising a metal complex to detect a signal from the labeled metal complex, wherein detecting the presence of a signal from the label in the tissue indicates that the tissue is malignant; diagnosing the affected tissue of an oncological subject; classifying the subject as susceptible to an albumin-bound chemotherapeutic agent; and administering to the subject a therapeutically effective amount of an albumin-bound chemotherapeutic agent. In some embodiments, the invention provides a method comprising: administering to a subject a metal complex or pharmaceutical composition containing a metal complex disclosed herein (including, for example, a metal complex containing a radioactive label), wherein the metal complex binds to albumin to form a metal complex-albumin conjugate, wherein metal complex-albumin conjugate accumulates in malignant tissue; performing imaging of a subject after administration of a metal complex or a pharmaceutical composition comprising a metal complex to detect the metal complex (or metal complex tag), wherein detection of the metal complex (or metal complex tag) in tissue indicates that the tissue is malignant; diagnosing the affected tissue of an oncological subject; classifying the subject as susceptible to an albumin-bound chemotherapeutic agent; and administering a therapeutically effective amount of an albumin-bound chemotherapeutic agent to the subject.

[0222] In some embodiments, the invention provides a method of visualizing a target site in a subject, comprising: administering to the subject a metal complex or pharmaceutical composition containing a metal complex disclosed herein (including, for example, a metal complex containing a radioactive label), wherein the metal complex binds to albumin to formation of a metal complex - albumin conjugate, while the metal complex - albumin conjugate accumulates at the target site; and performing imaging at a target site in a subject after administration of the metal complex or a pharmaceutical composition comprising the metal complex.

[0223] In some embodiments, the invention provides a method of assessing the sensitivity of a cancer subject to an albumin-bound chemotherapeutic agent, comprising: administering to the subject a metal complex or pharmaceutical composition containing a metal complex disclosed herein (including, for example, a metal complex containing a radioactive label), at in this case, the metal complex binds to albumin to form a metal complex - albumin conjugate, while the metal complex - albumin conjugate accumulates in malignant tissue; performing imaging of a subject after administration of a metal complex or a pharmaceutical composition comprising a metal complex to detect a signal from the labeled metal complex, wherein detection of the presence of a signal from a radioisotope in the tissue indicates that the tissue is malignant; diagnosing the affected tissue of an oncological subject; and classifying the cancer subject as susceptible to the albumin-bound chemotherapeutic agent. In some embodiments, the invention provides a method for assessing the sensitivity of a cancer subject to an albumin-bound chemotherapeutic agent, comprising: administering to the subject a metal complex or pharmaceutical composition comprising a metal complex disclosed herein (comprising, for example, a metal complex including a radioisotope label), wherein the metal complex binds with albumin to form a metal complex - albumin conjugate, while the metal complex - albumin conjugate accumulates in malignant tissue; performing imaging of a subject after administration of a metal complex or a pharmaceutical composition comprising a metal complex to detect the metal complex (or a radioisotope label from the metal complex), wherein detection of the presence of the metal complex (or a radioisotope label from the metal complex) in the tissue indicates that the tissue is malignant; diagnosing the affected tissue of an oncological subject; and classifying the subject as having a cancer sensitive to the albumin-bound chemotherapeutic agent.

[0224] In some embodiments, the invention provides a method for selectively accumulating a radiolabeled metal complex disclosed herein within target cells of a subject, including administering to the subject a metal complex or a pharmaceutical composition comprising a metal complex provided herein. In some embodiments, the target cells are tumor cells.

[0225] In some embodiments, the invention provides a method of delivering a radioisotope to a target site in a subject, which includes administering to the subject a metal complex or pharmaceutical composition comprising a metal complex disclosed herein, wherein the metal complex includes a radioisotope label, and wherein the metal complex binds to albumin to form a conjugate. metal complex - albumin, while the metal complex - albumin conjugate accumulates in the target area.

[0226] In some embodiments, imaging is performed at a time point between about 5 minutes and 96 hours after administration of the metal complex or pharmaceutical composition. In some embodiments, imaging is performed at a time point between approximately 5 minutes and 10 hours after administration of the metal complex or pharmaceutical composition. In some embodiments, imaging is performed at a time point between approximately 5 minutes and 5 hours after administration of the metal complex or pharmaceutical composition. In some embodiments, imaging is performed at a time point between approximately 5 minutes and 4 hours after administration of the metal complex or pharmaceutical composition. In some embodiments, imaging is performed at a time point between approximately 5 minutes and 3 hours after administration of the metal complex or pharmaceutical composition. In some embodiments, imaging is performed at a time point between approximately 5 minutes and 2 hours after administration of the metal complex or pharmaceutical composition. In some embodiments, imaging is performed at a time point between approximately 5 minutes and 1 hour after administration of the metal complex or pharmaceutical composition. In some embodiments, imaging is performed at a time point between approximately 5 minutes and 30 minutes after administration of the metal complex or pharmaceutical composition. In some embodiments, imaging is performed at a time point between approximately 10 and 20 hours after administration of the metal complex or pharmaceutical composition. In some embodiments, imaging is performed at a time point between approximately 20 and 30 hours after administration of the metal complex or pharmaceutical composition. In some embodiments, imaging is performed at a time point between approximately 30 and 40 hours after administration of the metal complex or pharmaceutical composition. In some embodiments, imaging is performed at a time point between approximately 40 and 50 hours after administration of the metal complex or pharmaceutical composition. In some embodiments, imaging is performed at a time point between approximately 50 and 60 hours after administration of the metal complex or pharmaceutical composition to the disease. In some embodiments, imaging is performed at a time point between approximately 70 and 80 hours after administration of the metal complex or pharmaceutical composition. In some embodiments, imaging is performed at a time point between approximately 80 and 90 hours after administration of the metal complex or pharmaceutical composition. In some embodiments, imaging is performed at a time point greater than 90 hours after administration of the metal complex or pharmaceutical composition. In some embodiments, imaging is performed at a time point approximately 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 55 minutes after administration of the metal complex or pharmaceutical composition.

In some embodiments, imaging is performed at time points approximately: 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 or 96 hours after administration of the metal complex or pharmaceutical composition.

[0227] In some embodiments, the metal complex or pharmaceutical composition comprising the metal complex is administered to a subject as a metal complex-albumin conjugate formed ex vivo. In some embodiments, the metal complex is administered to a subject and the metal complex-albumin conjugate is formed in vivo.

[0228] In some embodiments, the metal complex or pharmaceutical composition comprising the metal complex is administered to a subject as a metal complex-albumin conjugate formed ex vivo, wherein the metal complex albumin conjugate is formed: by conjugating albumin with a functional group corresponding to the TBG of the metal complex; followed by chelation of M. Albumin could be autogenous or heterogeneous for the subject.

[0229] In some embodiments, the metal complex or pharmaceutical composition comprising the metal complex is administered to a subject as a metal complex-albumin conjugate formed ex vivo, wherein the metal complex-albumin conjugate is formed by: chelation of M to form the metal complex; followed by conjugation of albumin with the TBG of the metallocomplex to form a metallocomplex-albumin conjugate. Albumin may be autogenous or heterogeneous to the subject. In some embodiments, the metal complex or a pharmaceutical composition comprising the metal complex is administered to a subject and the metal complex-albumin conjugate is formed in vivo.

[0230] In some embodiments, the diagnostic methods presented herein can be used for radioimaging a disease selected from cancer, a viral disease, an autoimmune disease, an acute or chronic inflammatory disease, a disease caused by bacteria, fungi, or other microorganisms.

[0231] In some embodiments, the cancer is a blood cancer or a solid tumor. In some embodiments, the cancer is selected from carcinoma, sarcoma, leukemia, lymphoma, multiple myeloma, or melanoma.

In some embodiments, a malignancy such as adenocarcinoma, uveal melanoma, acute leukemia, acoustic neuroma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, connective tissue tumors, bladder cancer, bronchial carcinoma, non-small cell bronchial carcinoma, breast cancer glands, Burkitt's lymphoma, uterine body cancer, malignant tumor syndrome without an identified primary focus (CUP), colon cancer, small intestinal cancer, ovarian cancer, endometrial carcinoma, gallbladder cancer, gallbladder carcinoma, uterine body cancer, cervical cancer, tumors neck, nose and ear, hematologic neoplasia, hairy cell leukemia, urethral cancer, skin cancer, gliomas, testicular cancer, Kaposi's sarcoma, laryngeal cancer, bone cancer, colorectal carcinoma, head/neck tumors, colon carcinoma, craniopharyngeoma, liver cancer, leukemia , lung cancer, non-small cell lung carcinoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, stomach cancer, colon cancer, meduloblastoma, melanoma, meningioma, renal cancer, renal cell carcinomas, oligodendroglioma, esophageal carcinoma, osteoplastic carcinomas and osteolytic carcinomas, osteosarcoma, ovarian carcinoma, pancreatic carcinoma, penile cancer, prostate cancer, tongue cancer, ovarian carcinoma and lymph node cancer.

[0232] In some embodiments, imaging is performed using positron emission tomography (PET) or single photon emission computed tomography (SPECT). In some embodiments, additional imaging is performed using magnetic resonance imaging (MRI) or computed tomography (CT).

[0233] In some embodiments, the subject is a mammal. In some embodiments, the subject is a cattle, cat, dog, mouse, horse, or human. In some embodiments, the subject is a human.

Sets

[0234] Another aspect of the present invention provides a kit. In some embodiments, the kit includes the metal complex presented herein. In some embodiments, the kit is for diagnosing cancer. In other embodiments, the kit is for diagnosing a cancer patient who is susceptible to an albumin-bound chemotherapeutic agent. A kit is a set of materials or components including, at least as presented herein, a metal complex or a pharmaceutical composition including a metal complex.

[0235] In some embodiments, the kit is an imaging kit for detecting albumin in a subject. In other embodiments, the kit is designed to determine the extent of albumin uptake and distribution at pathological sites in a subject (eg, a tumor).

[0236] In some embodiments, the kit is for diagnosing cancer in a subject and includes a metal complex or composition as provided herein; instructions for use of the metal complex or composition for the diagnosis of cancer, including instructions for use of the metal complex or composition in a subject; instructions for imaging a subject after administration of a metal complex or composition to detect a signal from a tracer or from a radioactive isotope in which abnormal accumulation of signal indicates the presence of cancer in the subject.

[0237] In some embodiments, the kit is for diagnosing a cancer subject that may be susceptible to an albumin-bound chemotherapeutic agent, the kit comprising a metal complex or composition as provided herein; instructions for use of the metal complex or composition for diagnosing a cancer patient for susceptibility to an albumin-bound chemotherapeutic agent, including instructions for use of the metal complex or composition in a subject; instructions for imaging a subject after administration of a metal complex or composition to detect a signal from a tracer or from a radioactive isotope in which abnormal accumulation of signal indicates the presence of cancer in the subject.

[0238] The exact physical and chemical characteristics of the formed kits depend on their recommended use. For example, in some embodiments, the kits are generated for the purpose of diagnosing cancer. In other embodiments, they are formed to determine the susceptibility of a cancer subject to an albumin-bound chemotherapeutic agent. In some embodiments, the kit is configured specifically for the purpose of diagnosing mammalian subjects. In another embodiment, the set is generated specifically for the purpose of diagnosing a person. In subsequent embodiments, the kit is formulated for use in veterinary medicine in the diagnosis of subjects such as, but not limited to, cattle, pets and laboratory animals.

[0239] Instructions for use may be included in the kit. "Instructions for use" typically include a clear description of the technique to be used for the components of the kit to achieve a desired result, for example, diagnosing cancer in a subject or diagnosing the susceptibility of a cancer subject to an albumin-bound chemotherapeutic agent. The instructions may include, for example, instructions for administering the metal complex or composition to a subject; instructions for imaging a subject after administration of a metal complex or composition to detect a signal from a tracer or from a radioactive isotope in which the accumulation of a signal indicates the presence of cancer in the subject, or that the subject will respond to an albumin-bound chemotherapeutic agent.

[0240] Optionally, the kit also contains other useful components, such as diluents, buffers, pharmaceutically acceptable carriers, syringes, catheters, applicators, pipettes or measuring instruments, or other useful components that are recognized in the art.

[0241] The materials or components collected in the kit may be provided to the consumer stored in any convenient and suitable ways that do not impair their functionality and performance. For example, the components may be in dissolved, dehydrated or lyophilized form; stored at ambient temperature, refrigerated or frozen. The components are usually housed in appropriate packaging material. As used herein, the phrase “packaging material” refers to one or more packaging units used to secure the kit provided. The packaging material is developed by known methods aimed at providing and maintaining a sterile environment. The packaging materials used in the kit are those traditionally used in cancer diagnosis and/or for compositions containing radioactive compositions. As used herein, the term “packaging” refers to a suitable solid matrix or material, such as glass, plastic, paper, foil, etc., capable of supporting the individual components of the kit. The packaging material is typically provided with external markings indicating the contents and/or purpose of the kit and/or its components.

Variations and modifications

[0242]In the presented document can There may be variations, modifications and other implementations of the content presented herein according to generally accepted criteria, without departing from the spirit and scope of the invention. Accordingly, the invention should not be limited by the previous description or the following examples.

Presentation of examples

[0243] The aspects of the invention presented generally will be more readily appreciated by the following examples, which are included only for the purpose of illustrating specific characteristics and embodiments of the invention and are not intended to be limiting.

Equivalents

[0244] Those skilled in the art recognize, or will be able to provide, common experimental use of multiple equivalents of metal complexes, compositions and methods of use in the presented document. Such equivalents are intended to be within the spirit and scope of the invention.

EXAMPLES

Example 1

Materials and methods for preparing metal complexes

[0245] All reactions were performed under an inert atmosphere of N ₂ unless otherwise stated. Commercially available reagents were used without further purification unless otherwise stated. Anhydrous solvents were purchased in anhydrous form (dichloromethane, dimethyl sulfoxide, N, N -dimethylformamide, tetrahydrofuran, etc.), and all other solvents used were reagents or belonged to the "HPLC-use" classification.

[0246] Nuclear magnetic resonance spectra were recorded at ambient temperature (unless otherwise stated) on a 400 MHz spectrometer: Bruker Avance 400 Ultrashield (400 MHz for ¹ H, 100 MHz for ¹³ C). All chemical shift values for the proton are presented in parts per million (δ), calibrated to the deuterated proton in _CDCl3 ( δ 7.26) or the deuterated proton of DMSO- _d6 (δ 2.50) or the deuterated proton of _D2O ( δ 4 ,79). All chemical shift values for carbon are presented in parts per million (δ ) and calibrated to carbon uptake in CDCl ₃ (δ 77.0) or DMSO-d _6.

( δ 39.52). NMR spectroscopy results are represented by the following characteristics: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, quin=quintet, m=multiplet, br=broad, dd=doublet/doublet), splitting constant= J (Hz=Hertz) and integrated.

[0247] Low-resolution mass spectra were collected on a Bruker Amazon SL spectrometer (ESI) or a Thermo Fisher LCQ attachment (ESI).

[0248] Glassware and magnetic stirrers are typically oven dried at 140°C for at least 12 hours and then cooled under N ₂ until used. The vials were equipped with a restrictive membrane to maintain positive N ₂ pressure unless otherwise noted. All other reactions were performed in round-bottom flasks sealed with rubber stoppers. Plastic syringes or glass pipettes were used to transfer liquid reagents. The reactions were carried out with stirring on a magnetic stirrer using Teflon-coated magnets. Analytical thin layer chromatography (TLC) was performed using aluminum plates precoated with a 0.25 mm layer of 230-400 mesh silica gel and impregnated with a fluorescent indicator (254 nm). TLC plates were visualized by irradiation with ultraviolet light and/or application of a KMnO ₄ dye solution. Organic solutions were concentrated under reduced pressure using KNF RC 600 and Heidolph Hei-VAP rotary evaporators.

[0249] Flash column chromatography is performed on silica gel prepacked FLASH columns using the Biotage Isolera™ One and Biotage Isolera™ SL (high volume) purification system.

[0250] Trifluoroacetic acid (TFA) content was determined using an evaporative light scattering detector (ELSD LT-II, Shimadzu) and an Acclaim Trinity Pl ion exchange column (3.0 μm, 3.0 x 150 mm). Determination of the amount of TFA was performed in triplicate for each sample and calculated from a 7-point calibration curve.

[0251]pH values solutions were measured at room temperature using a WTW Inolab 7310 pH meter with SenTix electrodes^® mic-D.

[0252] HPLC was performed using a Shimadzu Nexera XR HPLC system equipped with an SPD-M20A photodiode array detector.

[0253]Lyophilization performed on a Martin Christ Alpha 2-4 LSCplus installation.

[0254] Centrifugation was performed on an Eppendorf 5810 R refrigerated centrifuge, with an A-4-81 rotor.

HPLC methods

[0255] HPLC Method 1: Used to monitor the reaction and determine purity. Column: Phenomenex Kinetex Polar: C18 (150 x 4.6 mm, 2.6 µm, 100 Å), Gradient: Mobile phase A: water (0.1% TFA), Mobile phase B: acetonitrile (0.1% TFA ). Phase B elution gradient: 0% - 3.5 minutes; 30%, 3.5-20 minutes; 30-80%, 20-22 minutes; 80-100%, 22-24 minutes; 100%, 24-27 minutes; 100-30%, 27-30 minutes; 30%, 30 minutes; end of run, flow rate =1.0 ml/minute.

[0256] HPLC Method 2: Used to monitor the reaction and determine purity. Column: Phenomenex Kinetex Polar: C18 (150 x 4.6 mm, 2.6 µm, 100 Å), Gradient: Mobile phase A: water (0.1% TFA), Mobile phase B: acetonitrile (0.1% TFA ). Phase B elution gradient: 0% - 3.5 minutes; 5%, 3.5-20 minutes; 5-40%, 20-22 minutes; 40-65%, 22-24 minutes; 65%, 24-27 minutes; 65-5%, 27-30 minutes; 5%, 30 minutes; end of run, flow rate =1.0 ml/minute.

[0257] HPLC Method 3: Used to monitor the reaction and determine purity. Column: Phenomenex Kinetex Polar: C18 (150 x 4.6 mm, 2.6 µm, 100 Å), Gradient: Mobile phase A: water (0.1% TFA), Mobile phase B: acetonitrile (0.1% TFA ). Phase B elution gradient: 0-5.5 minutes: 1%, 5.5-20 minutes; 1-40%, 20-22 minutes; 40-65%, 22-24 minutes; 65%, 24-27 minutes; 65-1%, 27-30 minutes; 1%, 30 minutes: end of run, flow rate =1.0 ml/minute.

[0258] HPLC Method 4: Used to monitor the reaction and determine purity. Column: Phenomenex Kinetex Polar: C18 (150 x 4.6 mm, 2.6 µm, 100 Å), Gradient: Mobile phase A: water (0.1% TFA), Mobile phase B: acetonitrile (0.1% TFA ). Phase B elution gradient: 0-1.5 minutes; 1%, 1.5-8 minutes; 1-65%, 8-10 minutes; 65-95%, 10-13 minutes; 95%, 13-14 minutes; 95-1%, 14-16 minutes; 1%, 15 minutes: end of run, flow rate =1.0 ml/minute.

[0259] HPLC Method 5: Used to monitor the reaction and determine purity. Reverse phase column: Phenomenex Kinetex Polar: C18 (150 x 4.6 mm, 2.6 µm, 100 Å), gradient: mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile (0. 1% TPA). Phase B elution gradient: 0-1.5 minutes: 5%, 1.5-8 minutes; 5-65%, 8-13 minutes; 65-95%, 13-15 minutes; 95-5%, 15 minutes; end of run, flow rate =1.0 ml/minute.

[0260] HPLC Method 6: was used to monitor the reaction and assess purity. Reverse phase column: Phenomenex Kinetex Polar: C18 (150 x 4.6 mm, 2.6 µm, 100 Å), gradient: mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile (0. 1% TPA). Phase B elution gradient: 0-1.5 minutes; 15%, 1.5-8 minutes; 15-70%, 8-10 minutes; 70-95%, 10-13 minutes; 95%, 13-15 minutes; 95-15%, flow rate = 1.0 ml/minute.

[0261] HPLC Method 7 was used to monitor the reaction and assess purity. Reverse phase column: Phenomenex Kinetex Polar: C18 (150 x 4.6 mm, 2.6 µm, 100 Å), gradient: mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile (0. 1% TPA). Phase B elution gradient: 0-1.5 minutes; 5%, 1.5-20 minutes; 5-65%, 20-22 minutes; 65-95%, 24-30 minutes; 95-5%, 30 minutes: end of run, flow rate =1.0 ml/minute.

[0262] HPLC Method 8: used for radiochemical monitoring and purity assessment Reverse phase column: Phenomenex Kinetex Polar: C18 (150 x 4.6 mm, 2.6 µm, 100 Å), gradient: mobile phase A: water (0 .1% TFA), mobile phase B: acetonitrile (0.1% TFA). Phase B elution gradient: 0-1.5 minutes; 5%, 1.5-20 minutes; 5-40%, 20-22 minutes; 40-65%, 22-24 minutes; 65%, 24-25 minutes; 65-5%, 25-30 minutes; 5%. 30 minutes; end of run, flow rate =1.0 ml/minute. Column temperature control: 37 °C.

[0263] HPLC Method 9: used to bind serum albumin. Column: Phenomenex Aeris WP C18 (250 x 4.6 mm, 3.6 µm, large pore), gradient: mobile phase A: water with 0.1% TFA, mobile phase B: acetonitrile with 0.1% TFA. Phase B elution gradient: 0-1.5 minutes; 5%, 1.5-20.0 minutes; 5-60%, 20-22.0 minutes; 60-85%, 22-24.0 minutes; 85-85%, 24-27.0 minutes; 85-5%, 30 minutes; end of run, flow rate =1.0 ml/minute. Column temperature control: 37 °C.

Liquid chromatography-mass spectrometry (LC-MS) method

[0264] LC-MS method: Column: Phenomenex Kinetex Polar: C18 (150 x 4.6 mm, 2.6 µm, 100 Å), Gradient: Mobile phase A: 0.1% fluoroacetic (FA) acid in H ₂ O: acetonitrile, mobile phase B: 0.1% FU in CH ₃ CN. Phase B elution gradient: 0-1.0 minute; 15%, 1.0-10.0 minutes; 15-100%, 10.0-11.5 minutes; 100%, 11.50-12.50 minutes; 15%, 12.50-15.0 minutes; 15%, 15.0 minutes; end of run, 15 minutes: end of run, flow rate=0.4 ml/minute.

Determination of the amount of TFA (trifluoroacetic) acid

[0265] The TPA content of the purified chelates was determined using an evaporative light scattering detector (ELSD LT-II, Shimadzu, level indicator up to 5, T=30 °C) and an Acclaim Trinity Pl ion exchange column (3.0 μm, 3.0× 150 mm). Mobile phase A: 90% acetonitrile/10% Millipore water. Mobile phase B: 0.2 M ammonium acetate pH. = 4.3. Phase B elution gradient: 0-4.0 minutes; 25%, 4.0-10.0 minutes; 25-90%, 10.0-13.0 minutes; 90%, 13.0-15.0 minutes; 90-25%, 15.0-20.0 minutes; 25%, 20.0 minutes; end of run. Flow rate=0.6 ml/minute. Injected volume: 30 µl. Determination of the amount of TPA was performed in triplicate for each sample (dissolved in 0.2 M HCl.) and calculated from a 7-point calibration curve (calibration range from 1.15 mM to 6.49 mM). A: 6.5 mM TPA stock solution was injected at least 4 times to fill the column before loading the batch.

Radiochemical labeling and purity

[0266] Preparation of lyophilized composition: C4-DTPA was dissolved in lyophilization buffer at a final concentration of 0.09 mg/ml. The lyophilization buffer contained 2 mg/mL gentistic acid, 10 mg/mL inositol, 5.6 mg/mL sodium citrate, and 0.4 mg/mL citric acid. The dissolved chelate was filtered under sterile conditions through an Acrodisc Fluorodyne II filter syringe (0.2 μm). Sterile solutions were pipetted into lyophilization vials, which were then partially sealed with rubber stoppers. The vials were then placed in a freezer for lyophilization. The vials were gradually frozen over 9 hours until a final temperature of -40°C was reached. The main drying began at the end of the freezing cycle and was carried out at a temperature between -40°C and -20°C for 52 hours (vacuum 0.08 mbar). Upon completion of the main drying cycle, a final drying was performed for 12 hours at 25 °C (0.08 mbar vacuum). After completion of the cycle, the vials were sealed under vacuum.

[0267] Radiolabeling and quality control: Radiolabeling of C4-DTPA was performed by adding 42.4 ± 7.6 mBq (C4-DTPA) ¹¹¹ InC1 ₃ in HCl solution to vials containing lyophilized test compound (MAP Medical , Finland). The vials were shaken until the solution became completely clear and incubated for 30 minutes at +37°C. Radioactive isotope labeling was performed in triplicate.

[0268] The radiochemical purity of the radiolabeled product ¹¹¹ In-C4-DTPA was measured on a C18 reverse phase column (Agilent 1260 Infinity II Chromatography System, Method 8). The sample was diluted 1:10 (v/v) with water, and 10 μL of sample was injected into the HPLC system.

[0269] Chromatography: Infinity II 1260 HPLC System (Agilent Inc., Santa Clara, CA, USA) consisting of G711A Solvent Delivery System, G7129A Temperature Controlled Autosampler, G7114A UV Sensor, G1364C Analytical Collection Collector, and RF Sensor PosiRAM (LabLogic Systems Ltd). The HPLC system was controlled by a LAURA controller and analysis software (LabLogic Systems Ltd., UK). Samples for analysis were separated in a flow gradient on an RP-HPLC column (Kinetex Polar C18 (4.6 mm 150 mm, with pre-column). HPLC method 8 was used.

Example 2

Synthesis examples

[0270] Compounds 3a - d presented in Scheme 5 are prepared as described below.

General procedure for the synthesis of compounds 3a - 3d

[0271] p -NH ₂ -Bn-DTPA*4 HCl 1 (1.0 '1 eq.) was mixed with anhydrous acetonitrile (2 ml/100 mg) in a 12 ml plastic tube. DIPEA (11 eq.) was added and the mixture dissolved by sonication. A solution of maleimido N -hydroxysuccinimide ester 2a-2d (2 eq.) in dry MeCN (2 mL) was then added to the DTPA solution, the mixture was stirred at room temperature, and the progress of the reaction was monitored by HPLC. After 18 hours, acetic acid (11 eq.) was added to neutralize the base and stop the reaction. The product was precipitated from MTBE (8 ml), and the resulting precipitate was centrifuged (4 minutes, 4000 rpm) and purified by RP-Flash chromatography. For purification by RP flash chromatography, the precipitate was dissolved in a mixture of 600 μL MeCN and 600 μL water. The resulting solution was diluted with water to a volume of 6 ml (10% MeCN). The solution was purified by RP flash chromatography on a Biotage Isolera ^™ One Flash Purification System on a SNAP Ultra C18 30g precolumn using a gradient step containing 0.1% TFA and acetonitrile containing 0.1% TFA. Product fractions were analyzed by HPLC (method 2, at 220 nm), and purified fractions were pooled and lyophilized to obtain the light, finely crystalline residue 3a-3d.

Output and characterization results for 3a-3d

[0272] Compound (R)-2,2'-((2-((2-(bis(carboxymethyl)amino)-3-(4-(3-(2,5-dioxo-2,5-dihydro- l H -pyrrol-l-yl)propanamido)phenyl)propyl)(carboxymethyl)amino)ethyl)azanedyl)diacetic acid 3a, prepared as described above. Yield: 35 mg (35%) (TPA content: 0.75 ± 0.03 mol eq.). HPLC (method 2, 220 nm) greater than 95%. LRMS-ESI (m/z) calculated content for: C ₂₈ H ₃₆ N ₅ O ₁₃ [M+H] ⁺ : 650.23. Determined: 650.08. ¹ H NMR (400 MHz, D ₂ O) δ 7.35 (d, J= 8.4 Hz, 2H), 7.27 (d, J= 8.4 Hz, 2H), 6.84 (s, 2H), 3.99-3.71 (m., 12H), 3.68-3.58 (m., 1H), 3.47-3.10 (m., 7H), 2.77-2, 62 (m., 3H). ¹³ C NMR (101 MHz, D ₂ O, as TPA salt, TPA signals not included), δ 172.67, 172.59, 172.20, 171.28, 170.66, 135.78, 134.43, 133.14, 129.88, 122.32, 62.01, 55.52, 54.48, 54.16, 51.24, 49.88, 35.50, 34.42, 31.92. ¹⁹ F NMR (376 MHz, D ₂ O) δ - 75.59.

[0273] (R)-2,2'-((2-((2-(bis(carboxymethyl)amino)-3-(4-(3-(2,5-dioxo-2,5-dihydro-l H -pyrrol-l-yl)butanamido)phenyl)propyl)(carboxymethyl)amino)ethyl)azanedyl), diacetic acid 3b, C4-DTPA was prepared as described above. Yield: 114 mg (22%) (TFA content: 1.29 ± 0.22 mol eq.). HPLC (method 2, at 220 nm) greater than 95%. LRMS-ESI (m /z) calculated: C ₂₉ H ₃₆ N ₅ O ₁₃ [M+H] ^- : 662.23. Defined: 662.33. ¹ H NMR (400 MHz, D ₂ O) 8 7.34 (d, J=8.1 Hz, 2H), 7.21 (d, J=8.2 Hz, 2H), 6.71 (s, 2H), 4.00-3.65 (m, 10H), 3.64-3.54 (m., 1H), 3.51 (t, J=6.5 Hz, 2H), 3.45- 3.00 (m., 7H), 2.65 (dd, J=13.9, 9.2 Hz, 1H), 2.36 (t, J=7.0 Hz, 2H), 1.92 ( p., J=6.8 Hz, 2H). ¹³ C NMR (101 MHz, D ₂ O, as TPA salt, TPA signals not included), δ 173.92, 173.06, 172.77, 170.93, 170.56, 136.05, 134.27, 132.76, 129.80, 121.92, 62.00, 55.26, 54.63, 53.99, 52.62, 51.10, 49.95, 36.95, 33.47, 31, 94, 23,33. ¹⁹ F NMR (376 MHz, D ₂ O) δ-75.65.

[0274] (R)-2,2'-((2-((2-(bis(carboxymethyl)amino)-3-(4-(3-(2,5-dioxo-2,5-dihydro-l H -pyrrol-l-yl)pentanamido)phenyl)propyl)(carboxymethyl)amino)ethyl)azanedyl)diacetic acid 3c was synthesized as described above. Yield: 47.0 mg (22%) (TFA content: 1.05 ± 0.01 mol eq.). HPLC (method 5, at 220 nm) greater than 95%. LRMS-ESI (m/z) calculated for C ₃₀ H ₃₉ N ₅ O ₁₃ [M+H] ⁺ : 678.26.

Defined: 678.23. TPA content (per mole of compound): 1.05 mol eq. ¹ H NMR (400 MHz, D ₂ O) δ7.36 (d, J= 8.4 Hz, 2H), 7.21 (d, J= 8.4 Hz, 2H), 6.75 (s, 2H ), 4.00-3.67 (m, 10H), 3.60-3.53 (m 1H), 3.45 (t, J= 6.2 Hz, 2H), 3.38-3.02 (m, 7H), 2.63 (dd, J= 13.6, 9.5 Hz, 1H), 2.35 (t, J= 6.5 Hz, 2H), 1.64-1.49 ( m., 4H); ¹³ C NMR (101 MHz, D ₂ O, as TPA salt, TPA signals not included), δ 174.97, 173.18, 172.85, 170.82, 170.61, 136.08, 134.20, 132.82, 129.82, 122.04, 61.99, 55.15, 54.50, 54.03, 52.52, 50.98, 49.98, 37.13, 35.72, 31, 90, 27.00, 22.39.

[0275] (R)-2,2'-((2-((2-(bis(carboxymethyl)amino)-3-(4-(3-(2,5-dioxo-2,5-dihydro-l H -pyrrol-l-yl)hexanamido)phenyl)propyl)(carboxymethyl)amino)ethyl)azanedyl), diacetic acid 3-d was synthesized as described above. Yield: 23 mg (21%) (TPA content: 1.17 ± 0.10 mol eq.). HPLC (method 2, at 220 nm) greater than or equal to 95%. LRMS-ESI (m/z) calculated content for: C ₃₁ H ₄₂ N ₅ O ₁₃ [M+H] ⁺ : 692.28. Defined: 692.26. ^1H NMR (400 MHz, DMSO _- d6 ) δ 9.83 (s, 1H), 7.52 (d, J= 8.5 Hz, 2H), 7.17 (d, J= 8.5 Hz , 2H), 7.00 (s, 2H), 4.52-4.35 (m., 2H), 3.59-3.31 (m., 14H), 3.17 (d, J =11 ,0 Hz, 1H), 3.05-2.97 (m., 2H), 2.93 (dd, J= 13.5, 5.1 Hz, 1H), 2.48-2.44 (m ., 1H), 2.26 (t, J= 7.4 Hz, 2H), 1.62-1.53 (m., 2H), 1.54-1.46 (m., 2H), 1 .24 (p, J= 7.7, 7.2 Hz, 2H). ¹³ C NMR (101 MHz, DMSO d ₆ as TPA salt, TPA signals not included), δ 173.97, 172.43, 171.13, 171.01, 167.77, 137.81, 134.48, 132 ,23, 129.33, 119.17, 59.03, 55.40, 53.89, 53.28, 52.07, 51.46, 48.72, 37.00, 36.16, 33.21 , 27.82, 25.85, 24.63.

[0276] Compounds 6a-d and 7a-d presented in Scheme 6 were prepared as described below.

General procedure for the synthesis of compounds 6 and 7

[0277]Step 1: To the cooled solution (-15°C)tetra-tBu-DTPA 4(1.00 eq.) in tetrahydrofuran (THF) (1000 µl/150 mg) added diisopropylethyleneamine (DIPEA) (2.00 eq.) and isobutyl chloroform (1.10 eq.). After 10 minutes, the amino maleimide derivative was added dropwise to the THF suspension (3000 μl). 5a-dor 5a'-d'(1.00 eq.). The mixture was stirred for 30 minutes at -15°C and then warmed to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by flash chromatography in the first Biotage Isolera™ One flash chromatography purification system, with a SNAP Ultra 25 g pre-column in a gradient of 0% to 10% methanol in chloroform, to obtain the compound 6a-d,as viscous oily mixture of brown color.

[0278] Step 2: A mixture of trifluoroacetic acid (220 eq) and anisole (7.75 eq) is added to the vial containing the product from step 1, 6a-d (1.00 eq). The mixture was stirred at 25°C for 24 hours. The reaction mixture was transferred dropwise into a plastic test tube containing 30 ml of diethyl ether. The resulting white precipitate formed instantly. The test tube was left for 1 hour in the refrigerator at -20 °C. The precipitate was then centrifuged (4000 rpm, 5 minutes), washed with 5 ml diethyl ether and dried in vacuo for 20 hours to obtain compound 7a-d as a white microcrystalline solid.

Output and characteristics of connections 6a-d and 7a-d

[0279] Tetra-tert-butyl 2,2',2",2"'-((((2-((2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-l-yl )ethyl)amino)-2-oxoethyl)azanedyl)bis(ethane2,l-diyl))bis(azanetril)),tetraacetate 6a was synthesized as described above. Yield: 147 mg (83%), HPLC (method 1, at 220 nm) more than 95%. LRMS-ESI (m/z) calculated for C ₃₆ H ₆₂ N ₅ O ₁₁ [M+H] ⁺ : 740.44. Determined: 740.53.

[0280] 2,2',2",2"'-((((2-((2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethyl)amino) -2-oxoethyl)azanedyl)bis(ethane-2,l-diyl))bis(azanetrile)),tetraacetic acid 7a was synthesized as described above. Yield: 73 mg (89%) (TPA content: 1.13 ± 0.20 mol eq.). HPLC (method 3, at 220 nm) greater than 97%. LRMS-ESI (m/z) calculated for C ₂₀ H ₃₀ N ₅ O ₁₁ [M+H] ⁺ : 516.19. Defined: 516.20. ^1H NMR (400 MHz, deuterium oxide) δ 6.86 (s, 2H), 4.09 (s, 8H), 3.74-3.62 (m., 2H), 3.54 (d, J = 3.5 Hz, 2H), 3.49 (t, J = 6.4 Hz, 4H), 3.44-3.35 (m., 2H), 3.18 (t, J = 6.4 Hz, 4H). ¹³ C NMR (101 MHz, D ₂ O, as TPA salt, TPA signals not included), δ 173.02, 171.10, 169.92, 134.44, 55.63, 55.38, 52.46, 50.12, 38.06, 36.97.

[0281] Amine 5b or 5b' was synthesized according to a previously described procedure (Horstmann et al., Bioorganic Chemistry, 57:155-161 (2014)). Tetra-tert-butyl 2,2',2",2"'-((((2-((4-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)butyl) amino)-2-oxoethyl)azanedyl)bisethane 2, l-diyl))bis(azanetril))tetraacetate 6b was synthesized as described above. Yield: 99 mg (80%), HPLC (method 1, at 220 nm) = 95%. LRMS-ESI (m/z) calculated for C ₃₈ H ₆₆ N ₅ O ₁₁ [M+H] ⁺ : 768.48. Defined: 768.58.

[0282] 2,2',2",2"'-((((2-((4-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)butyl)amino) -2-oxoethyl)azanedyl)bis(ethane-2,l-diyl))bis(azanetril))tetraacetic acid 7b was synthesized as described above. Yield: 78 mg (99%) (TPA content: 1.07 ± 0.20 mol eq.). HPLC (method 2, at 220 nm) greater than 98%. LRMS-ESI (m/z) calculated for C ₂₂ H ₃₄ N ₅ O ₁₁ [M+H] ⁺ : 544.22. Defined: 544.21. ^1H NMR (400 MHz, D2O) δ 6.80 (s, 2H), 3.98 (s, 8H), 3.55-3.40 (m., 8H), 3.24-3.08 ( m., 6H), 1.67-1.41 (m., 4H). ¹³ C NMR (101 MHz, deuterium oxide) δ 173.35, 170.85, 170.02, 134.30, 56.08, 55.88, 52.35, 49.84, 38.74, 37.18 , 25.55, 25.04.

[0283] Tetra-tert-butyl 2,2',2",2"'-((((2-((5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-l-yl )Pentyl)amino)-2-oxoethyl)azanedyl)bis(ethane-2,l-diyl))bis(azanetril))tetraacetate 6c was synthesized as described above. Yield: 120 mg (47%), HPLC (method 1, at 220 nm) more than 95%. LRMS-ESI (m/z) calculated for: C ₃₉ H ₆₈ N ₅ O ₁₁ [M+H] ⁺ : 782.49. Defined: 782.60. ¹ NMR (400 MHz, CDCl ₃ ) δ 8.11 (s, 1H), 6.66 (s, 2H), 3.49 (t, J= 7.2 Hz, 2H), 3.40 (s, 8H), 3.21 (q, J= 6.9 Hz, 2H), 3.09 (s, 2H), 2.76 (s, 4H), 2.60 (s, 4H), 1.63- 1.50 (m., 4H), 1.43 (s, 36H), 1.35-1.22 (m., 2H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 170.91, 170.71, 170.66, 134.15, 81.14, 58.77, 55.97, 53.87, 52.21, 39.10 , 37.88, 29.36, 28.40, 28.28, 24.36.

[0284] 2,2',2",2"'-((((2-((5-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)pentyl)amino) -2-oxoethyl)azanedyl)bis(ethane-2,l-diyl))bis(azanetril))tetraacetic acid 7c was synthesized as described above. Yield: 65.0 mg (89%) (calculated as TPA salt. TPA content: 0.81 ± 0.16 mol eq.). HPLC (method 2, at 220 nm) greater than or equal to 95%. LRMS-ESI (m/z) calculated for: C ₂₃ H ₃₆ N ₅ O ₁₁ [M+H] ⁺ : 558.24. Defined: 558.24. ^1H NMR (400 MHz, _DMSO -d6 ) 6 8.38 (s, 1H), 7.00 (s, 2H), 3.92 (s, 2H), 3.47 (s, 8H), 3 .38 (t, J= 7.1 Hz, 2H), 3.20 (s, 4H), 3.13-3.04 (m., 2H), 2.97 (s, 4H), 1.53 -1.46 (m., 2H), 1.47-1.37 (m., 2H), 1.27-1.15 (m., 2H). ¹³ C NMR (101 MHz, DMSO _- d6 , as TFA salt, TFA signals not included), δ 173.30, 173.23, 171.57, 134.93, 54.96, 54.81, 52.61 , 49.69, 38.96, 37.41, 28.78, 28.11, 23.

[0285] Amine 5d or 5d' was synthesized according to a previously described procedure (Horstmann et al., Bioorganic Chemistry, 57:155-161 (2014)). Tetra-tert-butyl 2,2',2",2"'-((((2-((6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexyl) amino)-2-oxoethyl)azanedyl)bis(ethane-2,l-diyl))bis(azanetril))tetraacetate 6d was synthesized as described above. Yield: 21 mg (16%), HPLC analysis greater than 94% (method 1, at 220 nm), LRMS-ESI (m/z) calculated for: C ₄₀ H ₇₀ N ₅ O ₁₁ [M+H] ⁺ : 796 ,50. Determined: 796.67, ^1H NMR (300 MHz, CDCl ₃ ) δ 8.05 (brs, 1H), 6.65 (s, 2H), 3.47 (t, 2H, J= 7.3 Hz) , 3.38 (s, 8H), 3.21-3.16 (q, 2H, J= 6.8 Hz), 3.08 (brs, 2H), 2.77-2.73 (m., 4H), 2.61-2.57 (m., 4H), 1.57-1.22 (m., 5H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 171.84, 170.90, 170.61, 134.12, 81.10, 58.78, 55.94, 53.87, 52.20, 39.14 , 37.88, 29.70, 28.57, 28.45, 28.26, 28.05, 26.65, 26.54.

[0286] 2,2',2",2"'-((((2-((6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexyl)amino) -2-oxoethyl)azanedyl)bis(ethane-2,l-diyl))bis(azanetrile)),tetraacetic acid 7d was synthesized as described above. Yield: 5.0 mg, 33%, (calculated as TPA salt. TPA content: 0.92 ± 0.17 mol eq.). HPLC analysis: purity 97.69% (method 1, at 220 nm), LRMS-ESI (m/z) calculated for: C ₂₄ H ₃₈ N ₅ O ₁₁ [M+H] ⁺ : 572.25. Determined: 572.29, ^1H NMR (300 MHz, CDCl ₃ ) δ 6.83 (s, 2H), 4.01 (s, 8H), 3.59 (s, 2H), 3.52-3, 47 (m., 6H), 3.23-3.17 (m., 6H), 1.60-1.47 (m., 4H), 1.36-1.18 (m., 4H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 173.41, 170.42, 169.54, 134.24, 55.60, 51.93, 50.58, 39.30, 37.44, 28.07 , 27.43, 25.48, 25.40.

[0287] Compounds 10 bd were synthesized as shown in Scheme 7 and according to the general procedure as presented below.

General procedure for the synthesis of compound 10b-10d

[0288] To a suspension of DTPA dianhydride 9 (1 eq, 560 μM, 200 mg) in anhydrous DMF (3 mL) in a 15 mL plastic tube, add trifluoroacetate linker 5b-5d (0.6 eq) in three portions over 2 hours ) in anhydrous DMF (1 ml) (333 μl/hour), the suspension was stirred for a few seconds, and the reaction was stirred for 3 hours. Water (4 ml) was added to the suspension. The resulting solution was directly injected into a C18 reverse phase cartridge and purified by flash chromatography. Purification was performed using a step gradient, from 100% water (0.1% TFA) to 100% acetonitrile (0.1% TFA) over 10 column volumes. Fractions containing the product were combined and lyophilized to obtain the desired compound as a white microcrystalline solid.

Output and results characteristics for 10b-10d

[0289] 2-({2-[bis(carboxymethyl)amino]ethyl}({2-[(carboxymethyl)({[4-(2,5-dioxo-2,5-dihydro-lH-pyrrole-l- yl)butyl]carbamoyl}methyl)amino]ethyl})amino)acetic acid 10b was prepared as described above. Yield: 44 mg (35% relative to linker) (calculated as TPA salt. TPA content: 1.83 ± 0.23 mol eq.). HPLC (method 2, at 220 nm) - 98%. LRMS-ESI (m/z) calculated for C ₂₂ H ₃₃ N ₅ O ₁₁ [M+H] ⁺ : 544.53. Defined: 544.27. ¹ H NMR (400 MHz, D ₂ O) δ 6.82 (s, 2H), 4.11 (s, 4H), 4.04 (s, 2H), 4.03 (s, 2H), 3, 72 (s, 2H), 3.54-3.45 (m., 6H), 3.27-3.20 (m., 6H), 1.62-1.46 (m., 4H); ¹³ C NMR (101 MHz, D ₂ O, as TPA salt, TPA signals not included), δ 173.30, 172.91, 169.91, 166.51, 134.28, 56.27, 55.60, 55.54, 53.77, 52.56, 50.03, 49.93, 38.90, 37.08, 25.43, 24.96.

[0290] 2-{[2-({2-[bis(carboxymethyl)amino]ethyl}(carboxymethyl)amino)ethyl]({[5-(2,5-dioxo-2,5-dihydro-lH-pyrrole -l-yl)pentyl]carbamoyl}methyl)amino)acetic acid 10c was prepared as described above. Yield: 87 mg (36% relative to linker) (calculated as TPA salt. TPA content: 1.46 ± 0.25 mol eq.). HPLC (method 2, at 220 nm) - 98%. LRMS-ESI m/z) calculated for C ₂₃ H ₃₅ N ₅ O ₁₁ [M+H] ⁺ : 558.56. Defined: 558.26. ¹ H NMR (400 MHz, D ₂ O) δ 6.82 (s, 2H), 4.08 (s, 4H), 4.02 (s, 2H), 4.00 (s, 2H), 3, 73 (s, 2H), 3.53-3.45 (m., 6H), 3.26-3.21 (m., 6H), 1.60-1.49 (m., 4H), 1 .30-1.22 (m., 2H); ^13C NMR (101 MHz, _D2O , as TPA salt, TPA signals not included), δ 173.38, 172.85, 170.12, 170.05, 166.56, 134.26, 56.31, 55.72, 55.66, 53.83, 52.47, 50.11, 49.98, 39.31, 37.37, 27. 65, 27.21, 23.22.

[0291] 2-{[2-({2-[bis(carboxymethyl)amino]ethyl}(carboxymethyl)amino)ethyl]({[6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl) hexyl]carbamoyl}methyl)amino)acetic acid10dreceived, as described above. Yield: 66 mg (26%, based on linker) (calculated as TPA salt. TPA content: 1.73 ± 0.25 mol eq.). HPLC (method 2, at 220 nm) - 98%. LRMS-ESI (m/z) calculated for C₂₄H₃₇N₅O_eleven [M+H] ⁺: 572.58. Determined: 572.27. ¹H NMR (400 MHz, D₂O) δ 6.83 (s, 2H), 4.05 (s, 4H), 4.01 (s, 2H), 3.97 (s, 2H), 3.73 (s, 2H), 3, 53-3.44 (m., 6H), 3.27-3.21 (m., 6H), 1.59-1.47 (m., 4H), 1.36-1.24 (m. , 4H); ¹³C NMR (101 MHz, D₂O, as TPA salt, TPA signals not included), δ 173.41, 172.92, 169.89, 169.87, 166.34, 134.24, 56.28, 55.59, 55.56, 53 .77, 52.58, 50.00, 49.93, 39.41, 37.44, 27.96, 27.43, 25.40, 25.39.

[0292] The metal compounds and complexes presented in Scheme 7 are prepared as described below according to Route A or Route B.

[0293] Compounds 17, 18, and 14b were synthesized as described according to route A of Scheme 7 above, as shown and presented below in Scheme 8.

[0294]_(R)-2,2'-((2-((2-(bis(carboxymethyl)amino)-3-(4-(3-((tert-butoxycarbonyl) amino)propanamido)phenyl)propyl)(carboxymethyl) amino)ethyl)azanediyl)diacetic acid 17was synthesized as follows. To the solution p-NH₂-Bn-DTPA*4 HCl 1(1.00 eq., 0.46 mM, 300 mg) in anhydrous MeCN (6 ml) under N atmosphere₂ added DIEA (11.0 eq, 5.06 mM, 881 µl) and 2,5-dioxopyrrolidin-l-yl 3-((tert-butoxycarbonyl)amino)propanoate 16(2.00 eq., 0.93 mM, 266 mg, as a solution in anhydrous MeCN, 2.00 ml). The reaction mixture was stirred at room temperature, the reaction progressed with the formation of the final product 17confirmed by LCMS and HPLC (PDA 220 nm). After ∼18 h, the reaction was inhibited by the addition of acetic acid (290 μL, 5.06 mmol) and the solvents were partially removed by distillation in vacuo at room temperature. Primary product 17redissolved in MeCN (2 ml), the solution was cooled to 4°C and added to cooled MTBE (25 ml). The resulting precipitate was centrifuged, and the supernatant was filtered. This process was repeated twice. For FC purification, the final precipitate was redissolved in water (3 mL) and then purified in a Biotage Isolera One flash chromatography purification system with SNAP ULTRA C-18 12 g precolumn cartridge, Biotage® HP-Sphere™ Cl8, 25 µm spherical silica gel (gradient system from 100% water, 0.1% TFA to 100% MeCN, 0.1% TFA). Product containing fractions were pooled and frozen in liquid nitrogen and lyophilized for 48 hours to obtain the final product 17,as whitish fine crystalline powder.

Yield: 91.0 mg (29%), HPLC (method 6, at 220 nm) greater than 95%. LRMS-ESI (m/z) calculated for C ₂₉ H ₄₃ N ₅ O ₁₃ [M+H] ⁺ : 670.29. Defined: 670.25. ¹ H NMR (400 MHz, D ₂ O) δ 7.41-7.39 (m., 2H), 7.31-7.23 (m., 2H), 3.93-3.70 (m. , 10H), 3.68-3.57 (m., 1H), 3.44-3.08 (m., 9H), 2.74-2.67 (m., 1H), 2.52 ( t, J= 6.3 Hz, 2H), 1.33 (s, 9H); ¹³ C NMR (101 MHz, D2O) δ 172.98, 172.53, 172.40, 171.35, 170.50, 135.80, 132.97, 129.81, 122.12, 62.06, 55.70, 55.58, 54.54, 54.09, 52.67, 51.45, 51.35, 49.76, 49.64, 35.47, 31.91, 29.54, 27, 54.

[0295] (R)-2,2'-((2-((3-(4-(3-aminopropanamido)phenyl)-2-(bis(carboxymethyl)amino)propyl)(carboxymethyl)amino)ethyl)azanediyl )Diacetic acid 18 was synthesized as follows. To a solution of (R)-2,2'-((2-((2-(bis(carboxymethyl)amino)-3-(4-(3-((tert-butoxycarbonyl)amino)propanamido)phenyl)propyl) ( carboxymethyl)amino)ethyl)azanediyl) diacetic acid 17 (1.00 eq., 0.13 mM, 91.0 mg) in anhydrous dichloromethane (2 ml) at 4°C, TFA (400 eq., 52, 0 mM, 4 ml). The reaction mixture was stirred at room temperature for 4 hours. After this time, completion of the reaction was confirmed by LCMS and HPLC (PDA 220 nm). Solvents were removed by distillation in high vacuum, and the resulting residue was triturated in a mixture of MeCN, MeOH, and MTBE at 4°C. The precipitate was centrifuged, separated from the supernatant and washed twice with chilled MTBE (15 ml). The resulting powder was dried in vacuum for 48 hours to obtain the final compound 18 as a whitish, finely crystalline powder. Yield: 63.2 mg (82%), HPLC (method 7, 220 nm) greater than 91%. LRMS-ESI (m/z) calculated for C ₂₄ H ₃₅ N ₅ O ₁₁ [M+H] ⁺ : 570.24. Determined: 570.16. ¹ H NMR (400 MHz, D ₂ O) δ 7.42 (d, J= 8.5 Hz, 2H), 7.28 (d, J=8.5Hz, 2H), 3.94-3.61 (m, 11H), 3.50-3.35 (m., 2H), 3.31 (t, J=6.5Hz, 2H), 3.27-3.03 (m., 5H), 2 .83 (t, J= 6.6 Hz, 2H), 2.77-2.71 (m., 1H); ¹³ C NMR (101 MHz, D ₂ O) δ 172.08, 171.90, 170.71, 170.17, 135.84, 132.77, 129.88, 122.13, 62.20, 56, 12, 54.23, 54.09, 51.83, 49.28, 35.48, 32.50, 31.83.

[0296] (R)-2,2'-((2-((2-(bis(carboxymethyl)amino)-3-(4-(3-(2-(2,5-dioxo-2,5- Dihydro-lH-pyrrol-l-yl)acetamido)propanamido)phenyl)propyl)(carboxymethyl)amino)ethyl)azanediyl)diacetic acid 14b was synthesized as follows. To a solution of (R )-2,2 '-((2-((3-(4-(3-aminopropanamido)phenyl)-2-(bis(carboxymethyl)amino)propyl) (carboxymethyl)amino)ethyl)azanediyl) diacetic acid 18 (1.00 eq., 0.08 mM, 47.6 mg) in anhydrous MeCN/DMF (2.0:1.5 ml) under N ₂ , DIEA (11.0 eq., 0. 88 mM, 153 µl) and maleimidoacetic acid ester N -hydroxysuccinnimide 19 (2.00 eq., 0.17 mM, 42.0 mg, as a solution in anhydrous MeCN, 2.00 ml). The reaction mixture was stirred quickly at room temperature. After this, the reaction was inhibited by the addition of acetic acid (50 μl, 0.88 mM), and the solvents were removed by distillation under high vacuum at room temperature. The final residue was washed twice with MTBE (20 ml), redissolved in water (3 ml) and then purified in a Biotage Isolera One flash chromatography purification system with SNAP ULTRA pre-column, 12g cartridge, Biotage® HP-Sphere™ C18, 25 µm silica gel, (gradient system from 100% water, 0.1% TFA to 100% MeCN, 0.1% TFA). Product-containing fractions were pooled, frozen in liquid nitrogen, and lyophilized for 48 hours to obtain the final compound 14b, in the form of an off-white, fine-crystalline powder. Yield: 6.0 mg (10%) (calculated as TPA salt. TPA content: 0.47 ± 0.14 mol eq.). HPLC (method 5, at 220 nm) 90%. LRMS-ESI (m/z) calculated for C ₃₀ H ₃₈ N ₆ O ₁₄ [M+H] ⁺ : 707.25. Defined: 707.26. ¹ H NMR (400 MHz, D ₂ O): ¹ H NMR (400 MHz, D ₂ O): δ 7.41 (d, J=8.4Hz, 2H), 7.31 (d, J= 8, 4 Hz, 2H), 6.90 (s, 2H), 4.23 (s, 2H), 3.95-3.74 (m., 11H), 3.58 (t, J= 6.3 Hz , 2H), 3.52-3.11 (m., 7H), 2.80-2.77 (m., 1H), 2.62 (t J= 6.3 Hz, 2H).

[0297] Compounds 20, 21 and 14a in Scheme 9 are synthesized as shown below according to route B of Scheme 7.

Scheme 9

[0298]Di-tert-butyl 2,2 '-((2-((2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)-3-(4-(2-((tert-butoxycarbonyl) amino)acetamido)phenyl)propyl)(2-(tert-butoxy)-2-oxoethyl)amino)ethyl)azanedyl)(R)-diacetate 20was synthesized as follows. HATU (1.30 eq, 0.21 mM, 79.8 mg) and HOAt (1.30 eq, 0.21 mM, 28.6 mg) were added to the Boc-Gly-OH solution 11a(1.30 eq., 0.21 mM, 36.8 mg) in DMF (3.00 ml). The reaction mixture was stirred at room temperature for 5 minutes, and then the solution was added p-NH₂-Bn-DTPA-penta (t-Bu ether) 13(1.00 eq., 0.16 mM, 125 mg) in DMF (2 ml). The reaction mixture was stirred at room temperature for 5 minutes, and then 4-methylmorpholine (2.00 equiv., 0.32 mmol, 35.0 μl) was added. The mixture was stirred for 4 hours at room temperature and then added to the cooled saturated NaCl solution (25 ml). After centrifugation, the precipitate was separated by decantation, washed with cold water (25 ml) and dried overnight in a high vacuum. This is the primary connection 20was cleared in Biotage Isolera One flash chromatography purification system with SNAP ULTRA pre-column, 25 g cartridge, Biotage® HP-Sphere™ spherical silica gel (linear gradient from 100% CHCl₃ up to 90/10 CHCl₃/methanol). Solvents were removed first by rotary evaporation at 35°C and then under high vacuum for 48 hours to obtain the final compound 20in the form of a whitish fine-crystalline powder. Yield: 138 mg (92%), HPLC (method 6, at 220 nm) greater than 95%. LRMS-ESI (m/z) calculated for C₄₈H₈₁N₅O₁₃ [M+H] ⁺: 936.59. Defined: 936.81.

[0299] (R)-2,2'-((2-((3-(4-(2-aminoacetamido)phenyl)-2-(bis(carboxymethyl)amino)propyl)(carboxymethyl)amino)ethyl)azanedyl )Diacetic acid 21 was synthesized as follows. To a solution of di-tert-butyl 2,2'-((2-((2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)-3-(4-(2-((tert- butoxycarbonyl)amino)acetamido)phenyl)propyl)(2-(tert-butoxy)-2-oxoethyl)amino)ethyl)azanedyl) (R )-diacetate (1.00 eq., 0.15 mM, 138 mg) in anhydrous anisole (3.00 ml) at 4°C, TFA (350 eq., 52.2 mM, 4.00 ml) was added dropwise.

The reaction mixture was stirred at room temperature for 24 hours. After this time, completion of the reaction was confirmed by LC-MS. Solvents were removed under high vacuum and the product was triturated in a mixture of MeCN, MeOH and MTBE at 4°C. The final pellet was centrifuged, separated from the supernatant, and washed twice with cold MTBE (15 ml). The final powder was redissolved in water (5 ml) and then purified in a Biotage Isolera One flash chromatography purification system with SNAP ULTRA pre-column, 30g cartridge, Biotage® HP-Sphere™ on C18, with 25 µm spherical silica gel (gradient system from 100% water, 0.1% TFA to 85% water, 0.1% TFA: 15%- MeCN, 0.1% TFA). The product containing fractions were combined, frozen in liquid nitrogen and lyophilized for 48 hours to obtain the final product 21 as an off-white powder. Yield: 65.8 mg (80%), HPLC (method 5, at 220 nm) greater than 95%. LRMS-ESI (m/z) calculated for C ₂₃ H ₃₃ N ₅ O ₁₁ [M+H] +: 556.23. Defined: 556.22. ¹ H NMR (400 MHz, D ₂ O) δ 7.45 (d, J= 8.3 Hz, 2H), 7.29 (d, J= 8.3 Hz, 2H), 4.00 (s, 2H), 3.92-3.70 (m., 10-H), 3.69-3.58 (m., 1H), 3.49-3.05 (m., 7H), 2.72 (dd, J= 13.8, 9.3 Hz, 1H); ¹³ C NMR (101 MHz, D ₂ O) δ 172.34, 171.58, 170.43, 165.38, 135.52, 133.08, 129.98, 121.75, 62.07, 55, 82, 54.42, 54.13, 52.84, 51.52, 49.64, 40.94, 31.93.

[0300] (R)-2,2'-((2-((2-(bis(carboxymethyl)amino)-3-(4-(2-(3-(2,5-dioxo-2,5- Dihydro-lH-pyrrol-l-yl)propanamido)acetamido)phenyl)propyl)(carboxymethyl)amino)ethyl)azanedyl)diacetic acid 14a was synthesized as follows. To a solution of ( R )-2,2'-((2-((3-(4-(2-aminoacetamido)phenyl)-2-(bis(carboxymethyl)amino)propyl) (carboxymethyl)amino)ethyl)azanediyl) diacetic acid (1.00 eq, 0.11 mM, 60.0 mg) in anhydrous MeCN: DMF (2.00:1.00 ml) under N ₂ atmosphere, DIEA (11.0 eq, 1.21 mM) was added , 211 µl) and 3-maleimidopropionate 22 N-succinimidyl (2.00 eq., 0.22 mM, 57.5 mg, as a solution in anhydrous MeCN:DMF, 2.00:0.50 ml). The reaction mixture was stirred overnight at room temperature. The reaction was then inhibited by the addition of acetic acid (1.21 mM, 69.0 μL), and the solvents were removed under high vacuum at room temperature. The final residue was washed twice with MTBE - 20.0 ml. The final precipitate was redissolved in water (3.00 ml) and then purified in a Biotage Isolera One flash chromatography purification system with SNAP ULTRA precolumn, 12 g cartridge, Biotage® HP-Sphere™ C18, with 25 µm spherical silica gel (gradient system from 100% water/0.1% TFA to 100%% MeCN/0.1% TFA).

Product-containing fractions were pooled, frozen in liquid nitrogen, and lyophilized for 48 hours to obtain the final compound 14a as an off-white, fine-crystalline powder. Yield: 18.0 mg (24%) (calculated as TPA salt. TPA content: 0.63 ± 0.14 mol eq.). HPLC (220 nm, method 5) greater than 96%. LRMS-ESI (m/z) calculated for C ₃₀ H ₃₈ N ₆ O ₁₄ [M+H] ⁺ : 707.25. Defined: 707.28. ¹ H NMR and ¹³ C NMR: ¹ H NMR (400 MHz, D ₂ O): ¹ H NMR (400 MHz, D ₂ O) 3 7.41 (d, J= 8.5 Hz, 2H), 7, 30 (d, J= 8.5 Hz, 2H), 6.82 (s, 2H), 3.99 (s, 2H), 3.94-3.88 (m., 6H), 3.87- 3.76 (m., 6H), 3.69-3.58 (m., 1H), 3.47-3.11 (m., 7H), 2.81-2.71 (m., 1H ), 2.63 (t, J= 8.0 Hz, 2H); ¹³ C NMR (101 MHz, D ₂ O) δ 174.23, 172.65, 172.61, 171.23, 170.59, 169.76, 135.59, 134.39, 133.17, 129, 88, 122.49, 62.05, 55.48, 54.50, 54.09, 52.71, 51.26, 49.87, 43.08, 34.19, 31.92.

Example 3

Binding of serum albumin to ¹¹¹ In-C4-DTPA and stability of the complex

[0301] Radiolabeling with C4-DTPA was performed by adding 57.7 ± 0.7 Mbq (C4-DTPA) ¹¹¹ InCl ₃ in HCl solution (MAP Medical, Finland) to vials containing lyophilized test compound. The vials were shaken until a clear solution was formed and incubated for 30 minutes at +37°C.

[0302] The radiochemical purity of the radiolabeled product ¹¹¹ In-C4-DTPA was measured on an Aeris Widepore C18 reverse phase column (Agilent 1260 Infinity II chromatography system, HPLC method 9). The sample was diluted 1:30 (v/v) with water, and 5 μL was injected into the radio-HPLC system. Binding assay for ¹¹¹ In-C4-DTPA complex in serum: NMRI mouse serum and human serum were removed from storage at -80°C and equilibrated to room temperature. Thawed sera were centrifuged at 13.6 kRPM for 60 seconds, the supernatant was filtered through a needle filter (5 μm) and then through a 0.45 μm CA membrane.

[0303] The serum was incubated at 37°C for 30 minutes before adding ¹¹¹ In-C4-DTPA. After pre-incubation of the serum for 30 minutes, ¹¹¹ In-C4-DTPA solution was added to the serum at a ratio of 1:30 (v/v). Samples were collected at 1 minute, 5 minutes, and 30 minutes and analyzed by radio-HPLC, with 5 μL of sample injected onto the column at each time point. All binding experiments were performed in triplicate (n=3). The stability of ¹¹¹ In-C4-DTPA-albumin conjugate in mouse serum was further tested for 48 hours at 37 °C. The concentration of free indium unbound with ¹¹¹ In-C4-DTPA and with the ¹¹¹ In-C4-DTPA-albumin conjugate was determined in each dimension as represented by the HPLC XRD patterns in FIG. 1. Albumin binding was determined by comparing the AUC for each measurement with that of ¹¹¹ In-C4-DTPA in water, the level of binding and stability of the complex is presented in Figure 2.

Example 4

Pharmacokinetics study in NMRI nude mice

[0304] Radiolabeling: C4-DTPA radiolabeling was performed as above, except using 220 MBq of ¹¹¹ In in labeling and a 1:40 dilution with water for the quality control sample.

[0305] Dosing: ¹¹¹ In-C4-DTPA (6.2 ± 0.1 Mbq) was administered intravenously to 20 NMRI mice. The total injection volume was 100 μl, which was prepared by mixing 35 μl of the labeled metal complex and 65 μl of sterile saline (B. Braun).

[0306] Sampling endpoints: Samples were collected at 10 minutes, 1 hour, 6 hours, 24 hours and 48 hours after intravenous administration (n=4). At the indicated time point, mice were killed with an overdose of CO ₂ and the chest was opened. Blood samples were collected during cardiac puncture. A small volume of blood was collected in a separate tube, and the remaining blood sample was kept on ice until plasma was obtained. Plasma was separated by centrifugation, 2000 g for 10 minutes at +4 ° C. Radioactivity was measured on a gamma counter (Wizard II, Perkin Elmer). The results are presented in Fig. 4 as % of administered dose/g tissue (%ID/g).

Example 5

In vivo imaging with SPECT/CT

[0307]Leno tumors: female immunodeficient NMRI hairless mice were provided by Charles River Nursery, Freiburg, Germany. Animals were implanted bilaterally subcutaneously with a tumor model PDX LXFL 529 (NSCLC) or OVXF 899 (ovarian cancer) under isoflurane anesthesia. The animals were kept in cages, the temperature in the cages was maintained at 25 ± 1°C with a relative humidity of 45-65% and a rate of air exchange in the cage 60 times per hour. They were kept under an artificial summer cycle of 14 hours light/10 hours dark. Food and water were provided ad libitum. Imaging studies were performed when individual tumors were visible and reached a volume of 100-400 mm³. Body weight and SC tumor size of NMRI tumor-bearing mice were measured daily (n=8 per tumor model). The tumor diameter was measured with a caliper along two axes, the tumor volume was calculated using the formula V⁼ (L x W x W)/2, where V is the volume of the tumor, W is the width of the tumor, L is the length of the tumor.

[0308]Visualization SPECT/CT: after the average tumor volume in animals reaches between 100 mm³-300 mm³, was administered intravenously to mice under anesthesia. ¹¹¹In-C4-DTPA (approximately 20 MBq). SPECT/CT imaging was performed in small animals using SPECT/CT (NanoSPECT/CT Plus, Mediso) at 0-1 hour, 24 hours, 48 hours and 72 hours after administration. Three-dimensional CT images of the animals were obtained to visualize the biodistribution of the labeled agent. The imaging protocol consisted of planar tomography images, which were used as a control to select the imaging field (tumors located in the center of the field of view). After selecting the imaging area, helical CT was performed (180 projections, 55 kVp, exposure time 750 milliseconds). Helical SPECT imaging was then performed at the same coordinates using a frame period of 90 sec. To improve resolution, a high-resolution multi-needle aperture channel was used. After imaging, reconstruction of spiral SPECT images was performed. Image analysis was performed using PMOD software version 3.7. See Figures 5A, 5B, 6, 8A, 8B and 9.

[0309] Endpoint sampling points: After the 72 hour imaging point, mice were killed with an overdose of CO ₂ and the chest was opened. Blood samples were collected during cardiac puncture. A small volume of blood was collected into separate tubes, and the remaining blood samples were stored on ice until plasma was obtained. Plasma was separated by centrifugation, 2000 g for 10 minutes at +4 ° C.

[0310] Tissue samples from the lung, heart, liver, spleen, kidney, tumors, and thigh muscle were collected in pre-weighed tubes. After sample collection, the tubes were reweighed and radioactivity measured in a gamma counter (Wizard II, Perkin Elmer). Results are presented as % administered dose/g tissue (%ID/g). See FIG. 7 and 10.

[0311]Private Cases of embodiments of the invention are formulated in the following numbered paragraphs:

1. Metal complex having the structure of Formula (I) or (II) or (III):

or their conjugate acids, or their pharmaceutically acceptable salts, or their hydrates;

wherein:

M is ¹¹¹ In ^{3 +} , ⁶⁷ Ga ³⁺ , _, ^99m Tc ⁴⁺ or ^99m Tc ^{3 +} ;

X is absent or selected from -NH-, and -O-;

R ¹ is absent or optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl each optionally independently substituted with -OCH ₂ CH ₂ -;

Y is missing or selected from -O-C (O)-, C (O)-O-, -NH-C (O)-, C (O)-NH-, -NH-C (O) - NH-, -O-C (O)-O-, -NH-C (O)-O-, and-O-C (O)-NH-;

R ² is optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl each optionally independently substituted with -OCH ₂ CH ₂ -; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

2. Metal complex according to point 1, having the structure of Formula (I):

Formula (I),

or its conjugate acid base, or a pharmaceutically acceptable salt, or a hydrate thereof; wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺ ;

X is absent or selected from -NH-, and -O-;

R ¹ is absent or optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl each optionally independently substituted with -OCH ₂ CH ₂ -;

Y is absent or selected from -O-C (O)-, -C(O)-O-, -NH-C (O)-, -C(O)-NH-, -NH-C(O)-NH-, -O-C(O)-O-, -NH-C(O)-O-, and -O-C(O)-NH-;

R ² is optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl each optionally independently substituted with -OCH ₂ CH ₂ -; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

3. Metal complex according to point 1, having the structure of Formula (II):

Formula (II),

or its conjugate acid, or a pharmaceutically acceptable salt, or a hydrate thereof, wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺ ;

R ¹ is absent or optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl each optionally independently substituted with -OCH ₂ CH ₂ -;

Y is absent or selected from -O-C(O)-, -C(O)-O-, -NH-C(O)-, -C(O)-NH-, -NH-C(O)-NH-, -O-C(O)-O-, -NH-C(O)-O-, and -O-C(O)-NH-;

R ² is optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl each optionally independently substituted with -OCH ₂ CH ₂ -; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

4. Metal complex according to point 1, having the structure of Formula (III):

Formula (III),

or its conjugate acid base, or a pharmaceutically acceptable salt, or a hydrate thereof;

wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺ ;

R ¹ is absent or optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl each optionally independently substituted with -OCH ₂ CH ₂ -;

Y is absent or selected from -O-C(O)-, -C(O)-O-, -NH-C(O)-, -C(O)-NH-, -NH-C(O)-NH-, -O-C(O)-O-, -NH-C(O)-O-, and -O-C(O)-NH-;

R ² is optionally substituted with C1-C18 alkyl, with up to six carbon atoms in the above C1-C18 alkyl each optionally independently substituted with -OCH ₂ CH ₂ -; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

5. Metal complex according to paragraph 1, having the structure of formulas (IV), (V) or (VI):

or their conjugate acids, or their pharmaceutically acceptable salts, or their hydrates; wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ , or ^99m Tc ³⁺

m=1 or 2;

n=1-5;

o=1-12; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

6. Metal complex according to paragraph 5, having the structure of Formula (IV):

Formula (IV),

or its conjugate acid, or a pharmaceutically acceptable salt, or a hydrate thereof; wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ , or ^99m Tc ³⁺

m=1 or 2;

n=1-5;

o=1-12; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optionally substituted acetylene group.

7. Metal complex according to point 5, having the structure of Formula (V):

Formula (V),

or its conjugate acid base, or a pharmaceutically acceptable salt or hydrate thereof; wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ , or ^99m Tc ³⁺

n=1-5;

o=1-12; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

8. Metal complex according to paragraph 5, having the structure of Formula (VI):

Formula (VI),

or its conjugate acid base, or a pharmaceutically acceptable salt, or a hydrate thereof; wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺

n=1-5;

o=1-12; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

9. Metal complex according to paragraph 1, having the structure of Formula (VII), (VIII) or (IX):

or their conjugate acids, or their pharmaceutically acceptable salts, or their hydrates; wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺

m=1 or 2;

n=1-5; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

10. Metal complex according to paragraph 9, having the structure of Formula (VII):

Formula (VII),

or its conjugate acid base, or a pharmaceutically acceptable salt, or a hydrate thereof; wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ , or ^99m Tc ³⁺

m=1 or 2;

n=1-5; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

11. Metal complex according to paragraph 9, having the structure of Formula (VIII):

Formula (VIII),

or its conjugate acid base, or a pharmaceutically acceptable salt, or a hydrate thereof; wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺

n=1-5; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

12 Metal complex according to paragraph 9, having the structure of Formula (IX):

Formula (IX),

or its conjugate acid base, or a pharmaceutically acceptable salt, or a hydrate thereof; wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺

n=1-5; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

13. Metal complex of 1, having the structure of Formula (X), (XI) or (XII):

or their conjugate acids, or their pharmaceutically acceptable salts, or their hydrates; wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ or ^99m Tc ³⁺

p=1-12; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

14. Metal complex according to paragraph 13, having the structure of Formula (X):

Formula (X),

or its conjugate acid base, or a pharmaceutically acceptable salt, or a hydrate thereof; wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ , or ^99m Tc ³⁺

p=1-12; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

15. Metal complex according to paragraph 13, having the structure of Formula (XI):

Formula (XI),

or its conjugate acid base, or a pharmaceutically acceptable salt, or a hydrate thereof; wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ , or ^99m Tc ³⁺

p=1-12; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optionally substituted acetylene group.

16. Metal complex according to paragraph 13, having the structure of Formula (XII):

Formula (XII),

or its conjugate acid base, or a pharmaceutically acceptable salt, or a hydrate thereof; wherein:

M is ¹¹¹ In ³⁺ , ⁶⁷ Ga ³⁺ , ^99m Tc ⁴⁺ , or ^99m Tc ³⁺

p=1 -12; And

the thiol-linking group (TBG) is selected from an optionally substituted maleimide group, an optionally substituted haloacetamide group, an optionally substituted haloacetate group, an optionally substituted pyridyldithio group, an optionally substituted isothiocyanate group, an optionally substituted vinylcarbonyl group, an optionally substituted aziridine group, an optionally substituted disulfide group and optional substituted acetylene group.

17. The metal complex of any one of claims 1 to 16, its conjugate acid, or a pharmaceutically acceptable salt or hydrate thereof, wherein TBG is an optionally replaceable maleimide group.

18. The metal complex according to any one of paragraphs 1-17, its conjugate acid, or a pharmaceutically acceptable salt or hydrate thereof, wherein TBG is a maleimide group.

19. The metal complex according to any one of paragraphs 1-18, its conjugate acid, or a pharmaceutically acceptable salt or hydrate thereof, wherein M is ¹¹¹ In ^{3 +} .

20. Metal complex according to point 1, which is selected from:

or their conjugate acids, or pharmaceutically acceptable salts, or hydrates thereof.

21. Metal complex according to point 1, selected from:

or their conjugate acids, or pharmaceutically acceptable salts, or hydrates thereof.

22. Metal complex according to point 1, selected from:

or their conjugate acids, or pharmaceutically acceptable salts, or hydrates thereof.

23. Metal complex according to point 1, selected from:

or their conjugate acids, or pharmaceutically acceptable salts, or hydrates thereof.

24. The metal complex according to any one of paragraphs 1-23, in which the countercation of the pharmaceutically acceptable salt is selected from: one or two Na ⁺ , K ⁺ , or NH4 ⁺ ; or one Ca ²⁺ or Mg ²⁺ .

25. A pharmaceutical composition comprising the metal complex of any one of claims 1 to 24, its conjugate acid, or a pharmaceutically acceptable salt or a hydrate thereof, optionally including one or more pharmaceutically acceptable carriers.

26. The pharmaceutical composition according to paragraph 25, in which the metal complex is covalently linked to the thiol group of cysteine 34 from endogenous or exogenous albumin.

27. A method for diagnosing a disease selected from cancer, a viral disease, an autoimmune disease, an acute or chronic inflammatory disease, and a disease caused by bacteria, fungi, or other microorganisms, comprising administering to a subject in need thereof a diagnostically effective amount of a metal complex according to any from paragraphs 1-24 or the pharmaceutical composition according to paragraph 25 or 26, and subsequent imaging using SPECT (single photon emission computed tomography).

28. The method of claim 27, wherein the disease is cancer.

29. A method for diagnosing cancer in a subject, comprising: administering to the subject a detectable amount of a metal complex according to any of paragraphs 1-24 or a pharmaceutical composition of paragraph 25 or 26; imaging the subject after administration of the metal complex or pharmaceutical composition to detect a signal from the labeled metal complex in which the presence of the isotope in the tissue indicates that the tissue is malignant, thereby diagnosing cancer in the subject.

30. A method for diagnosing cancer in a subject, comprising:

administering to the subject a detectable amount of the metal complex of any of paragraphs 1-24 or the pharmaceutical composition of paragraphs 25 or 26;

imaging the subject following administration of a metal complex or pharmaceutical composition to detect a signal from the labeled metal complex, wherein the presence of higher signal accumulation in the tissue compared to non-cancerous tissue of the same type indicates that the tissue is malignant, thereby diagnosing cancer in the subject.

31. A method for diagnosing cancer in a subject, comprising:

administering to the subject the metal complex of any of claims 1-24 or the pharmaceutical composition of claims 25 or 26, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate, wherein the metal complex-albumin conjugate accumulates in the malignant tissue;

imaging the subject after administration of the metal complex or pharmaceutical composition to detect a signal from the labeled metal complex, wherein the presence of the isotope in the tissue indicates that the tissue is malignant, thereby diagnosing cancer in the subject.

32. A method of treating cancer in a subject, comprising:

administering to the subject the metal complex of any of claims 1-24 or the pharmaceutical composition of claims 25 or 26, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate, wherein the metal complex-albumin conjugate accumulates in the malignant tissue;

imaging the subject after administration of the metal complex or pharmaceutical composition to detect a signal from the labeled metal complex, wherein the presence of the isotope in the tissue indicates that the tissue is malignant;

diagnosing the affected tissue of an oncological subject; And

administering to the subject a therapeutically effective amount of a chemotherapeutic agent.

33. A method for diagnosing and treating a cancer patient who is susceptible to an albumin-bound chemotherapy agent, comprising:

administering to the subject the metal complex of any of claims 1-24 or the pharmaceutical composition of claims 25 or 26, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate, wherein the metal complex-albumin conjugate accumulates in the malignant tissue;

imaging the subject after administration of the metal complex or pharmaceutical composition to detect a signal from the labeled metal complex, wherein the presence of the isotope in the tissue indicates that the tissue is malignant;

diagnosing a cancer subject that is susceptible to treatment with an albumin-related chemotherapeutic agent; And

administering to the subject a therapeutically effective amount of an albumin-bound chemotherapeutic agent.

34. A method comprising:

administering to the subject the metal complex of any of claims 1-24 or the pharmaceutical composition of claims 25 or 26, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate, wherein the metal complex-albumin conjugate accumulates in the malignant tissue;

imaging the subject after administration of the metal complex or pharmaceutical composition to detect a signal from the labeled metal complex, wherein the presence of the isotope in the tissue indicates that the tissue is malignant;

diagnosing the affected tissue of an oncological subject; And

administering to the subject a therapeutically effective amount of an albumin-bound chemotherapeutic agent.

35. A method comprising:

administering to the subject the metal complex of any of claims 1-24 or the pharmaceutical composition of claims 25 or 26, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate, wherein the metal complex-albumin conjugate accumulates in the malignant tissue;

imaging the subject after administration of the metal complex or pharmaceutical composition to detect a signal from the labeled metal complex, wherein the presence of the isotope in the tissue indicates that the tissue is malignant;

diagnosing the affected tissue of an oncological subject;

classifying the subject's sensitivity to an albumin-bound chemotherapeutic agent; And

administering to the subject a therapeutically effective amount of an albumin-bound chemotherapeutic agent.

36. A method for assessing the sensitivity of a cancer subject to an albumin-bound chemotherapeutic agent, comprising:

administering to the subject the metal complex of any of claims 1-24 or the pharmaceutical composition of claims 25 or 26, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate, wherein the metal complex-albumin conjugate accumulates in the malignant tissue;

imaging the subject after administration of the metal complex or pharmaceutical composition to detect a signal from the radiolabeled metal complex, wherein the presence of the isotope in the tissue indicates that the tissue is malignant;

diagnosing the affected tissue of an oncological subject; And

classification of the cancer of a subject susceptible to an albumin-bound chemotherapeutic agent.

37. The method according to any of paragraphs 27-36, in which the metal complex is administered as a metallocomplex-albumin conjugate formed under ex vivo conditions.

38. The method of paragraph 37, in which the metallocomplex-albumin conjugate is formed by conjugation of albumin with a molecule corresponding to the TBG of the metallocomplex and subsequent chelation of M.

39. The method according to claim 37, in which the metal complex-albumin conjugate is formed by chelation of M to form the metal complex; followed by conjugation of albumin with the TBG metal complex to form the metal complex albumin conjugate.

40. The method according to any one of paragraphs 27-38, in which the malignancy is selected from adenocarcinoma, uveal melanoma, acute leukemia, acoustic neuroma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, connective tissue tumor, bladder cancer, bronchial cancer carcinoma, non-small cell bronchial carcinoma, breast cancer, Burkitt's lymphoma, uterine corpus cancer, CUP syndrome, colon cancer, small intestine cancer, ovarian cancer, endometrial carcinoma, gallbladder cancer, gallbladder carcinoma, uterine cancer, cervical cancer, neck, nose and ear tumors, hematological neoplasia, hairy cell leukemia, urethral cancer, skin cancer, glioma, testicular cancer, Kaposi's sarcoma, laryngeal cancer, bone cancer, colorectal carcinoma, head/neck tumor, colon carcinoma colon, craniopharyngiomas, liver cancer, leukemia, lung cancer, non-small cell lung carcinoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, stomach cancer, colon cancer, meduloblastoma, melanoma, meningioma, renal cancer, renal cell carcinoma, oligodendroglioma, esophageal carcinoma, osteoplastic carcinomas and osteolytic carcinomas, osteosarcoma, ovarian carcinoma, pancreatic carcinoma, penile cancer, prostate cancer, tongue cancer, ovarian carcinoma and lymph node cancer.

41. A kit for diagnosing a cancer patient susceptible to an albumin-bound chemotherapeutic agent, which contains the metal complex according to any of paragraphs 1-24.

42. Use of the metal complex of any one of claims 1-24 for the production of a dosage form for diagnosing cancer in a subject.

43. Use of the metal complex of any one of claims 1 to 24 for the production of a dosage form for diagnosing cancer in a subject sensitive to an albumin-bound chemotherapeutic agent.

44. Use of the metal complex of any one of claims 1-24 to prepare a dosage form for assessing the sensitivity of a subject to an albumin-bound chemotherapeutic agent.

45. Use of the metal complex according to any one of claims 1-24 for the manufacture of a dosage form for assessing the susceptibility of a cancer subject to an albumin-bound chemotherapeutic agent.

46. Use according to any of paragraphs 44-47, wherein the malignancy is selected from adenocarcinoma, uveal melanoma, acute leukemia, acoustic neuroma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, connective tissue tumor, bladder cancer, bronchial cancer carcinoma, non-small cell bronchial carcinoma, breast cancer, Burkitt's lymphoma, uterine corpus cancer, CUP syndrome, colon cancer, small intestine cancer, ovarian cancer, endometrial carcinoma, gallbladder cancer, gallbladder carcinoma, uterine cancer, cervical cancer, neck, nose and ear tumors, hematological neoplasia, hairy cell leukemia, urethral cancer, skin cancer, glioma, testicular cancer, Kaposi's sarcoma, laryngeal cancer, bone cancer, colorectal carcinoma, head/neck tumor, colon carcinoma colon, craniopharyngiomas, liver cancer, leukemia, lung cancer, non-small cell lung carcinoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, stomach cancer, colon cancer, meduloblastoma, melanoma, meningioma, renal cancer, renal cell carcinoma, oligodendroglioma, esophageal carcinoma, osteoplastic carcinomas and osteolytic carcinomas, osteosarcoma, ovarian carcinoma, pancreatic carcinoma, penile cancer, prostate cancer, tongue cancer, ovarian carcinoma and lymph node cancer.

47. The metal complex of any one of claims 1-24 for use in diagnosing cancer in a subject.

48. The metal complex of any one of claims 1-24 for use in diagnosing a cancer subject that is sensitive to an albumin-bound chemotherapeutic agent.

49. The metal complex of any one of claims 1-24 for use in assessing the sensitivity of a subject to an albumin-bound chemotherapeutic agent.

50. The metal complex of any one of claims 1-24 for use in assessing the susceptibility of a cancer subject to an albumin-bound chemotherapeutic agent.

The metal complex of any one of claims 1-24 for use in evaluating the therapeutic potential of an albumin-bound chemotherapeutic agent for treating cancer in a subject.

Claims (81)

1. Metal complex of Formula (I) Formula I, or a pharmaceutically acceptable salt thereof, where M is ¹¹¹ In ³⁺ ; X is missing; R ¹ represents C ₁ -C ₁₈ alkyl; Y is absent or selected from -NH-C(O)- and -C(O)-NH-; R ² represents C ₁ -C ₁₈ alkyl; And TBG is a maleimide group. 2. Metal complex according to claim 1, characterized in that it has the structure of Formula (X) Formula (X), or a pharmaceutically acceptable salt thereof, where M is ¹¹¹ In ^{3 +} ; p=1-12; And TBG is a maleimide group. 3. Metal complex according to any one of paragraphs. 1, 2, or a pharmaceutically acceptable salt thereof, characterized in that TBG is . 4. Metal complex according to claim 1, characterized in that said metal complex is selected from: or a pharmaceutically acceptable salt thereof. 5. Metal complex according to claim 1, characterized in that said metal complex is selected from or a pharmaceutically acceptable salt thereof. 6. Pharmaceutical composition for assessing the sensitivity of a subject with cancer to an albumin-binding chemotherapeutic agent, comprising: a) a metal complex according to any one of paragraphs. 1-5 or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable carrier. 7. Pharmaceutical composition according to claim 6, characterized in that the metal complex is covalently bound to the thiol group of cysteine-34 of endogenous or exogenous albumin. 8. A method for diagnosing a disease in a subject, wherein said disease is cancer, comprising administering to said subject a diagnostically effective amount of a metal complex according to any one of claims. 1-5 or the pharmaceutical composition according to claim 6 or 7 and subsequent imaging of the specified subject using the SPECT method (single photon emission computed tomography). 9. A method for diagnosing cancer in a subject, comprising: administering to the subject a detectable amount of the metal complex according to any one of claims. 1-5 or pharmaceutical compositions 6 or 7; performing imaging on the specified subject after administration of the metal complex or pharmaceutical composition to detect a signal from the radiolabeled metal complex, wherein detecting the presence of said signal from a radioactive isotope in the tissue indicates that the tissue is malignant, thereby diagnosing cancer in the subject. 10. A method for diagnosing cancer in a subject, comprising: administering to the subject a detectable amount of the metal complex according to any one of claims. 1-5 or a pharmaceutical composition according to claim 6 or 7; carrying out imaging on the specified subject after administration of the metal complex or pharmaceutical composition to detect a signal from the radioactive label of the metal complex, wherein the detection of increased accumulation of signal from said radiolabel in the tissue compared to non-cancerous tissue of the same type indicates that the tissue is malignant, thereby diagnosing cancer in the subject. 11. A method for diagnosing cancer in a subject, comprising: administration to the subject of the metal complex according to any one of paragraphs. 1-5 or the pharmaceutical composition according to claim 6 or 7, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate and said metal complex-albumin conjugate accumulates in malignant tissue; subjecting said subject to imaging after administration of a metal complex or pharmaceutical composition to detect a signal from a radioactive tracer of the metal complex, wherein detection of the presence of a signal from a radioactive tracer in the tissue indicates that the tissue is malignant, thereby diagnosing cancer in the subject. 12. A method of treating cancer in a subject, comprising: administration to the subject of the metal complex according to any one of paragraphs. 1-5 or the pharmaceutical composition of claim 6 or 7, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate and said metal complex-albumin conjugate accumulates in malignant tissue; subjecting said subject to imaging after administration of a metal complex or pharmaceutical composition to detect a signal from a radioactive tracer of the metal complex, wherein detection of the presence of a signal from a radioactive tracer in the tissue indicates that the tissue is malignant; diagnosing the subject with cancer in said tissue; And administering to the subject a therapeutically effective amount of a chemotherapeutic agent. 13. A method of diagnosing a subject with cancer that is susceptible to an albumin-binding chemotherapeutic agent, comprising: administration to the subject of the metal complex according to any one of paragraphs. 1-5 or the pharmaceutical composition according to claim 6 or 7, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate and said metal complex-albumin conjugate accumulates in malignant tissue; subjecting the subject to imaging after administration of a metal complex or pharmaceutical composition to detect a signal from a radioactive tracer of the metal complex, wherein detection of the presence of said radioactive tracer signal in the tissue indicates that the tissue is malignant; diagnosing a subject with cancer that is sensitive to therapy with an albumin-binding chemotherapeutic agent. 14. A method of treating a subject with cancer that is susceptible to an albumin-binding chemotherapeutic agent, comprising: administration to the subject of the metal complex according to any one of paragraphs. 1-5 or the pharmaceutical composition of claim 6 or 7, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate and said metal complex-albumin conjugate accumulates in malignant tissue; conducting imaging on a subject after administration of a metal complex or pharmaceutical composition to detect a signal from a radioactive tracer of the metal complex, wherein detection of the presence of said signal from a radioactive tracer in the tissue indicates that the tissue is malignant, diagnosing a subject with cancer that is susceptible to therapy with an albumin-binding chemotherapeutic agent; And administering to the subject a therapeutically effective amount of said albumin-binding chemotherapeutic agent. 15. A method for assessing the sensitivity of a subject with cancer to an albumin-binding chemotherapeutic agent, comprising: administration to the subject of the metal complex according to any one of paragraphs. 1-5 or the pharmaceutical composition according to claim 6 or 7, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate and said metal complex-albumin conjugate accumulates in malignant tissue; subjecting the subject to imaging after administration of the metal complex or pharmaceutical composition to detect a signal from a radioactive tracer of the metal complex, wherein the presence of said radioactive tracer signal in the tissue indicates that the tissue is malignant; diagnosing the subject with cancer in said tissue; And classifying said subject as susceptible to the albumin-binding chemotherapeutic agent. 16. A method of assessing the susceptibility of a cancer in a subject to an albumin-binding chemotherapeutic agent, comprising: introduction to the subject of the metal complex according to any one of paragraphs. 1-5 or the pharmaceutical composition according to claim 6 or 7, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate and said metal complex-albumin conjugate accumulates in malignant tissue; subjecting the subject to imaging after administration of a metal complex or pharmaceutical composition to detect the presence of a signal from a radioactive tracer of the metal complex, wherein detection of the presence of said signal from a radioactive tracer in the tissue indicates that the tissue is malignant; diagnosing the subject with cancer in said tissue; And classifying said cancer in the subject as susceptible to the albumin-binding chemotherapeutic agent. 17. A method for assessing the ability of an albumin-binding chemotherapeutic agent to treat cancer in a subject, comprising: administration to the subject of the metal complex according to any one of paragraphs. 1-5 or the pharmaceutical composition according to claim 6 or 7, wherein the metal complex binds to albumin to form a metal complex-albumin conjugate and said metal complex-albumin conjugate accumulates in malignant tissue; subjecting the subject to imaging after administration of a metal complex or pharmaceutical composition to detect a signal from a radiolabel of the metal complex, wherein detection of the presence of said signal from a radiolabel in the malignant tissue indicates that the albumin-binding chemotherapeutic agent is capable of treating cancer in the subject. 18. Method according to any one of paragraphs. 8-17, characterized in that the metal complex is administered in the form of a metal complex-albumin conjugate obtained ex vivo. 19. The method of claim 18, characterized in that the metal complex-albumin conjugate is obtained by conjugating albumin with a fragment corresponding to the TBG group in the metal complex, followed by chelation with M. 20. The method of claim 18, characterized in that the metal complex-albumin conjugate is obtained by chelation with M to form a metal complex, followed by conjugation of albumin with the TBG group of the specified metal complex to obtain a metal complex-albumin conjugate. 21. Method according to any one of paragraphs. 8-20, characterized in that said cancer is selected from adenocarcinoma, uveal melanoma, acute leukemia, acoustic neuroma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, connective tissue tumor, bladder cancer, bronchial carcinoma, non-small cell bronchial carcinoma , breast cancer, Burkitt's lymphoma, uterine body cancer, CUP syndrome, colon cancer, small intestine cancer, ovarian cancer, endometrial carcinoma, gallbladder cancer, gallbladder carcinomas, uterine cancer, cervical cancer uterus, neck, nose and ear tumors, hematologic neoplasia, hairy cell leukemia, urethral cancer, skin cancer, gliomas, testicular cancer, Kaposi's sarcoma, laryngeal cancer, bone cancer, colorectal carcinoma, head/neck tumors, colon carcinoma, craniopharyngiomas, cancer liver, leukemia, lung cancer, non-small cell lung cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, gastric cancer, medulloblastoma, melanoma, meningioma, renal cancer, renal cell carcinoma, oligodendroglioma, esophageal carcinoma, osteoplastic carcinoma and osteolytic carcinoma, osteosarcoma, testicular carcinoma Nika, pancreatic carcinoma, penile cancer, prostate cancer, tongue cancer, ovarian carcinoma and lymph node cancer. 22. A kit for diagnosing the susceptibility of a subject with cancer to an albumin-binding chemotherapeutic agent, where the above kit includes a metal complex according to any one of paragraphs. 1-5 or the pharmaceutical composition according to claim 6 or 7. 23. Use of a metal complex according to any one of paragraphs. 1-5 for the manufacture of a medicament for diagnosing cancer in a subject. 24. Use of a metal complex according to any one of paragraphs. 1-5 for the manufacture of a medicament for diagnosing a subject with cancer that is sensitive to an albumin-binding chemotherapeutic agent. 25. Use of a metal complex according to any one of paragraphs. 1-5 for the manufacture of a medicament for assessing the susceptibility of a subject to an albumin-binding chemotherapeutic agent. 26. Use of a metal complex according to any one of paragraphs. 1-5 for the manufacture of a medicament for assessing the susceptibility of a subject's cancer to an albumin-binding chemotherapeutic agent. 27. Application according to any one of paragraphs. 23-26, characterized in that said cancer is selected from adenocarcinoma, uveal melanoma, acute leukemia, acoustic neuroma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, connective tissue tumor, bladder cancer, bronchial carcinoma, non-small cell bronchial carcinoma , breast cancer, Burkitt's lymphoma, uterine body cancer, CUP syndrome, colon cancer, small intestine cancer, ovarian cancer, endometrial carcinoma, gallbladder cancer, gallbladder carcinomas, uterine cancer, cervical cancer uterus, neck, nose and ear tumors, hematologic neoplasia, hairy cell leukemia, urethral cancer, skin cancer, gliomas, testicular cancer, Kaposi's sarcoma, laryngeal cancer, bone cancer, colorectal carcinoma, head/neck tumors, colon carcinoma, craniopharyngiomas, cancer liver, leukemia, lung cancer, non-small cell lung cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, gastric cancer, medulloblastoma, melanoma, meningioma, renal cancer, renal cell carcinoma, oligodendroglioma, esophageal carcinoma, osteoplastic carcinoma and osteolytic carcinoma, osteosarcoma, testicular carcinoma Nika, pancreatic carcinoma, penile cancer, prostate cancer, tongue cancer, ovarian carcinoma and lymph node cancer. 28. Metal complex according to any one of paragraphs. 1-5 for use in diagnosing cancer in a subject. 29. Metal complex according to any one of paragraphs. 1-5 for use in diagnosing a subject with cancer that is susceptible to an albumin-binding chemotherapeutic agent. 30. Metal complex according to any one of paragraphs. 1-5 for use in assessing the susceptibility of a subject's cancer to an albumin-binding chemotherapeutic agent. 31. Metal complex according to any one of paragraphs. 1-5 for use in assessing the susceptibility of a subject's cancer to an albumin-binding chemotherapeutic agent. 32. Metal complex according to any one of paragraphs. 1-5 for use in assessing the ability of an albumin-binding chemotherapeutic agent to treat cancer in a subject.