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WO2025210087A1 - Nouveaux composés pour le diagnostic de protéinopathies à tdp-43 - Google Patents

Nouveaux composés pour le diagnostic de protéinopathies à tdp-43

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Publication number
WO2025210087A1
WO2025210087A1 PCT/EP2025/058993 EP2025058993W WO2025210087A1 WO 2025210087 A1 WO2025210087 A1 WO 2025210087A1 EP 2025058993 W EP2025058993 W EP 2025058993W WO 2025210087 A1 WO2025210087 A1 WO 2025210087A1
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Prior art keywords
tdp
compound
aggregates
disease
formula
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English (en)
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Nicolas Dreyfus
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AC Immune SA
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AC Immune SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to compounds which are suitable for imaging TDP-43 (Transactive response (TAR) DNA binding protein 43 kDa) aggregates.
  • Said compounds can be used, for example, for diagnosing a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), frontotemporal dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE).
  • ALS amyotrophic lateral sclerosis
  • AD Alzheimer’s disease
  • FTD frontotemporal dementia
  • LATE limbic-predominant age-related TDP-43 encephalopathy
  • the present invention also relates to processes for the preparation of said compounds, diagnostic compositions comprising said compounds, methods of using said compounds, kits comprising said compounds and the uses thereof.
  • BACKGROUND OF THE INVENTION Age-associated brain disorders characterized by pathological aggregation of proteins in the CNS (proteinopathies) and peripheral organs represent one of the leading causes of disability and mortality in the world.
  • the best characterized protein that forms extracellular aggregates is amyloid beta (Abeta) in Alzheimer ⁇ s disease (AD) and Abeta-related disorders.
  • TDP-43 proteinopathies include, but are not limited to, amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), including frontotemporal lobar dementia with TDP-43 pathology (FTLD-TDP, frontotemporal lobar degeneration with TDP-43 inclusions) and limbic-predominant age-related TDP- 43 encephalopathy (LATE).
  • TDP-43 introduction Transactive response (TAR) DNA binding protein 43 kDa (TDP-43) is a 414-amino acid protein encoded by the TARDBP gene on chromosome 1p36.2 (ALS10).
  • TARDBP is comprised of six exons (exon 1 is non-coding; exons 2-6 are protein-coding).
  • TDP-43 belongs to the family of heterogeneous ribonucleoprotein (hnRNP) RNA binding proteins (Wang et al., Trends in Molecular Medicine, Vol. 14, No. 11, 2008, 479-485; Lagier-Tourenne et al., Human Molecular Genetics, 2010, Vol. 19, Review Issue 1 R46-R64).
  • hnRNP heterogeneous ribonucleoprotein
  • TDP-43 contains five functional domains ( Figure 1 in Warraich et al., The International Journal of Biochemistry & Cell Biology, 42 (2010) 1606–1609): two RNA recognition motifs (RRM1 and RRM2), which have two highly conserved hexameric ribonucleoprotein 2 (RNP2) and octameric ribonucleioprotein 1 (RNP1) regions, a nuclear export signal (NES) and a nuclear localization signal (NLS) enabling it to shuttle between the nucleus and the cytoplasm transporting bound mRNA, and a glycine rich domain at the C-terminal, which mediates protein-protein interactions.
  • RRM1 and RRM2 two RNA recognition motifs
  • RNP2 highly conserved hexameric ribonucleoprotein 2
  • RNP1 octameric ribonucleioprotein 1
  • NES nuclear export signal
  • NLS nuclear localization signal
  • TDP-43 is involved in multiple aspects of RNA processing, including transcription, splicing, transport, and stabilization (Buratti and Baralle, FEBS Journal, 277 (2010) 2268–2281). It is a highly conserved, ubiquitously expressed protein with a tightly autoregulated expression level that shuttles continuously between the nucleus and cytoplasm but is normally localized predominantly to the nucleus.
  • TDP-43 was identified as the protein that accumulates in the vast majority of cases of frontotemporal lobar degeneration (FTLD) with tau-negative, ubiquitin-positive inclusions (then referred to as FTLD-TDP), and in most cases of amyotrophic lateral sclerosis (ALS) (Arai et al., Biochemical and Biophysical Research Communications, 351 (2006) 602–611; Neumann et al., Science, 314, (2006), 130-133).
  • FTLD frontotemporal lobar degeneration
  • ALS amyotrophic lateral sclerosis
  • TDP-43 Thirty-eight negative-dominant mutations in TDP-43 have been identified in sporadic and familial ALS patients as well as in patients with inherited FTD (K263E, N267S), mainly located in the glycine-rich domain ( Figure 1; Lagier-Tourenne and Cleveland, Cell, 136, 2009, 1001-1004). TDP-43 is inherently aggregation-prone, as shown by sedimentation assays, and this propensity is increased by some ALS-associated TARDBP mutations (Ticozzi et al., CNS Neurol. Disord. Drug Targets, 2010, 9(3), 285-296.).
  • TDP-43 in FTD Frontotemporal dementia is a clinical term that covers a wide spectrum of disorders based on the degeneration of frontal and temporal lobes – a pathological feature termed frontotemporal lobar degeneration (FTLD).
  • FTD is the second most abundant cause of early degenerative dementias in the age group below 65 years (Le Ber, Revue Neurodoubtedly, 169 (2013), 811-819).
  • TDP-43 in LATE Limbic-predominant age-related TDP-43 encephalopathy (LATE) neuropathological change (LATE- NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology.
  • LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer’s-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. There is no molecule-specific biomarker for LATE.
  • a discovery of a TDP-43 PET tracer may enable accurate, potentially earlier diagnosis as well as monitoring of disease progression to facilitate longitudinal drug efficacy measurements in patients during clinical trials (including as a potential exclusion criterion for Alzheimer’s disease clinical trials) and longitudinal studies of the clinical and pathological progression of LATE (Nelson et al., Brain, 2019, Vol.142; issue 6, 1503 - 1527).
  • TDP-43 represents a secondary or independent pathology that shares overlapping features with AD by targeting the medial temporal lobe.
  • Pathologic TDP-43 follows a stereotypical pattern of deposition that was captured by the TDP-43 in AD (TAD) staging scheme: TDP-43 first deposits in the amygdala (stage I) followed by hippocampus, limbic, temporal, and finally frontostriatum (stage V) (Josephs KA et al., Acta Neuropathol., 2014;127(6): 811-824; Josephs KA et al., Acta Neuropathol., 2014; 127(3): 441–450).
  • TDP-43 concentration is increased in cerebrospinal fluid (CSF) of clinically defined FTD or FTD-MND populations, although there is a significant overlap with control or AD subjects and it remains unclear if such an approach will prove clinically useful (Foulds et al., Acta Neuropathol., 2008, 116: 141-146; Steinacker et al., Arch. Neurol., 2008; 65(11): 1481–1487). Levels of total Tau or Thr181–phosphorylated Tau do not discriminate FTLD-Tau from control.
  • CSF cerebrospinal fluid
  • a possible diagnostic tool for the differentiation of FTLD-Tau and FTLD-TDP is the reduced CSF p-Tau181 to Tau ratio below a value of 0.37 (Hu et al., Neurology., 2013; 81(22): 1945-1952).
  • CSF phosphorylated Tau levels are positively associated with cerebral Tau burden in FTD and might help to distinguish TDP-43 proteinopathy from tauopathy (Irwin et al., Ann. Neurol., 2017 Aug; 82(2):247-258).
  • the development of imaging biomarkers will enable early and specific detection of the pathology in FTD and ALS.
  • TDP-43 deposition in the brain will be a substantial achievement for diagnosis and drug development for FTD, ALS and other neurodegenerative disorders.
  • Progressive TDP-43 accumulation in the CNS is associated with disease progression and represents an obvious target for development of novel therapeutics and diagnostic tools to study pharmacodynamics and disease progression.
  • the development of a PET-tracer targeting this protein is at its beginning.
  • most of the compound’s reported so far are not specific for TDP-43 and no direct binding to the target was demonstrated for any of these compounds.
  • a number of challenges are associated with the development of a TDP-43-specific PET-tracer including low abundance and heterogenic distribution of the target in the patient's brain as well as the lack of reference compounds.
  • TDP-43 imaging compounds should bind with high affinity and selectivity to the target.
  • imaging compounds need to penetrate the blood brain barrier and pass into the relevant regions of the brain.
  • cell permeability is a further requirement of imaging compounds.
  • the compounds of the present invention should be useful for identification and differentiation of patients and patient groups with TDP-43 proteinopathies (such as FTD, FTLD- TDP, LATE and ALS) and for differentiating TDP-43 proteinopathies from other proteinopathies.
  • TDP-43 proteinopathies such as FTD, FTLD- TDP, LATE and ALS
  • the present inventors have surprisingly found that compounds having the formula (I) can recognize and bind to TDP-43 aggregates.
  • compounds of the invention display high selectivity to TDP-43 aggregates over co-pathologies such as Abeta and Tau in AD brain homogenates, as well as over a-syn in PD brain homogenates.
  • the present invention refers to a compound having the formula (I) or a detectably labelled compound, stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein n is 1 or 2; R 1 is H, OH, F, -(C1-C3alkyl)OH (preferably hydroxyethyl or hydroxymethyl, more preferably hydroxymethyl), or -COORA (wherein RA is (C1-C4)alkyl); R 2 is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with – (C1-C3alkyl)halo, F, NH2, CN and/or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S.
  • R 1 is H, OH, F, -(C1-C3alkyl)OH (preferably hydroxyethyl or hydroxymethyl, more preferably hydroxymethyl), or
  • the present invention provides a diagnostic composition
  • a diagnostic composition comprising a compound according to the definition of a compound of formula (I), or subformulae thereof, as defined herein, and optionally at least one physiologically acceptable carrier, diluent, adjuvant and/or excipient.
  • Said compounds can be used for imaging of TDP-43 aggregates, particularly wherein the imaging is conducted by positron emission tomography or for diagnosing a disease, disorder or abnormality associated with TDP-43 aggregates, particularly wherein the diagnosis is conducted by positron emission tomography.
  • the invention provides a compound according to the definition of a compound of formula (I), or subformulae thereof, which can be used in the following methods: ⁇ A method of diagnosing a disease, disorder or abnormality associated with TDP-43 aggregates, in a subject; ⁇ A method of positron emission tomography (PET) imaging of TDP-43 aggregates in a tissue of a subject; ⁇ A method for the detection and optionally quantification of TDP-43 aggregates in a tissue of a subject; ⁇ A method of the diagnostic imaging of the brain of a subject; ⁇ A method of collecting data for the diagnosis of a disease, disorder or abnormality associated with TDP-43 aggregates or for the diagnosis of a TDP-43 proteinopathy; ⁇ A method of collecting data for determining a predisposition to a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy; ⁇ A method of collecting data for monitoring the progression of a disease, disorder or abnormality associated with TDP-
  • the methods of the present invention can be in vitro or in vivo.
  • the invention provides a compound according to the definition of a compound of formula (I), or subformulae thereof, that can also be used as a TDP-43 aggregates’ biomarker or a TDP-43 proteinopathy biomarker, as a TDP-43 proteinopathy diagnostic agent or diagnostic tool or as an in vitro analytical reference or an in vitro screening tool.
  • Another aspect of the present invention provides a method of preparing a compound according to the definition of a compound of formula (I), or subformulae thereof.
  • the present invention relates to kit for preparing a radiopharmaceutical preparation, said kit comprising a precursor of a compound of formula (I), or subformulae thereof.
  • kit for preparing a radiopharmaceutical preparation said kit comprising a precursor of a compound of formula (I), or subformulae thereof.
  • Compounds of the invention may have one or more optically active carbons that can exist as racemates and racemic mixtures, stereoisomers (including diastereomeric mixtures and individual diastereomers, enantiomeric mixtures and single enantiomers, mixtures of conformers and single conformers), tautomers, atropoisomers, and rotamers.
  • the terms “compound of formula (I)” or “compound of the (present) invention” refers to compounds of formula (I), and subformulae thereof, and isotopically labelled compounds (including, but not limited to 18F and 3H substitutions).
  • the terms “compound of formula (I)” or “compound of the (present) invention” refers to a compound as defined in any one of embodiments mentioned herein below.
  • the term “polymorphs” refers to the various crystalline structures of the compounds of the invention. This may include, but is not limited to, crystal morphologies (and amorphous materials) and all crystal lattice forms. Salts can also be crystalline and may exist as more than one polymorph.
  • Solvates, hydrates as well as anhydrous forms of salt are also encompassed by the invention.
  • the solvent included in the solvates is not particularly limited and can be any pharmaceutically acceptable solvent. Examples include C 1–4 alcohols (such as methanol or ethanol).
  • “Pharmaceutically acceptable salts” are defined as derivatives of the compounds of the present invention wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as, but not limited to, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • the pharmaceutically acceptable salts of the compound of formula (I) can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
  • Organic solvents include, but are not limited to, nonaqueous media like ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile.
  • the pharmaceutically acceptable salts are salts of amine residues in the compounds of the present invention.
  • the “patients” or “subjects” in the present invention are typically animals, particularly mammals, more particularly humans and mice. Even more particularly humans.
  • a "diagnostic composition” is defined in the present invention as a composition comprising the compound of the invention in a form suitable for administration to a patient, wherein the patient is e.g. a mammal such as a human.
  • TDP-43 aggregates are TDP-43-positive multimeric rich assemblies of TDP-43. They can be found in intracellular deposits in a range of diseases termed TDP-43 proteinopathies, in particular in amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), frontotemporal dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). TDP-43 aggregates can be found in the following morphologies: compact oval or crescentic neuronal cytoplasmic inclusions (NCI), lentiform neuronal intranuclear inclusions (NII), glial cytoplasmic inclusions (GCI), dystrophic neurites (DN) and long tortous neurites.
  • NCI compact oval or crescentic neuronal cytoplasmic inclusions
  • NII lentiform neuronal intranuclear inclusions
  • GCI glial cytoplasmic inclusions
  • DN dystrophic neurites
  • TDP-43 In pathological aggregates TDP-43 often displays a substantial increase in post-translational modifications such as phosphorylation, ubiquitination, acetylation, sumoylation and proteolytic cleavage to generate C-terminal fragments.
  • the "preclinical state" of disease is defined as the phase of disease where disease-associated changes on the molecular level are not leading to overt clinical representation in the patient.
  • the "clinical state” of a disease is defined as the phase of a disease where disease-associated changes on the molecular level led to overt clinical representation in the patient.
  • diagnosis generally refer to the process or act of recognizing, deciding on or concluding on a disease or condition in a patient on the basis of symptoms and signs and/or from results of a diagnostic procedure.
  • a "normal control value” is determined by conducting the respective method with a plurality of healthy subjects, measuring the amount of the compound bound to the TDP-43 aggregates, if any, for each healthy subject and calculating an average thereof.
  • a “healthy control subject” or “healthy subject” is a person showing no clinical evidence of neurodegenerative disease. Said person needs to meet the following criteria: ⁇ Male and female subjects which are healthy with no clinically relevant findings upon physical examination.
  • a "preclinical control value" is determined by conducting the respective method with a plurality of subjects who are in a preclinical state, measuring the amount of the compound bound to the TDP-43 aggregates, if any, for each subject and calculating an average thereof.
  • a “clinical control value” is determined by conducting the respective method with a plurality of subjects who are in a clinical state, measuring the amount of the compound bound to the TDP-43 aggregates, if any, for each subject and calculating an average thereof.
  • the terms "predicting” or “prediction” generally refer to an advance declaration, indication or foretelling of a disease or condition in a patient not having a disease, disorder or abnormality.
  • a prediction of a disease, disorder or abnormality in a patient may indicate a probability, chance or risk that the patient will contract the disease, disorder or abnormality, for example within a certain time period or by a certain age.
  • Detectable labels include suitable isotopes such as radioisotopes, in particular positron emitters or gamma emitters, and include 2H, 3H, 18F, 123I, 124I, 125I, 131I, 11C, 13N, 15O, 99mTc and 77Br, preferably 2H, 3H, 11C, 13N, 15O, and 18F, more preferably 2H, 3H and 18F, even more preferably 3H and 18F, most preferably 18F.
  • the term "Hal”, “halogen” or “halo” means F, Cl, Br or I, particularly Br or I, more particularly Br.
  • carbocyclic refers to a 5- or 6-membered carbocyclic ring which is not particularly limited and includes any 5- or 6-membered, saturated or unsaturated carbocyclic ring.
  • Unsaturated carbocyclic rings include, but are not limited to, aromatic rings.
  • Examples of 5- or 6-membered carbocyclic rings include, for instance, phenyl, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl. Phenyl being preferred.
  • heterocyclic ring refers to a stable 5- or 6-membered heterocyclic ring, is not particularly limited and includes any 5- or 6-membered, saturated or unsaturated heterocyclic ring.
  • Unsaturated heterocyclic rings include, but are not limited to, aromatic rings.
  • the heterocyclic ring contains one or more heteroatoms (for instance, one or two heteroatoms) selected from N, O and S.
  • the heteroatom is/are preferably N or O, more preferably N.
  • 5- or 6-membered heterocyclic rings include, for instance, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, furanyl, tetrahydrofuranyl, thiophenyl, imidazolidinyl, pyrazolidinyl, imidazolyl, pyrazolyl, oxathiolidinyl, isoxthiolidinyl, oxathiolyl, isoxathiolyl, thiazolidinyl, iosthiazolidinyl, thiazolyl, and isothiazolyl, preferably pyrazolyl, pyridinyl, and pyrimidinyl.
  • R1 is -COORA, wherein RA is (C1-C4)alkyl, preferably ethyl or methyl, more preferably methyl.
  • R1 is selected from the group consisting of -OH, and -CH2-OH.
  • the present invention refers to a compound of formula (I), wherein R2 is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with –(C 1 -C 3 alkyl)halo-, F, NH 2, CN and/or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S.
  • any reference to “F” in the present invention covers 19F (stable) or 18F (detectable label).
  • Any reference to “H” covers 1H (stable) or 3H (detectable label, so called tritium and represented herein as “T”).
  • Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples and Preparative Examples hereinafter using appropriate isotopic variations of suitable reagents, commercially available or prepared by known synthetic techniques. Radioisotopes, in particular positron emitters or gamma emitters, can be included into the compounds of the invention by methods which are usual in the field of organic synthesis.
  • 18F can be attached at any position which is suitable for attaching a fluorine.
  • 18F-labeled compounds are particularly suitable for imaging applications such as positron emission tomography (PET).
  • PET positron emission tomography
  • the corresponding compounds which include natural fluorine isotope 19F are also of particular interest as they can be used as analytical standards and references during manufacturing, quality control, release, and clinical use of their 18F-analogs.
  • 18F can be present, for instance, as the F substituent of R2 or as R 1 .
  • R 1 Preferably it is present as R 1 .
  • 3H is employed as a detectable label it is preferably attached as -T or -CT3 at any suitable position (T means 3H).
  • 3H may be in the form of –CT3 at any position at which a CH3 group can be attached. Substitution with radioisotopes such as 3H may afford certain diagnostic advantages resulting from greater metabolic stability by reducing, for example, defluorination, increasing in vivo half-life or reducing dosage requirements, while keeping or improving the original compound efficacy.
  • the present invention relates to Tritium ( 3 H) detectably labeled compounds having the formula (I), as described above, wherein at least one Hydrogen (H) is replaced by a detectable label selected from Tritium ( 3 H).
  • Tritium ( 3 H) detectably labeled compounds having the formula (I) are preferably defined wherein 1 to 3 Hydrogens (H) are replaced by Tritium ( 3 H).
  • the present invention relates to a compound of formula (I-T) or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein n is 1 or 2; R1 is H, OH, –(C -C alkyl)OH, A A 1 3 F or -COOR , wherein R is (C1-C4)alkyl; T is 3H; and wherein wherein H a 6 nd R is T or H; or wherein R2 is , wherein R12 is T or H 6 and R is T or H; or wherein R2 is (v) , wherein R5 is –(C1-C4alkyl)halo R12 is T or H, p is 1 or 2 and R 6 is T or H; or wherein R2 is , where 12 6 in R is T or H and R is T or H; and wherein (I-T) has at least one T, preferably 2 T.
  • R6 is T or H, wherein R2 is substituted at least one of the hydrogen atoms in R2 is replaced by T, and/or wherein at least one of the hydrogen atoms in R1 is replaced by T.
  • R6 is T or H, and/or wherein R2 is substituted by at least one CT3 or at least one of the hydrogen atoms in R2 is replaced by T.
  • T is 3H.
  • R6 is T.
  • at least one of the hydrogen atoms in R2 is replaced by T.
  • R6 is T and at least one of the hydrogen atoms in R2 is replaced by T.
  • at least one of the hydrogen atoms in R1 is replaced by T.
  • the present invention relates to a compound of formula (I-T) wherein n is 1 or 2; R1 is H, OH, –(C -C alk A A 1 3 yl)OH, F or -COOR , wherein R is (C1-C4)alkyl; R6 is T or H; preferably T; T is 3H; and wherein R8 is T and, if applicable, the other is H; preferably R7 is T; and R8 is T; or wherein R8 is CN, R4 is -NH2, and at least one of R7 and R3 is T and, if applicable, the other is H; in one embodiment R7 is T; and R3 is T; in another embodiment R7 is T; and R3 is H.
  • the present invention relates to a compound of formula (I-T), wherein n is 1 or 2; preferably n is 2; R 1 is H or F (preferably H); R6 is T; and wherein R3 is F; R4 is NH2; and at least one of R7 and R8 is T and, if applicable, the other is H.
  • R7 is T; and R3 is T; or in another embodiment R7 is T; and R3 is H; or R2 is , wherein R5 is – 12 (C1-C4alkyl)halo R is T, p is 1 or 2 or R2 is (iii) selected from , wherein R9 is selected from H, F, NH2 or CH3;
  • the present invention relates to a compound of formula (I-T) wherein n is 1 or 2; preferably n is 2; R 1 is F; R 6 is H; and , wherein R5 is –(C1-C4alkyl)halo R12 is T, p is 1 or 2.
  • the present invention relates to a compound of formula (I-T) wherein n is 1 or 2; R 1 is F; R 6 is H; and , wherein R5 is CT3
  • the present invention relates to a compound of formula (I-T), wherein n is 1 or 2; preferably n is 2; R 1 is H or F; R6 is T; and
  • the present invention relates to a compound of formula (I-T), wherein n is 2; R 1 is hydroxy(C1-C4)alkyl, preferably -CH2OH; R6 is T; and
  • the present invention relates to a compound of formula (I-T), wherein n is 1 or 2; R 1 is H or F, preferably H; R6 is T; and R2 is (iii) .
  • the present invention relates to a compound of formula (I-T), wherein n is 1 or 2; preferably 2; R 1 is H or F, preferably H; R6 is T; and In another embodiment, the present invention relates to a compound of formula (I-T), wherein n is 1 or 2; preferably 2; R 1 is H or F, preferably H; In another embodiment, the present invention relates to a compound of formula (I-T), wherein n is 1 or 2; preferably 2; R 1 is H or F, preferably H; R6 is T; and R2 is In another embodiment, the present invention relates to a compound of formula (I-T), wherein n is 1 or 2; preferably 2; R 1 is H or F, preferably H; R6 is T; and R2 is (vii) R 6 is H In another embodiment, the present invention relates to a compound of formula (I-T), wherein n is 1 or 2; R 1 is H or F, preferably H; R6 is T; and ,
  • the present invention relates to a compound of formula (I-T’), or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein n is 1 or 2; R6 is T or H; R1 is –(C1-C3alkyl)OH, or -COORA, wherein RA is (C1-C4)alkyl substituted by one or two, preferably two, T, wherein T is 3H; and R 2 is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with –(C1-C3alkyl)halo, F, NH2, CN and/or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S.
  • n 1 or 2
  • R6 is T or H
  • R1 is –(C1-C3alkyl)OH, or -COORA, wherein RA is (C1
  • the present invention provides a 18F detectably labeled compound of formula (I-F) or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein F is 19F; n is 1 or 2; R1 is 18F; R 2 is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with –(C1-C3alkyl)halo, F, NH2, CN and/or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S.
  • the present invention provides a 18F detectably labeled compound of formula (I-F) or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein n is 1 or 2; R1 is H, OH, –(C1-C3alkyl)OH, or -COORA, wherein RA is (C1-C4)alkyl, and R2 is , wherein R9 is H; wherein R5 is –(C1-C4alkyl)halo, preferably –(C1-C2alkyl)F.
  • n is 1 or 2; and R9 is selected from H, and F, NH2 or CH3; or R5 is H, –(C1-C3alkyl)halo, or CH3 preferably -CH2CH2-F; or R7 is H, and R8 is H; or R3 is H, R4 is NH2, R7 is H, and R8 is CN.
  • the present invention relates to a compound of formula (I-F), wherein n is 1 or 2; R1 is 18F (detectable label); and , wherein R9 is H; or R2 is , wherein R5 is –(C1-C4alkyl)halo, preferably –(C1-C2alkyl)F.
  • n is 1.
  • n is 2.
  • (I-F) is the following compound or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein n is 1 or 2; R 1 is –(C 1 -C 3 alkyl)OH, preferably hydroxyethyl or hydroxymethyl, more preferably hydroxymethyl; or R1 is -COORA, wherein RA is (C1-C4)alkyl; and R 2 is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with -(C 1 -C 3 alkyl)halo, F, NH 2, CN and/or CH 3 , wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S.
  • (I-F) is the following compound or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof; wherein n is 1 or 2; R1 is –(C1-C3alkyl)OH, or -COORA, wherein RA is (C1-C4)alkyl, and , wherein R9 is H.
  • R2 is , wherein R5 is -CH2-CH2-halo, CH3 or H, preferably -CH2-CH2F; or R2 is , wherein R9 is selected from H, and F, NH2 or CH3; or R2 is .
  • n is 1 or 2, preferably 2; R 1 is –(C1-C3alkyl)OH, preferably hydroxyethyl or hydroxymethyl, more preferably hydroxymethyl; or OH, and R2 is , wherein R9 is selected from H, and F, NH2 or CH3, preferably H.
  • the present invention relates to a compound of formula (I-F), wherein n is 1 or 2, preferably 2; and R 1 is –(C 1 -C 3 alkyl)OH, preferably hydroxyethyl or hydroxymethyl, more preferably hydroxymethyl; and , wherein R9 is H.
  • the present invention relates to a diagnostic composition
  • a diagnostic composition comprising a compound of formula (I), as described above, and optionally at least one physiologically acceptable carrier, diluent, adjuvant and/or excipient.
  • the compounds of the present invention are particularly suitable for imaging TDP-43 aggregates.
  • the imaging can be conducted in mammals, preferably in humans.
  • the imaging is preferably in vitro imaging, ex vivo imaging, or in vivo imaging. More preferably the imaging is in vivo imaging. Even more preferably, the imaging is brain imaging.
  • the imaging can also be eye/retinal imaging or imaging of tissue of the central nervous system.
  • the compounds of the present invention are particularly suitable for use in diagnostics.
  • the diagnostics can be conducted for mammals, preferably for humans.
  • excipient must be acceptable in the sense of being not deleterious to the recipient thereof.
  • Pharmaceutically useful excipients, carriers, adjuvants and diluents that may be used in the formulation of the diagnostic composition of the present invention may comprise, for example, solvents such as monohydric alcohols such as ethanol, isopropanol and polyhydric alcohols such as glycols and edible oils such as soybean oil, coconut oil, olive oil, safflower oil cottonseed oil, oily esters such as ethyl oleate, isopropyl myristate, binders, adjuvants, solubilizers, thickening agents, stabilizers, disintegrants, glidants, lubricating agents, buffering agents, emulsifiers, wetting agents, suspending agents, sweetening agents, colorants, flavors, coating agents, preservatives, antioxidants, processing agents, drug delivery modifiers and enhancers such as calcium phosphate, magnesium stearate, talc, mono
  • the routes for administration (delivery) of the compounds of the invention include, but are not limited to, one or more of: intravenous, gastrointestinal, intraspinal, intraperitoneal, intramuscular, oral (e. g. as a tablet, capsule, or as an ingestible solution), topical, mucosal (e. g. as a nasal spray or aerosol for inhalation), nasal, parenteral (e. g. by an injectable form), intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, epidural and sublingual.
  • intravenous gastrointestinal
  • intraspinal intraperitoneal
  • intramuscular oral
  • oral e. g. as a tablet, capsule, or as an ingestible solution
  • mucosal e. g. as a nasal spray or aerosol
  • the preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. Typically, a physician will determine the actual dosage which will be most suitable for an individual patient.
  • the dose of the compounds of the present invention (for instance, detectably labeled compounds such as those with a 3H or 18F detectable label) will vary depending on the exact compound to be administered, the weight of the patient, size and type of the sample, and other variables as would be apparent to a physician skilled in the art. Generally, the dose could preferably lie in the range 0.001 ⁇ g/kg to 10 ⁇ g/kg, preferably 0.01 ⁇ g/kg to 1.0 ⁇ g/kg.
  • the compounds of the present invention are particularly suitable for use in the diagnosis of diseases, disorders or abnormalities associated with TDP-43 aggregates or the TDP-43 proteinopathy, such as disease, disorder or abnormality selected from, but not limited to, frontotemporal dementia (FTD, such as sporadic or familial with or without motor-neuron disease (MND), with progranulin (GRN) mutation, with C9orf72 mutations, with TARDBP mutation, with valosine-containing protein (VCP) mutation, linked to chromosome 9p, corticobasal degeneration, frontotemporal lobar degeneration (FTLD) including frontotemporal lobar dementia TDP-43 or frontotemporal lobar degeneration with ubiquitin-positive TDP-43 inclusions (FTLD-TDP), Argyrophilic grain disease, Pick's disease, semantic variant primary progressive aphasia (svPPA), behavioural variant FTD (bvFTD), Nonfluent Variant Primary Progressive Aphasia (such as
  • the diseases, disorders or abnormalities associated with TDP-43 aggregates or the TDP-43 proteinopathy is amyotrophic lateral sclerosis (ALS).
  • the diagnosis of diseases, disorders or abnormalities associated with TDP-43 aggregates or the TDP-43 proteinopathy is Alzheimer’s disease (AD).
  • the diagnosis of diseases, disorders or abnormalities associated with TDP-43 aggregates or the TDP-43 proteinopathy is frontotemporal dementia (FTD) including frontotemporal lobar dementia TDP-43 or frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP).
  • FDD frontotemporal dementia
  • FTLD-TDP frontotemporal lobar dementia
  • the diagnosis of diseases, disorders or abnormalities associated with TDP-43 aggregates or the TDP-43 proteinopathy is limbic-predominant age-related TDP-43 encephalopathy (LATE).
  • LATE age-related TDP-43 encephalopathy
  • the present invention relates to the methods and uses as listed below ⁇ A method of imaging a disease, disorder or abnormality associated with TDP-43 aggregates in a subject; ⁇ A method of positron emission tomography (PET) imaging of TDP-43 aggregates in a tissue of a subject; ⁇ A method for the detection and optionally quantification of TDP-43 aggregates in a tissue of a subject; ⁇ A method of the diagnostic imaging of the brain of a subject; ⁇ A method of determining an amount of TDP-43 aggregates in a sample or a specific body part or body area; ⁇ A method of diagnosing a disease, disorder or abnormality associated with TDP-43 aggregates or of diagnosing a TDP-43 proteinopathy; ⁇ A method of collecting
  • any of the compounds of the present invention can be used in the above summarized methods.
  • said compounds are detectably labeled compounds (e.g. such as those with a 3H or 18F detectable label).
  • the methods of the invention can include the step of bringing a sample, a specific body part or a body area suspected to contain TDP-43 aggregates into contact with a compound of the invention.
  • the body is preferably of a mammal, more preferably of a human, including the full body or partial body area/part of the patient suspected to contain TDP-43 aggregates.
  • the sample can be selected from tissue or body fluids suspected to contain TDP-43 aggregates, the sample being obtained from the patient.
  • the tissue is selected from tissue of the central nervous system (CNS), eye tissue or brain tissue, more preferably brain tissue.
  • body fluids include cerebrospinal fluid (CSF) or blood.
  • the sample can be obtained from a mammal, more preferably a human.
  • the sample is an in vitro sample from a patient.
  • An in vitro sample or a specific body part or body area obtained from a patient can be brought into contact with a compound of the invention by direct incubation.
  • the specific body part or body area can be brought into contact with a compound of the invention by administering an effective amount of a compound of the invention to the patient.
  • the effective amount of a compound of the invention is an amount which is suitable for allowing the presence or absence of TDP-43 aggregates in the specific body part or body area to be determined using the chosen analytical technique.
  • the step of allowing the compound of the invention to bind to the TDP-43 aggregates includes allowing sufficient time for said binding to happen.
  • the amount of time required for binding will depend on the type of test (e.g., in vitro or in vivo) and can be determined by a person skilled in the field by routine experiments. In an in vitro method the amount of time will depend on the sample or specific body part or body area and can range, for instance, from about 30 min to about 120 min.
  • the amount of time will depend on the time which is required for the compound of the invention to reach the specific body part or body area suspected to contain TDP-43 aggregates.
  • the amount of time should not be too long to avoid washout and/or metabolism of the compound of the invention.
  • the duration can range, for instance, from about 0 min to about 240 min (which is the duration of a PET scan during initial compound characterization (NHP PET and later FiH-study)).
  • the method of detecting the compound of the invention bound to the TDP-43 aggregates is not particularly limited and depends, among others, on the detectable label, the type of sample, specific body part or body area and whether the method is an in vitro or in vivo method.
  • Possible detection methods include, but are not limited to, a fluorescence imaging technique or a nuclear imaging technique such as positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), and contrast-enhanced magnetic resonance imaging (MRI).
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • MRI magnetic resonance imaging
  • MRI contrast-enhanced magnetic resonance imaging
  • the fluorescence imaging technique and/or nuclear imaging technique can be employed for monitoring and/or visualizing the distribution of the compound of the invention within the sample or the body.
  • the imaging system is such to provide an image of bound detectably label such as radioisotopes, in particular positron emitters or gamma emitters, as present in the tested sample, the tested specific body part or the tested body area.
  • the present invention relates to a method of detecting a neurological disease, disorder or abnormality associated with TDP-43 aggregates in a subject or a predisposition thereto, the method comprising the steps: (a) Administering a compound of the invention; or a diagnostic composition comprising a compound of the invention as disclosed herein, to the subject; (b) Allowing the compound to bind to the TDP-43 aggregates; and (c) Detecting the compound which is bound to the TDP-43 aggregates.
  • the present invention relates to a method (e.g.
  • the method comprising the steps: (a) Administering a compound of the invention as disclosed herein; or a diagnostic composition comprising a compound of the invention as disclosed herein, to the subject; (b) Allowing the compound to bind to the TDP-43 aggregates; and (c) Detecting and optionally quantifying the compound bound to the TDP-43 aggregates using positron emission tomography.
  • the present invention relates to a method of imaging TDP-43 aggregates in a sample or a patient, in particular in a brain or a sample taken from the patient's brain, the method comprising the steps: (a) Administering a compound of the invention; or a diagnostic composition comprising a compound of the invention as disclosed herein, to the subject; (b) Allowing the compound to bind to the TDP-43 aggregates; and (c) Detecting the compound bound to the TDP-43 aggregates.
  • the present invention relates to a method of imaging or diagnosing a disease, disorder or abnormality associated with TDP-43 aggregates in a subject or a predisposition thereto, the method comprising the steps: (a) Administering a compound of the invention; or a diagnostic composition comprising a compound of the invention as disclosed herein, to the subject; (b) Allowing the compound to bind to the TDP-43 aggregates; (c) Detecting the compound bound to the TDP-43 aggregates; and (d) Generating an image representative of the location and/or amount of the compound bound to the TDP-43 aggregates.
  • the present invention relates to a method of positron emission tomography (PET) imaging of TDP-43 aggregates in a tissue of a subject, the method comprising the steps: (a) Administering a compound of the invention; or a diagnostic composition comprising a compound of the invention as disclosed herein, to the subject; (b) Allowing the compound to bind to the TDP-43 aggregates; and (c) Detecting the compound bound to the TDP-43 aggregates by collecting a positron emission tomography (PET) image of the tissue of the subject.
  • the tissue is a tissue of the central nervous system (CNS), an eye tissue or a brain tissue. More preferably, the tissue is brain tissue.
  • the present invention relates to a method of imaging TDP-43 aggregates in a sample or a patient, the method comprises the steps: (a) Bringing a sample, a specific body part or body area suspected to contain TDP-43 aggregates into contact with a compound of the invention; or with a diagnostic composition comprising a compound of the invention as disclosed herein; (b) Allowing the compound to bind to the TDP-43 aggregates; and (c) Detecting the compound bound to the TDP-43 aggregates by imaging the sample, the specific body part or the body area with an imaging system.
  • the present invention relates to a method for imaging TDP-43 aggregates in an in vitro sample of a patient, the method comprising the steps: (a) Bringing the in vitro sample suspected to contain TDP-43 aggregated into contact with a compound of the invention; or with a diagnostic composition comprising a compound of the invention as disclosed herein; (b) Allowing the compound to bind to the TDP-43 aggregates; and (c) Detecting the compound bound to the TDP-43 aggregates by imaging the in vitro sample with an imaging system.
  • the present invention relates to a method of imaging TDP-43 aggregates in a patient or a specific body part or a body area of a patient, the method comprising the steps: (a) Bringing a sample or a specific body part or body area suspected to contain TDP-43 aggregates into contact with a compound of the invention,; or with diagnostic composition comprising a compound of the invention as disclosed herein; (b) Allowing the compound to bind to the TDP-43 aggregates; and (c) Detecting the compound bound to the TDP-43 aggregates by imaging the sample or the specific body part or the body area of the patient with an imaging system.
  • the step of imaging the sample, the patient, the specific body part or the body area of the patient with an imaging system includes detecting the compound of the invention bound to the TDP-43 aggregates using an imaging system as disclosed herein. Detecting the compound of the invention bound to the TDP-43 aggregates allows to identify by imaging the distribution of TDP-43 aggregates in the tested sample, the patient, the specific body part or body area.
  • the PET imaging should be conducted when the compound has penetrated the tissue and the compound has bound to the TDP- 43 aggregates.
  • the present invention relates to a method of determining the amount of TDP-43 aggregates in a sample, a specific body part or body area suspected to contain TDP-43 aggregates using a compound of the invention.
  • the present invention provides a method for determining the amount of TDP-43 aggregates in the sample, the specific body part or the body area suspected to contain TDP-43 aggregates, wherein the method comprises the steps of: (a) Bringing a sample, a specific body part or body area suspected to contain TDP-43 aggregates into contact with a compound of the invention; or with a diagnostic composition comprising a compound of the invention as disclosed herein; (b) Allowing the compound of the invention to bind to the TDP-43 aggregates; (c) Detecting the compound of the invention bound to the TDP-43 aggregates; (d) Determining the amount of compound of the invention bound to the TDP-43 aggregates; and (e) Optionally calculating the amount of TDP-43 aggregates in the sample, the specific body part or body area.
  • the present invention relates to a method of diagnosing a disease, disorder or abnormality associated with TDP-43 aggregates or TDP-43 proteinopathy or a predisposition thereto, the method comprising the steps of: (a) Detecting the compound of the invention bound to the TDP-43 aggregates; and (b) Correlating the presence or absence of the compound of the invention bound to TDP-43 aggregates with the disease, disorder or abnormality associated with TDP-43 aggregates or with the TDP-43 proteinopathy.
  • Examples of possible methods include, but are not limited to, a fluorescence imaging technique or a nuclear imaging technique such as positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), and contrast-enhanced magnetic resonance imaging (MRI).
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • MRI magnetic resonance imaging
  • MRI contrast-enhanced magnetic resonance imaging
  • the fluorescence imaging technique and/or nuclear imaging technique can be employed for monitoring and/or visualizing the distribution of the detectably labelled compound within the sample or a specific body part or body area.
  • the step of optionally correlating the presence or absence of the compound bound to the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or specific body part or body area comprises the steps of - determining the amount of the compound bound to the TDP-43 aggregates; - correlating the amount of the compound bound to the TDP-43 aggregates with the amount of TDP-43 aggregates in the sample or specific body part or body area; and - optionally comparing the amount of the compound bound with the TDP-43 aggregates in the sample or specific body part or body area to a normal control value in a healthy control subject.
  • the amount of compound bound with the TDP-43 aggregates can be compared to a normal control value which has been determined in a sample or a specific body part or body area of a healthy subject, wherein an increase in the amount of the compound bound with the TDP-43 aggregates compared to a normal control value may indicate that the patient is suffering from or is at risk of developing a disease, disorder or abnormality associated with TDP-43 aggregates. If the amount of the compound bound with the TDP-43 aggregates is higher than the normal control value, as defined herein, then it can be expected that the patient is suffering from or is likely to suffer from a disease, disorder or abnormality associated with TDP-43 aggregates or TDP-43 proteinopathy.
  • a further aspect of the present invention relates to a method of collecting data for determining a predisposition to a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP- 43 proteinopathy.
  • the method comprises the steps: (a) Bringing a sample or a specific body part or body area suspected to contain TDP-43 aggregates into contact with a compound of the invention; or with a diagnostic composition comprising a compound of the invention as disclosed herein; (b) Allowing the compound of the invention to bind to the TDP-43 aggregates; (c) Detecting the compound of the invention bound to the TDP-43 aggregates; and (d) Optionally correlating the presence or absence of the compound of the invention bound with the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or specific body part or body area.
  • the step of optionally correlating the presence or absence of the compound bound to the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or specific body part or body area comprises the steps of - determining the amount of the compound bound to the TDP-43 aggregates; - correlating the amount of the compound bound to the TDP-43 aggregates with the amount of TDP-43 aggregates in the sample or specific body part or body area; and - optionally comparing the amount of the compound bound with the TDP-43 aggregates in the sample or specific body part or body area to a normal control value in a healthy control subject.
  • the amount of the compound bound to the TDP-43 aggregates is higher than a normal control value of a healthy/reference subject this indicates that the patient/subject is suffering from or is at risk of developing a disease, disorder or abnormality associated with TDP-43 aggregates.
  • the amount of the compound bound to the TDP-43 aggregates is higher than what expected in a person showing no clinical evidence of neurodegenerative disease, it can be assumed that the patient has a disposition to a disease, disorder or abnormality associated with TDP-43 aggregates or with a TDP-43 proteinopathy.
  • the present invention relates to a method of monitoring the progression of a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy in a patient.
  • the patient is or has been undergoing treatment of the disease, disorder or abnormality associated with TDP-43 aggregates or is or with TDP-43 proteinopathy.
  • the treatment can involve administration of an anti-TDP-43 medicament.
  • the method of collecting data for monitoring the progression of a disease, disorder or abnormality associated with TDP-43 aggregates or for monitoring the progression of a TDP-43 proteinopathy in a patient comprises the steps: (a) Bringing a sample, a specific body part or body area suspected to contain TDP-43 aggregates into contact with the compound of the invention; (b) Allowing the compound of the invention to bind to the TDP-43 aggregates; (c) Detecting the compound of the invention bound to the TDP-43 aggregates; (d) Optionally correlating the presence or absence of the compound of the invention bound with the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or specific body part or body area; and (e) Optionally repeating steps (a) to (c) and, if present, optional step (d) at least one time.
  • steps (a) to (c) and optional step (d) (if present) can be repeated one or more times.
  • the steps should be repeated until no further progression of the disease is observed in the patient.
  • the step of optionally correlating the presence or absence of the compound bound to the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or specific body part or body area comprises the steps of - Determining the amount of the compound bound to the TDP-43 aggregates; - Correlating the amount of the compound bound to the TDP-43 aggregates with the amount of TDP-43 aggregates in the sample or specific body part or body area; and - Optionally comparing the amount of the compound bound with the TDP-43 aggregates in the sample or specific body part or body area to a normal control value in a healthy control subject.
  • the amount of the compound of the invention bound to the TDP-43 aggregates can be optionally compared at various points of time during the treatment, for instance, before and after onset of the treatment and/or at various points of time after the onset of the treatment.
  • a change, especially a decrease, in the amount of the compound of the invention bound to the TDP-43 aggregates may indicate that the disease is not progressing.
  • Predicting responsiveness In one embodiment, the present invention relates to a method of predicting responsiveness of a patient suffering from a disease, disorder or abnormality associated with TDP-43 aggregates, or suffering from a TDP-43 proteinopathy to a treatment of said disease, disorder or abnormality associated with TDP-43 aggregates or TDP-43 proteinopathy.
  • the method can be used to predict the treatment which is most suitable for the patient.
  • the treatment can involve administration of an anti-TDP-43 medicament.
  • the method for predicting responsiveness of a patient suffering from a disease, disorder or abnormality associated with TDP-43 aggregates or suffering from a TDP-43 proteinopathy to a treatment of said disease, disorder or abnormality associated with TDP-43 aggregates or TDP-43 proteinopathy can comprise the steps of: (a) Bringing a sample, a specific body part or body area suspected to contain TDP-43 aggregates into contact with a compound of the invention; or with a diagnostic composition comprising a compound of the invention as disclosed herein; (b) Allowing the compound of the invention to bind to the TDP-43 aggregates; (c) Detecting the compound of the invention bound to the TDP-43 aggregates; (d) Optionally correlating the presence or absence of the compound of the invention bound with the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or specific body part or body
  • the patient is / has been undergoing treatment of the disease, disorder or abnormality associated with TDP-43 aggregates or the TDP-43 proteinopathy.
  • the treatment can involve administration of a medicament which is suitable for treating the disease, disorder or abnormality associated with TDP-43 aggregates.
  • the present method allows to predict the responsiveness of a patient to a certain treatment.
  • the responsiveness can be estimated, e.g., by repeating steps (a) to (c) and, if present, optional step (d) and monitoring the amount of the compound of the invention bound with the TDP- 43 aggregates over a period of time during which the patient is undergoing treatment of the disease, disorder or abnormality associated with TDP-43 aggregates or with TDP-43 proteinopathy.
  • the control value may refer to the control value of healthy control subjects.
  • the control value may refer to the control value of subjects known to be responsive to a certain therapy, or to the control value may refer to the control value of subjects known to be non-responsive to a certain therapy.
  • the outcome with respect to responsiveness can either be "responsive" to a certain therapy, “non-responsive” to a certain therapy or “response undetermined” to a certain therapy. Response to the therapy may be different for the respective patients.
  • the step of optionally correlating the presence or absence of the compound bound to the TDP-43 aggregates with the presence or absence of TDP-43 aggregates in the sample or specific body part or body area comprises the steps of - Determining the amount of the compound bound to the TDP-43 aggregates; - Correlating the amount of the compound bound to the TDP-43 aggregates with the amount of TDP-43 aggregates in the sample or specific body part or body area; and - Optionally comparing the amount of the compound bound with the TDP-43 aggregates in the sample or specific body part or body area to a normal control value in a healthy control subject.
  • the control value can be, e.g., a normal control value, a preclinical control value and/or a clinical control value.
  • a “healthy control subject” or “healthy subject” is a person showing no clinical evidence of neurodegenerative disease. If in any of the above summarized methods the amount of the compound bound with the TDP-43 aggregates is higher than the normal control value, then it can be expected that the patient is suffering from or is likely to suffer from a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy.
  • Any of the compounds of the present invention can be used in the above summarized methods. Preferably detectably labeled compounds of the present invention, as disclosed herein, are employed in the above summarized methods.
  • the present invention relates to the use of the compounds of the invention as a TDP-43 aggregates’ diagnostic agent or diagnostic tool.
  • the present invention relates to the use of the compounds of the invention as an in vitro analytical reference or an in vitro screening tool. Said compounds of the invention are also useful in in vivo diagnostic methods. In such instances, the compounds of the invention may be detectably labeled compounds or contain cold isotopes.
  • the present invention further relates to the use of the compounds of the present invention, more specifically detectably labelled compounds of the invention as defined herein, as diagnostic biomarkers enabling more efficient and precise patient selection, e.g., for longitudinal monitoring in clinical studies, or for supporting the development of novel therapeutics for treating TDP-43 proteinopathies.
  • the present invention further relates to the use of the compounds of the present invention, more specifically detectably labelled compounds of the invention as defined herein, as a TDP-43 aggregates’ biomarker or a TDP-43 proteinopathy biomarker.
  • the compounds of the invention may be employed for research use, in particular, as an analytical tool or reference molecule.
  • kits for use in one or more of the methods of the invention wherein the kit comprises a compound of the invention as described herein.
  • the kit typically comprises a container holding the compound of the invention and instructions for using the compound of the invention.
  • the kit comprises a compound of formula (I), as disclosed herein.
  • the compound of the invention is a detectably labelled compound (e.g. compound of formula (I-T), (I-T'), (I-F) or (I-F')).
  • kit refers in general to any diagnostic kit known in the art. More specifically, the latter term refers to a diagnostic kit as described in Zrein et al., Clin. Diagn. Lab. Immunol., 1998, 5, 45-49.
  • the dose of the detectably labelled compounds of the present invention will vary depending on the exact compound to be administered, the weight of the patient, size and type of the sample, and other variables as would be apparent to a physician skilled in the art.
  • the dose could preferably lie in the range 0.001 ⁇ g/kg to 10 ⁇ g/kg, preferably 0.01 ⁇ g/kg to 1.0 ⁇ g/kg.
  • the radioactive dose can be, e.g., 100 to 600 MBq, more preferably 150 to 450 MBq.
  • such kits may be useful for performing the methods of the invention (which include, for example, but not limited to, imaging, diagnosing, and monitoring methods), e.g., for diagnosing of a disease, disorder or abnormality associated with TDP-43 aggregates or a TDP-43 proteinopathy.
  • Such kits may comprise all necessary components for performing the herein provided methods. Typically, each component is stored separately in a single overall packaging.
  • kits for example, buffers, detectable dyes, laboratory equipment, reaction containers, instructions and the like. Instructions for use may be tailored to the specific method for which the kit is to be employed.
  • the present invention relates further to a kit for the preparation of a detectably labeled compound of the invention, wherein in particular the detectable label is a radioisotope.
  • the kit comprises a precursor of the detectably labeled compound of the formula (I) and a labeling agent which reacts with the precursor to introduce a detectable (e.g., radioactive) label.
  • Preferred precursors are compounds of the formulae (II), (III) and (IV).
  • the labeling agent which reacts with the precursor can be an agent which introduces a detectable (e.g., radioactive) label such as 18F or 3H.
  • the labeling agent can be a 18F-fluorination agent.
  • the present invention relates to a method for preparing a compound of formula (I), as described above, the method comprising the step of: Reacting a compound of formula (II) with R10 to provide a compound of formula (I) wherein n, R1, and R2 are as defined above; R 10 is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with – -(C 1 -C 3 alkyl)halo, F, NH 2, CN and/or CH 3 , wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S, wherein the 5- or 6-membered carbocyclic or heterocyclic ring is substituted with Br or I.
  • R10 is selected from the following groups: , wherein R5 is -CH2-CH2-halo, CH3 or H, preferably -CH2-CH2F; and wherein Hal is Br or I; preferably Br, or R3 is F, R4 is NH2, R7 is H, and R8 is H; R3 is NH2, R4 is F, R7 is H, and R8 is H, R3 is CN, R4 is NH2, R7 is H, and R8 is H, R3 is H, R4 is NH , R7 is H 8 2 , and R is CN, R3 is H, R4 is NH2, R7 is H, and R8 is F, or R3 is H, R4 is NH 7 8 2, R is H, and R is CN; or , or preferably , wherein Hal is Br or I; preferably Br; and wherein R9 is selected from H, F, NH2 or CH3.
  • the method of reacting the compound having the formula (II) with R10 can be conducted by any suitable method.
  • the reaction can be conducted in the presence of a diamine chelator such as DMEDA, a base such as potassium carbonate, a catalyst such as CuI, and an aprotic solvent such as dioxane.
  • the reaction can be conducted under Pd-coupling conditions, in the presence of a Pd catalyst such as Pd[P(Ph) 3 ] 4 or Pd sources such as Pd(OAc) 2 and XantPhos.
  • the present invention provides a method for preparing the Tritium ( 3 H) detectably labeled compounds of the invention having the formula (I-T) or (I-T'), said method comprises the step of radiolabeling a precursor of the compound having the formula (I-T) or (I-T') with a radioisotope, wherein at least one leaving group of the precursor of the compound having the formula (I-T) or (I-T') is replaced by Tritium ( 3 H).
  • Tritium ( 3 H) detectably labeled compounds having the formula (I-T) or (I-T') preferably have at least 1 to 3 Hydrogen (H) which are each replaced by Tritium ( 3 H).
  • the present invention provides a method for preparing a compound of formula (I-T) or (I-T'), said method comprises the step of: Radiolabeling a precursor compound having the formula (III) with T (i.e., 3H) by either exchange of Br or I with T utilizing T2 and a suitable catalyst or introduction of a CT3-group or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or mixtures thereof, wherein Z and Z’ are independently selected from C-Br, C-I, and C-H, wherein n is 1 or 2; R1 is H, OH, –(C1-C3alkyl)OH, F or -COORA, wherein RA is (C1-C4)alkyl; R 11 is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with Br, I, F, NH 2, CN –(C 1 -C
  • the at least one Br or I is replaced by T; or R 11 comprises a NH moiety; wherein the NH-moiety is replaced by N-CT 3 , and wherein T is 3H.
  • Z’ is H and Z is C-Br or C-I, more preferably C-Br, and the Br or I is replaced by T.
  • Z is H and Z’ is C-Br or C-I, more preferably C-Br, and the Br or I is replaced by T.
  • R11 comprises Br or I and the Br or I is replaced by T.
  • Z’ is H, Z is C-Br or C-I and the Br or I is replaced by T; and R11 comprises Br or I and the Br or I is replaced by T.
  • the present invention provides a method for preparing a compound of formula (I-T) comprising radiolabeling a precursor compound having the formula (III) with T (i.e., 3H) or a stereoisomer, polymorph, racemic mixture, tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, or mixtures thereof, wherein n is 1 or 2; R 11 is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with F, NH 2, CN, –(C 1 -C 3 alkyl)halo and/or CH 3 , wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S, preferably N; R1 is -COORA, wherein RA is (C 1 1-C4)alkyl,
  • the method can be conducted in the presence of a catalyst such as palladium on carbon (Pd/C) or Lindlar’s catalyst, a solvent such as N,N-dimethylformamide (DMF) and a base such as N,N-diisopropylethylamine (DIEA).
  • a catalyst such as palladium on carbon (Pd/C) or Lindlar’s catalyst
  • a solvent such as N,N-dimethylformamide (DMF)
  • DIEA N,N-diisopropylethylamine
  • the 3H radiolabeling agent can be LiT, prepared from n-BuLi and tritium gas in the presence of TMEDA, in the presence of AlCl3 and a solvent such as THF.
  • R 10 is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with –-(C1-C3alkyl)halo, F, NH2, CN and/or CH3, wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S, wherein the 5- or 6-membered carbocyclic or heterocyclic ring is substituted with Br or I and may be optionally substituted with SEM.
  • R10 is selected from the following groups: , wherein Hal is Br or I; and R3 is F, R4 is NH2, R7 is H, and R8 is H; R3 is NH2, R4 is F, R7 is H, and R8 is H, R3 is CN, R4 is NH 7 8 2, R is H, and R is H, R3 is H, R4 is NH , R7 is H, 8 2 and R is CN, R3 is H, R4 is NH 7 8 2, R is H, and R is F; R3 is H, R4 is NH 7 8 2, R is H, and R is CN; , wherein R9 is selected from H, F, NH2 or CH3, wherein Hal is Br if Cl is present or Hal is I if Br is present; , wherein Hal is Br if Cl is present or Hal is I if Br is present; , wherein Hal is Br if Cl is present or Hal is I if Br is present; , wherein Hal is Br if Cl is present or Hal
  • the method of reacting the compound having the formula (II) with R10 can be conducted by any suitable method.
  • the reaction can be conducted in the presence of a diamine chelator such as DMEDA, a base such as potassium carbonate, a catalyst such as CuI, and an aprotic solvent such as dioxane.
  • the reaction can be conducted under Pd-coupling conditions, in the presence of a Pd catalyst such as Pd[P(Ph)3]4 or Pd(OAc)2, XantPhos.
  • Fluorine ( 18 F) detectably labeled compounds In one embodiment, the present invention provides a method for preparing the Fluorine ( 18 F) detectably labeled compounds of the invention, said method comprises radiolabeling a precursor having the formula (IV) with a radioisotope [ 18 F]: wherein n is 1 or 2; R 2 is as defined for formula (I); and R 14 is a leaving group (LG), preferably MsO. In one embodiment R14 is replaced by 18F in the radiolabeling step.
  • the present invention provides a method for preparing the fluorine ( 18 F) detectably labeled compounds of the invention, said method comprises radiolabeling a precursor having the formula (IV) with a radioisotope [ 18 F]: wherein n is 1 or 2; R1 is H, OH, –(C1-C3alkyl)OH, COORA, wherein RA is (C1-C4)alkyl, preferably R1 is OH or -CH2OH or -C(OOCH 3 ); R 2 is a 5- or 6-membered carbocyclic or heterocyclic ring which can be optionally substituted with –(C 1 -C 3 alkyl)halo, F, NH 2, CN and/or CH 3 , wherein the heterocyclic ring contains one or more heteroatoms selected from N, O and S, preferably R2 is , wherein R5 is –(C1-C3alkyl)halo, preferably -CH2CH2-F; wherein R5 is
  • R14 is replaced by 18F in the radiolabeling step.
  • the fluorination can be conducted in the presence of a 18F-fluorination agent which can be selected from K[18F], Cs18F, Na18F, Rb18F, Kryptofix[222]K18F, tetra(C1-6alkyl) ammonium salt of 18F, and tetrabutylammonium [ 18 F]fluoride.
  • the Leaving Group (LG) is C1–4 alkyl sulfonate or C6–10 aryl sulfonate or nitro, preferably mesylate, tosylate, nosylate, trimethyl ammonium or nitro.
  • the Leaving Group (LG) is mesylate, trimethyl ammonium or nitro.
  • Suitable solvents for the 18F-fluorination step are known to a skilled person.
  • the solvent can be, for example, selected from the group consisting of DMF, DMSO, acetonitrile, DMA, or mixtures thereof.
  • the solvent is acetonitrile or DMSO.
  • a method for preparing the Fluorine (18F) detectably labeled Compound 18 may comprise a radiolabeling step in which the Leaving Group (LG), which in this case is mesylate, of the precursor L1 is replaced with a Fluorine (18F) in the presence of the 18F-fluorinating agent, such as K[ 18 F] or [ 18 F]TBAF, as shown below:
  • a method for preparing the fluorine (18F) detectably labeled Compound 19 may comprise a radiolabeling step in which the Leaving Group (LG), which in this case is nitro, of the precursor 20 is replaced with a fluorine (18F) in the presence of the 18F-fluorinating agent, such as K[ 18 F] or [ 18 F]TBAF, as shown below:
  • the compounds of the invention can be prepared by one of the general methods shown in the following schemes.
  • Step-5 methyl 2-(2,6-difluoropyridin-3-yl)-4-(hydroxymethyl)thiazole-5-carboxylate (F)
  • DCM a stirred solution of (E) (900 mg, 2.2 mmol) in DCM (18 mL, 20 vol.) was added 4M HCl in 1,4- dioxane (9.0 mL, 10 vol) at 0 o C under N 2 atmosphere and the mixture was stirred at rt for 4 h. The reaction time was monitored by TLC. After completion of the reaction, solvent was removed under vacuum and the mixture was cooled to 0 o C. The mixture was treated with an aqueous saturated NaHCO3 (25 mL) solution until the pH reached up to 8-9.
  • Step-8 methyl 2-(2-fluoro-6-(4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-4-((pyridin-3- ylamino)methyl)thiazole-5-carboxylate (I)
  • H 70 mg, 0.2 mmol
  • piperidin-4-ylmethanol (12) 23 mg, 0.2 mmol
  • DIPEA 0.07 mL, 0.38 mmol
  • DMSO 7 mL, 100 vol
  • Step-9 2-(2-fluoro-6-(4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-4-((pyridin-3-ylamino) methyl) thiazole-5-carboxylic acid (J)
  • a solution of (I) 55 mg, 0.12 mmol) in (THF: water) (4:2, 5 mL, 90 vol.) was added lithium hydroxide (11 mg, 0.48 mmol) at rt.
  • the resulting mixture was stirred at rt for 5 h. Progress of the reaction was monitored by TLC. After completion as monitored by TLC, the mixture was cooled to 0 o C and treated with a saturated aqueous citric acid solution until the pH reached 3-4.
  • Example 2 Synthesis (Example Compound 2) Step-1: methyl 2-(2,6-difluoropyridin-3-yl)-4-((pyrimidin-2-ylamino)methyl)thiazole-5- carboxylate (K) To a solution of (G) (400 mg, 0.7 mmol) and pyrimidin-2-amine (267 mg, 2.8 mmol) in methanol (20 mL, 50 vol) was added glacial AcOH (0.16 mL, 2.8 mmol) at rt under N2. The mixture was stirred for 4 h at 80°C. Pic borane (300 mg, 2.8 mmol) was added at 0°C and the mixture was allowed to stir at rt for another 18 h.
  • Step-2 methyl 2-(2-fluoro-6-(4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-4-((pyrimidin- 2-yl amino) methyl)thiazole-5-carboxylate (L)
  • K 350 mg, 0.96 mmol
  • piperidin-4-ylmethanol (12) 110 mg, 0.96 mmol
  • DIPEA 0.58 mL, 3.3 mmol
  • DMSO 35 mL, 100 vol
  • Step-3 2-(2-fluoro-6-(4-(hydroxymethyl) piperidin-1-yl) pyridin-3-yl)-4-((pyrimidin-2-yl amino) methyl) thiazole-5-carboxylic acid (M)
  • Li lithium hydroxide
  • Step-4 2-(2-fluoro-6-(4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)-5-(pyrimidin-2-yl)-4,5- dihydro-6H-pyrrolo[3,4-d]thiazol-6-one (2)
  • HATU 170 mg, 0.45 mmol
  • DIPEA 0.12 mL, 0.68 mmol
  • reaction mixture was quenched with ice-cool water (20 mL) and the product was extracted with 5% MeOH in DCM (25 mL x 3). The organic layer was dried over Na 2 SO 4 and concentrated under vacuum. The residue was purified by chromatography over silica gel (230- 400 mesh) and eluted in 2% MeOH in DCM to afford the title product (2) as a yellow solid (30 mg, 31%).
  • reaction mixture was quenched with ice cold water (25 mL).
  • the crude reaction mass was filtered through a Büchner funnel and washed with hexane (5 mL X 3), dried under vacuum to afford (P) as a yellow solid (118 mg, 90%).
  • Step-3 (R)-2-(2-fluoro-6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)-5-(pyridin-3-yl)-4,5-dihydro- 6H-pyrrolo[3,4-d]thiazol-6-one (4)
  • HATU 165 mg, 0.43 mmol
  • DIPEA 0.1 mL, 0.65 mmol
  • Example 5 Synthesis (Example Compound 5) Step-1: methyl (S)-2-(2-fluoro-6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl)-4-((pyridin-3- ylamino)methyl)thiazole-5-carboxylate (R)
  • H 110 mg, 0.30 mmol
  • S S-pyrrolidin-3-ol
  • DIPEA 0.1 mL, 0.61 mmol
  • DMSO 11 mL, 100 vol
  • reaction mixture was quenched with ice cold water (25 mL).
  • the crude reaction mass was filtered through a Büchner funnel,washed with hexane (5 mL X 3),and dried under vacuum to afford (R) as a yellow solid (120 mg, 92%).
  • Step-3 (S)-2-(2-fluoro-6-(3-hydroxypyrrolidin-1-yl) pyridin-3-yl)-5-(pyridin-3-yl)-4,5-dihydro- 6H-pyrrolo[3,4-d]thiazol-6-one (5)
  • HATU 146 mg, 0.38 mmol
  • DIPEA 0 o C
  • the resulting mixture was stirred at rt under N 2 atmosphere for 20 h. Then the reaction mixture was quenched with ice-cool water (20 mL).
  • reaction mixture was quenched with ice-cool water (25 mL), filtered through a Büchner funnel, washed with hexane (5 mL X 3), and dried under vacuum to afford (6) as a yellow solid (58 mg, 60%).
  • Example 7 Synthesis (Example Compound 7) Step-1: methyl 2-(2,6-difluoropyridin-3-yl)-4-(((1-(2-fluoroethyl)-1H-pyrazol-4- yl)amino)methyl) thiazole-5-carboxylate (V) To a solution of (G) (500 mg, 1.7 mmol) and 1-(2-fluoroethyl)-1H-pyrazol-4-amine (454mg, 3.5 mmol) in methanol (25 mL, 50 vol) was added glacial AcOH (0.2 mL, 3.5 mmol) at rt under N 2 . Then the mixture was stirred for 4 h at 80°C.
  • Step-2 methyl 2-(2-fluoro-6-(4-(hydroxymethyl) piperidin-1-yl) pyridin-3-yl)-4-(((1-(2-fluoro ethyl) -1H-pyrazol-4-yl) amino) methyl) thiazole-5-carboxylate (W)
  • V 100 mg, 0.25 mmol
  • piperidin-4-ylmethanol (12) 29 mg, 0.25 mmol
  • DIPEA 0.09 mL, 0.5 mmol
  • DMSO 10 mL, 100 vol
  • Step-2 1-(6-fluoro-5-(6-oxo-5-(pyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2- yl)pyridin-2-yl)piperidine-4-carboxylic acid (Z)
  • HATU 330 mg, 8.7 mmol
  • DIPEA 0.2 mL, 1.3 mmol
  • Step-3 methyl 1-(6-fluoro-5-(6-oxo-5-(pyrimidin-2-yl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2- yl)pyridin-2-yl)piperidine-4-carboxylate (8)
  • H2SO4 0.001 mL, 0.018mmol

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Abstract

La présente invention concerne des composés appropriés pour l'imagerie d'agrégats de TDP-43 (protéine de liaison à l'ADN de réponse transactive (TAR) 43 kDa). Ces composés peuvent être utilisés, par exemple, pour diagnostiquer une maladie, un trouble ou une anomalie associés à des agrégats de TDP-43 ou une protéinopathie à TDP-43, telle que la sclérose latérale amyotrophique (SLA), la maladie d'Alzheimer (AD), la démence frontotemporale (FTD) et l'encéphalopathie à prédominance limbique TDP-43 liée à l'âge (LATE).
PCT/EP2025/058993 2024-04-03 2025-04-02 Nouveaux composés pour le diagnostic de protéinopathies à tdp-43 Pending WO2025210087A1 (fr)

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