WO2021234181A1 - Utilisation d'un inhibiteur de fap dans un procédé de diagnostic - Google Patents

Utilisation d'un inhibiteur de fap dans un procédé de diagnostic Download PDF

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WO2021234181A1
WO2021234181A1 PCT/EP2021/063901 EP2021063901W WO2021234181A1 WO 2021234181 A1 WO2021234181 A1 WO 2021234181A1 EP 2021063901 W EP2021063901 W EP 2021063901W WO 2021234181 A1 WO2021234181 A1 WO 2021234181A1
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alkyl
group
compound
butyl
heterocycle
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PCT/EP2021/063901
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English (en)
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Lorenz Lehmann
Markus Heckmann
Hugo Katus
Daniel FINKE
Finn REINHARDT
Uwe Haberkorn
Frederik Lars GIESEL
Clemens KRATOCHWIL
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Universität Heidelberg
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0446—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • the present invention relates to a compound, a pharmaceutical composition comprising or consisting of said compound, a kit comprising or consisting of said compound or pharmaceutical composition for use in the in vivo diagnosis of ischemia/cardiac remodelling.
  • Cardiac remodelling is commonly defined as a physiological or pathological state that may occur after conditions such as myocardial infarction, pressure overload, idiopathic dilated cardiomyopathy or volume overload.
  • FAP plays an important role in cancer growth and is discussed as a hot candidate for targeted oncotherapy.
  • TGFpi induced FAP expression is also crucial for cardiac wound healing and remodeling (Aghajanian et al. 2019; Nature 2019;573:430-433; Tillmanns et al. 2015, J Mol Cell Cardiol 2015;87:194-203).
  • Serial small animal FAPI PET-CT scans revealed a steady increase FAP activity after myocardial infarction until day 6 followed by a steady decline (Varasteh et al. 2019, J Nucl Med 2019).
  • chimeric antigen receptor T cells targeting FAP to reduce cardiac fibrosis and restore systolic function after myocardial infarction (Aghajanian et al supra).
  • the present invention discloses the use of FAPI tracers in the diagnosis of cardiac remodeling/ischemia, in particular of early stages before myocardial infarction.
  • the present invention provides a compound of Formula (I) wherein
  • Q, R, U, V, W, Y, Z are individually present or absent under the proviso that at least three of Q, R, U, V, W, Y, Z are present;
  • R 1 and R 2 are independently selected from the group consisting of -H, -OH, halo, C 1-6 -alkyl, -
  • R 3 is selected from the group consisting of -H , -CN , -B(OH)2, -C(O) -alkyl, -C(O) -aryl-, -
  • R 4 is selected from the group consisting of -H, -C 1-6 -alkyl, -O-C 1-6 -alkyl, -S-C 1-6 -alkyl, aryl, and - C 1-6 -aralkyl, each of said -C 1-6 -alkyl being optionally substituted with from 1 to 3 substituents selected from -OH, oxo, halo and optionally connected to Q, R, U, V, W, Y or Z;
  • R 5 is selected from the group consisting of -H, halo and C 1-6 -alkyl;
  • R 6 , and R 7 are independently selected from the group consisting of-H, under the proviso that R 6 and R 7 are not at the same time H, wherein L is a linker, wherein D, A, E, and B are individually present or absent, preferably wherein at least A, E, and B are present, wherein when present:
  • D is a linker
  • A is selected from the group consisting of NR 4 , O, S, and CH 2 ;
  • E is selected from the group consisting of
  • i is 1, 2, or 3; wherein j is 1, 2, or 3; wherein k is 1, 2, or 3; wherein m is 1, 2, or 3;
  • a and E together form a group selected from a cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein A and E can be mono-, bi- and multicyclic, preferably monocyclic.
  • Each A and E being optionally substituted by 1 to 4 residues from the group consisting of -H, -C 1-6 -alkyl, -O-C 1 - 6 - alkyl, -S-C 1-6 -alkyl, alkenyl, heteroalkenyl, cycloalkenyl, cycloheteroalkenyl, alkynyl, aryl, and -C 1-6 -aralkyl, each of said -C 1-6 -alkyl being optionally substituted with from 1 to 3 substituents selected from -OH, oxo, halo; and optionally connected to A, B, D, E or
  • B is selected from the group consisting of S, NR 4 , NR 4 -0, NR 4 -C 1 - 6 -alkyl, NR 4 -C 1-6 -alkyl-NR 4 , and a 5- to 10-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms, preferably wherein NR 4 -C I - 6 -alky 1-NR 4 and the N-containing heterocycle is substituted with 1 to 3 substituents selected from the group consisting of C 1-6 alky 1, aryl, C 1-6 -aralkyl; and;
  • R 8 is selected from the group consisting of radioactive moiety, chelating agent, fluorescent dye, a contrast agent and combinations thereof; is a 1-naphtyl moiety or a 5 to 10- membered N-containing aromatic or non- aromatic mono- or bicyclic heterocycle, wherein there are 2 ring atoms between the N atom and X; said heterocycle optionally further comprising 1, 2 or 3 heteroatoms selected from O, N and S; and X is a C atom; or a pharmaceutically acceptable tautomer, racemate, hydrate, solvate, or salt thereof; for use in a method of in vivo diagnosis of ischemia.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising or consisting of at least one compound of the first aspect, and, optionally, a pharmaceutically acceptable carrier and/or excipient for use in a method of in vivo diagnosis of ischemia.
  • the present invention relates to a kit comprising or consisting of the compound of the first aspect or the pharmaceutical composition of the second aspect and instructions for use in a method of in vivo diagnosis of ischemia.
  • Figure 1 Logistic regression and linear prediction model for fibroblast activation protein inhibitor signal in the myocardium
  • Figure 2 Bullseye 17 segment analysis of different subgroups with representative FAPI images.
  • the median signal intensity of the corresponding segment is displayed for each group.
  • the number of patients in a group are seen in the right lower corner of each bullseye above the grey scale.
  • the greyscale coding was converted from a spectral color scale ranging from 0.7 (blue) to 1.3 (red) with 1.0 (yellow) being the center.
  • Representative FAPI images are displayed below.
  • Signal intensity was generally increased in the septal basal segments. The apex exhibited the lowest signal intensity. This effect was most pronounced in arterial hypertension. Diabetes, arterial hypertension and obesity, all risk factors associated with metabolic stress and cardiac remodeling show the highest increase in fibroblast activation protein inhibitor (FAPI) signals.
  • Figure 3 Cardiac FAPI signal kinetics
  • FAPI signals were measured 10, 60 and 180 minutes after administration.
  • the median standardized uptake values (SUVs) and their respective interquartile ranges are depicted.
  • Cardiac signals were highest 10 minutes after administration and decreased continuously in time.
  • the median signal intensities for each segment and the number of patients scanned are reported in the corresponding bullseye.
  • FAPI and FDG signals in all patients who had an FDG and FAPI PET-CT examination within 12 months are portrayed for each patient (A) and signal ratios were calculated for different organs (B).
  • Myocardial standardized uptake values (SUV) were generally higher using an FDG tracer. Signal ratios were similar between FDG and FAPI for heart/blood pool as well as heart/lung. Heart/brain and heart/liver ratios were significantly higher while the heart/gluteus muscle ratio was lower using a FAPI tracer. Signal ratios were compared using a Kruskal- Wallis test. * p ⁇ 0.05, ****p ⁇ 0.0001
  • Standardized uptake values (SUV) are reported for each cancer entity.
  • Subgroups are organized thematically. The median signal intensity for each patient subgroup and the group size is reported in each bullseye.
  • Figure 8 FAPI standardized uptake value (SUV) and echocardiogrphic findings
  • the first row reports median signal intensities measured during the first and second scans for each segment. Differences are reported in the third column. Each patient is reported in a separated row. While there is a general increase in signal intensity over time, there is also one patient (patient 14), who showed a clear decrease in cardiac FAPI signals in the follow scan.
  • FIG. 10 FAPI signals in patients following myocardial infarction.
  • FIG. 11 Patients with FAPI scans after coronary intervention
  • ischemia refers in general to a restriction in or complete blockade of blood supply to a tissue, resulting in a shortage of oxygen as well as other components (nutrients etc.) required for cellular metabolism. This shortage in supply may result in damage to or death of the affected tissue.
  • coronary ischemia refers to an ischemia that directly affects the heart, in particular myocardial tissue and may lead inter alia to myocardial infarction.
  • presymptomatic and prodromal refer to very early stages of a disease.
  • presymptomatic stage the subject is without any symptoms of the disease.
  • Preferred examples of presymptomatic stages are subjects with an increased risk of developing a certain disease that have not yet displayed any symptoms of this disease.
  • prodromal stage of a disease early symptoms of a disease are already present although those symptoms are not diagnostically specific symptoms of this disease and may occur in other diseases as well.
  • alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl and alkynyl are provided.
  • alkyl refers to a saturated straight or branched carbon chain.
  • the chain comprises from 1 to 10 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 e.g. methyl, ethyl methyl, ethyl, propyl, iso-propyl , but yl,tyslo-b.0u0tyl, tert- butyl, pentyl, hexyl, pentyl, or octyl.
  • Alkyl groups are optionally substituted.
  • heteroalkyl refers to a saturated straight or branched carbon chain.
  • the chain comprises from 1 to 9 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 e.g. methyl, ethyl, propyl, iso- propyl, butyl, Ao-butyl, sec-butyl, tertbutyl, pentyl, hexyl, pentyl, octyl, which is interrupted one or more times, e.g. 1, 2, 3, 4, 5, with the same or different heteroatoms.
  • the heteroatoms are selected from O, S, and N, e.g.
  • cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively, with preferably 3, 4, 5, 6, 7, 8, 9 or 10 atoms forming a ring, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc.
  • cycloalkyl and “heterocycloalkyl” are also meant to include bicyclic, tricyclic and polycyclic versions thereof.
  • heterocycloalkyl preferably refers to a saturated ring having five of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N; a saturated ring having six members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N or two additional N atoms; or a saturated bicyclic ring having nine or ten members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms. “Cycloalkyl” and “heterocycloalkyl” groups are optionally substituted.
  • a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, and the like.
  • heterocycloalkyl examples include l-(l,2,5,6-tetrahydropyridyl), 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, 1,8 diazo-spiro-[4,5] decyl, 1,7 diazo-spiro-[4,5] decyl, 1,6 diazo-spiro-[4,5] decyl, 2,8 diazo-spiro[4,5] decyl, 2,7 diazo-spiro[4,5] decyl, 2,6 diazo-spiro[4,5] decyl, 1,8 diazo-spiro-[5,4] decyl, 1,7 diazo-spiro- [5,4] decyl, 2,8 diazo-spiro-[5,4] decyl, 2,7 diazo-spiro[5,4] decyl, 3,8 diazo-spiro[5,4] decyl, 3,7 diazo-
  • aryl preferably refers to an aromatic monocyclic ring containing 6 carbon atoms, an aromatic bicyclic ring system containing 10 carbon atoms or an aromatic tricyclic ring system containing 14 carbon atoms. Examples are phenyl, naphtyl or anthracenyl. The aryl group is optionally substituted.
  • aralkyl refers to an alkyl moiety, which is substituted by aryl, wherein alkyl and aryl have the meaning as outlined above.
  • An example is the benzyl radical.
  • the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g. methyl, ethyl methyl, ethyl, propyl, /.so- propyl, butyl, /.so-butyl, .svc-butenyl, tert- butyl, pentyl, hexyl, pentyl, octyl.
  • the aralkyl group is optionally substituted at the alkyl and/or aryl part of the group.
  • heteroaryl preferably refers to a five or six-membered aromatic monocyclic ring wherein at least one of the carbon atoms are replaced by 1, 2, 3, or 4 (for the five membered ring) or 1, 2, 3, 4, or 5 (for the six membered ring) of the same or different heteroatoms, preferably selected from O, N and S; an aromatic bicyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 8, 9, 10, 11 or 12 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S; or an aromatic tricyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 13, 14, 15, or 16 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S.
  • Examples are oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1-benzofuranyl, 2- benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2,1-benzosoxazoyl, benzothiazolyl, 1,2- benzisothiazolyl
  • heteroarylkyl refers to an alkyl moiety, which is substituted by heteroaryl, wherein alkyl and heteroaryl have the meaning as outlined above.
  • An example is the 2- alklypyridinyl, 3-alkylpyridinyl, or 2-methylpyridinyl.
  • the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g.
  • heteroaralkyl group is optionally substituted at the alkyl and/or heteroaryl part of the group.
  • alkenyl and cycloalkenyl refer to olefmic unsaturated carbon atoms containing chains or rings with one or more double bonds. Examples are propenyl and cyclohexenyl.
  • the alkenyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g.
  • cycloalkenyl ring comprises from 3 to 8 carbon atoms, i.e. 3, 4, 5, 6, 7, or 8, e.g.
  • alkynyl refers to unsaturated carbon atoms containing chains or rings with one or more triple bonds.
  • An example is the propargyl radical.
  • the alkynyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g. ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, hexynyl, pentynyl, octynyl.
  • carbon atoms or hydrogen atoms in alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, alkynyl radicals may be substituted independently from each other with one or more elements selected from the group consisting of O, S, N or with groups containing one or more elements selected from the group consisting of O, S, N.
  • Embodiments include alkoxy, cycloalkoxy, arykoxy, aralkoxy, alkenyloxy, cycloalkenyloxy, alkynyloxy, alkylthio, cycloalkylthio, arylthio, aralkylthio, alkenylthio, cycloalkenylthio, alkynylthio, alkylamino, cycloalkylamino, arylamino, aralkylamino, alkenylamino, cycloalkenylamino, alkynylamino radicals.
  • hydrogen atoms in alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, alkynyl radicals may be substituted independently from each other with one or more halogen atoms.
  • One radical is the trifluoromethyl radical.
  • radicals or two or more residues can be selected independently from each other, then the term “independently” means that the radicals or the residues may be the same or may be different.
  • a wording defining the limits of a range of length such as, e. g., “from 1 to 6” means any integer from 1 to 6, i. e. 1, 2, 3, 4, 5 and 6.
  • any range defined by two integers explicitly mentioned is meant to comprise and disclose any integer defining said limits and any integer comprised in said range.
  • halo refers to a halogen residue selected from the group consisting of F, Br, I and C1.
  • the halogen is F.
  • linker refers to any chemically suitable linker.
  • linker are not or only slowly cleaved under physiological conditions.
  • the linker does not comprise recognition sequences for proteases or recognition structures for other degrading enzymes.
  • the compounds of the invention are administered systemically to allow broad access to all compartments of the body and subsequently enrichment of the compounds of the invention wherever in the body the tumor is located, it is preferred that the linker is chosen in such that it is not or only slowly cleaved in blood. The cleavage is considered slowly, if less than 50% of the linkers are cleaved 2 h after administration of the compound to a human patient.
  • Suitable linkers comprises or consists of optionally substituted alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, aralkyl, heteroaralyl, alkenyl, heteroalkenyl, cycloalkenyl, cycloheteroalkenyl, alkynyl, sulfonyl, amines, ethers, thioethers phosphines, phosphoramidates, carboxamides, esters, imidoesters, amidines, thioesters, sulfonamides, 3-thiopyrrolidine-2,5-dion, carbamates, ureas, guanidines, thioureas, disulfides, oximes, hydrazines, hydrazides, hydrazones, diaza bonds, triazoles, triazolines, tetrazines, platinum complexes and amino acids, or
  • amino acid refers to any organic acid containing one or more amino substituents, e.g. a-, b- or g-amino, derivatives of aliphatic carboxylic acids.
  • amino substituents e.g. a-, b- or g-amino, derivatives of aliphatic carboxylic acids.
  • polypeptide notation e.g. Xaa5, i.e. Xaa1Xaa2Xaa3Xaa4Xaa5
  • Xaal to Xaa5 are each and independently selected from amino acids as defined
  • the left hand direction is the amino terminal direction
  • the right hand direction is the carboxy terminal direction, in accordance with standard usage and convention.
  • conventional amino acid refers to the twenty naturally occurring amino acids, and encompasses all stereomeric isoforms, i.e. D,L-, D- and L-amino acids thereof. These conventional amino acids can herein also be referred to by their conventional three- letter or one-letter abbreviations and their abbreviations follow conventional usage (see, for example, Immunology — A Synthesis, 2nd Edition, E. S. Golub and D. R. Gren, Eds., Sinauer Associates, Sunderland Mass. (1991)).
  • non-conventional amino acid refers to unnatural amino acids or chemical amino acid analogues, e.g. a,a-disubstituted amino acids, N-alkyl amino acids, homo-amino acids, dehydroamino acids, aromatic amino acids (other than phenylalanine, tyrosine and tryptophan), and ortho-, meta- or para-aminobenzoic acid.
  • Non-conventional amino acids also include compounds which have an amine and carboxyl functional group separated in a 1,3 or larger substitution pattern, such as b-alanine, g-amino butyric acid, Freidinger lactam, the bicyclic dipeptide (BTD) , amino-methyl benzoic acid and others well known in the art.
  • BTD bicyclic dipeptide
  • Statine- like isosteres, hydroxyethylene isosteres, reduced amide bond isosteres, thioamide isosteres, urea isosteres, carbamate isosteres, thioether isosteres, vinyl isosteres and other amide bond isosteres known to the art may also be used.
  • analogues or non-conventional amino acids may improve the stability and biological half-life of the added peptide since they are more resistant to breakdown under physiological conditions.
  • the person skilled in the art will be aware of similar types of substitution which may be made.
  • a non-limiting list of non- conventional amino acids which may be used as suitable building blocks for a peptide and their standard abbreviations (in brackets) is as follows: a-aminobutyric acid (Abu), L-N- methylalanine (Nmala), ⁇ -amino-a-methylbutyrate (Mgabu), L-N-methylarginine (Nmarg), aminocyclopropane (Cpro), L-N-methylasparagine (Nmasn), carboxylate L-N-methylaspartic acid (Nmasp), aniinoisobutyric acid (Aib), L-N-methylcysteine (Nmcys), aminonorbomyl (Norb), L-N-methylglutamine
  • N-containing aromatic or non-aromatic mono or bicyclic heterocycle refers to a cyclic saturated or unsaturated hydrocarbon compound which contains at least one nitrogen atom as constituent of the cyclic chain.
  • radioactive moiety refers to a molecular assembly which carries a radioactive nuclide.
  • the nuclide is bound either by covalent or coordinate bonds which remain stable under physiological conditions. Examples are [ 131 I]-3-iodobenzoic acid or 68 Ga- DOTA.
  • a “fluorescent isotope” as used herein emits electromagnetic radiation after excitation by electromagnetic radiation of a shorter wavelength.
  • a “radioisotope” as used herein is a radioactive isotope of an element (included by the term “radionuclide”) emitting ⁇ -, ⁇ -, and/or ⁇ -radioation.
  • the term “radioactive drug” is used in the context of the present invention to refer to a biologic active compound which is modified by a radioisotope.
  • Especially intercalating substances can be used to deliver the radioactivity to direct proximity of DNA (e.g. a 131 I- carrying derivative of Hoechst-33258).
  • chelating agent or “chelate” are used interchangeably in the context of the present invention and refer to a molecule, often an organic one, and often a Lewis base, having two or more unshared electron pairs available for donation to a metal ion.
  • the metal ion is usually coordinated by two or more electron pairs to the chelating agent.
  • identity chelating agent “tridentate chelating agent, and “tetradentate chelating agent” refer to chelating agents having, respectively, two, three, and four electron pairs readily available for simultaneous donation to a metal ion coordinated by the chelating agent.
  • the electron pairs of a chelating agent forms coordinate bonds with a single metal ion; however, in certain examples, a chelating agent may form coordinate bonds with more than one metal ion, with a variety of binding modes being possible.
  • fluorescent dye is used in the context of the present invention to refer to a compound that emits visible or infrared light after excitation by electromagnetic radiation of a shorter and suitable wavelength. It is understood by the skilled person, that each fluorescent dye has a predetermined excitation wavelength.
  • contrast agent is used in the context of the present invention to refer to a compound which increases the contrast of structures or fluids in medical imaging.
  • the enhancement is achieved by absorbing electromagnetic radiation or altering electromagnetic fields.
  • paramagnetic refers to paramagnetism induced by unpaired electrons in a medium.
  • a paramagnetic substance induces a magnetic field if an external magnetic field is applied.
  • the direction of the induced field is the same as the external field and unlike ferromagnetism the field is not maintained in absence of an external field.
  • nanoparticle refers to particles preferably of spheric shape, with diameters of sizes between 1 and 100 nanometers. Depending on the composition, nanoparticles can possess magnetical, optical or physico-chemical qualities that can be assessed. Additionally surface modification is achievable for many types of nanoparticles.
  • Suitable pharmaceutically acceptable salts of the compound of the present invention include acid addition salts which may, for example, be formed by mixing a solution of choline or derivative thereof with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate).
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • suitable organic ligands e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sul
  • compositions include but are not limited to: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecyl sulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the present invention provides compounds which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide a compound of formula (I).
  • a prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art.
  • esters for example, methyl, ethyl
  • cycloalkyl for example, cyclohexyl
  • aralkyl for example, benzyl, p- methoxybenzyl
  • alkylcarbonyloxyalkyl for example, pivaloyloxymethyl
  • Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxyl groups have been masked as esters and ethers.
  • EP 0 039 051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
  • Compounds according to the invention can be synthesized according to one or more of the following methods. It should be noted that the general procedures are shown as it relates to preparation of compounds having unspecified stereochemistry. However, such procedures are generally applicable to those compounds of a specific stereochemistry, e.g., where the stereochemistry about a group is (S) or (R). In addition, the compounds having one stereochemistry (e.g., (R)) can often be utilized to produce those having opposite stereochemistry (i.e., (S)) using well-known methods, for example, by inversion.
  • Certain compounds of the present invention can exist in unsolvated forms as well as in solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the present invention.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H ), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
  • composition refers to a substance and/or a combination of substances being used for the identification, prevention or treatment of a tissue status or disease.
  • the pharmaceutical composition is formulated to be suitable for administration to a patient in order to prevent and/or treat disease.
  • a pharmaceutical composition refers to the combination of an active agent with a carrier, inert or active, making the composition suitable for therapeutic use.
  • Pharmaceutical compositions can be formulated for oral, parenteral, topical, inhalative, rectal, sublingual, transdermal, subcutaneous or vaginal application routes according to their chemical and physical properties.
  • Pharmaceutical compositions comprise solid, semisolid, liquid, transdermal therapeutic systems (TTS).
  • Solid compositions are selected from the group consisting of tablets, coated tablets, powder, granulate, pellets, capsules, effervescent tablets or transdermal therapeutic systems. Also comprised are liquid compositions, selected from the group consisting of solutions, syrups, infusions, extracts, solutions for intravenous application, solutions for infusion or solutions of the carrier systems of the present invention.
  • Semisolid compositions that can be used in the context of the invention comprise emulsion, suspension, creams, lotions, gels, globules, buccal tablets and suppositories.
  • “Pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic agent is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as saline solutions in water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • a saline solution is a preferred carrier when the pharmaceutical composition is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E. W. Martin.
  • Fibroblast activation protein as used herein is also known under the term “seprase”. Both terms can be used interchangeably herein.
  • Fibroblast activation protein is a homodimeric integral protein with dipeptidyl peptidase IV (DPPIV)-like fold, featuring an alpha/beta-hydrolase domain and an eight-bladed beta-propeller domain.
  • DPPIV dipeptidyl peptidase IV
  • the present invention provides a compound of Formula (I) wherein
  • Q, R, U, V, W, Y, Z are individually present or absent under the proviso that at least three of Q, R, U, V, W, Y, Z are present;
  • R 1 and R 2 are independently selected from the group consisting of -H, -OH, halo, C 1-6 -alkyl, - O-C 1 -6 -alkyl, S-C 1-6 -alkyl;
  • R 4 is selected from the group consisting of -H, -C 1-6 -alkyl, -O-C 1 -6 -alkyl, -S-C 1-6 -alkyl, alkenyl, heteroalkenyl, cycloalkenyl, cycloheteroalkenyl, alkynyl, aryl, and -Ci-6-aralkyl, each of said - C 1-6 -alkyl being optionally substituted with from 1 to 3 substituents selected from -OH, oxo, halo and optionally connected to Q, R, U, V, W, Y or Z;
  • R 5 is selected from the group consisting of -H, halo and C 1-6 -alkyl
  • R 6 , and R 7 are independently selected from the group consisting of-H, , under the proviso that R 6 and R 7 are not at the same time H, preferably R 6 is attached to the 7- or 8-quinolyl position and R 7 is attached to the 5- or 6- quinolyl position; more preferably R 6 is attached to the 7-quinolyl position and R 7 is attached to the 6-quinolyl position, wherein L is a linker, wherein D, A, E, and B are individually present or absent, preferably wherein at least A, E, and B are present, wherein when present:
  • D is a linker
  • A is selected from the group consisting of NR 4 , O, S, and CH2;
  • E is selected from the group consisting of C 1-6 -alkyl, wherein i is 1, 2, or 3; wherein j is 1, 2, or 3; wherein k is 1, 2, or 3; wherein m is 1, 2, or 3; more preferably, E is C 1-6 -alkyl, most preferably, E is C3 or C4 alkyl;
  • a and E together form a group selected from: a cycloalkyl, heterocycloalkyl, aryl and heteroaryl, preferably heterocycloalkyl, wherein A and E can be mono-, bi- and multicyclic, preferably monocyclic.
  • Each A and E being optionally substituted with 1 to 4 substituents selected from -H, -C 1-6 -alkyl, -O-C 1-6 -alkyl, -S-C 1-6 -alkyl, alkenyl, heteroalkenyl, cycloalkenyl, cycloheteroalkenyl, alkynyl, aryl, and -C 1-6 -aralkyl, each of said -C 1-6 -alkyl being optionally substituted with from 1 to 3 substituents selected from -OH, oxo, halo; and optionally connected to A, B, D, E or
  • B is selected from the group consisting of S, NR 4 , NR 4 -0, NR 4 -C 1 -6 -alkyl, NR 4 -C 1-6 -alkyl-NR 4 , and a 5- to 10-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms, preferably wherein NR 4 -C 1 - 6 -alky 1-NR 4 and the N-containing heterocycle is substituted with 1 to 3 substituents selected the group consisting of C 1-6 -alkyl, aryl, C 1-6 -aralkyl; and
  • R 8 is selected from the group consisting of radioactive moiety, chelating agent, fluorescent dye, a contrast agent and combinations thereof; is a 1-naphtyl moiety or a 5 to 10- membered N-containing aromatic or non- aromatic mono- or bicyclic heterocycle, wherein there are 2 ring atoms between the N atom and X; said heterocycle optionally further comprising 1, 2 or 3 heteroatoms selected from O, N and S; and X is a C atom; or a pharmaceutically acceptable tautomer, racemate, hydrate, solvate, or salt thereof for use in a method of in vivo diagnosis of ischemia.
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • R 8 is a radioactive moiety.
  • R 8 is a chelating agent.
  • the ischemia is a coronary ischemia.
  • the ischemia preferably coronary ischemia
  • the ischemia is in a presymptomatic or prodromal stage.
  • the present invention is particular useful for the in vivo diagnosis in the very early stages, i.e. presymptomatic or prodromal stage, before the occurrence of typical symptoms/disease stages of ischemia, in particular coronary ischemia.
  • the present invention therefore allows to predict harmful consequences of ischemia, in particular myocardial infarction.
  • a diagnosis is therefore possible in a presymptomatic or prodromal stage and allows to identify patients at risk of suffering from the harmful consequences of coronary ischemia such as myocardial infarction.
  • the ischemia is in a presymptomatic or prodromal stage and allows to predict in advance acute ischemic complications, in particular myocardial infarction.
  • the prediction can be made at least 6, 5, 4, 3, 2, 1 month(s), preferably at least 3 months, more preferably 3 months, in advance.
  • Patients that benefit particularly from the method of diagnosis of the present invention are those fulfilling at least one of the following criteria: (a) critical ischemia, preferably critical coronary ischemia, (b) acute risk of myocardial tissue damage, (c) coronary heart disease, (d) lesions in the myocardial tissue, in particular multiple lesions, (e) overweight, in particular obesity, (f) diabetes, (g) metabolic syndrome, (h) anti-cancer treatment, in particular chemotherapy and/or radiation therapy.
  • the present invention is also particularly useful in preparation of any interventions, in particular surgical interventions.
  • the present invention allows for improved risk assessment and/or selection of most suited intervention.
  • a and E together form a group selected from the group consisting of a C 3 , C 4 , C 5 , C 6 , C 7 and C 8 monocyclic, preferably C5 or C6 monocyclic, or C 7 , C 8 , C 9 , C 10 , C 11 or C 12 bicyclic, preferably C 7 , C 8 , C 9 and C 10 bicyclic heterocycloalkyl, comprising 1, 2, 3, or 4, preferably 1 or 2 heteroatoms independently selected from the group consisting of N, O and S, preferably N and O, most preferably 1 or 2 N.
  • Q, R, U, V, W, Y, Z are individually present or absent under the proviso that at least three of Q, R, U, V, W, Y, Z are present;
  • R 1 and R 2 are independently selected from the group consisting of -H, -OH, halo, C 1-6 -alkyl, -
  • R 3 is selected from the group consisting of -H , -CN , -B(OH)2, -C(O) -alkyl, -C(O) -aryl-, -
  • R 4 is selected from the group consisting of -H, -C 1-6 -alkyl, -O-C 1-6 -alkyl, -S-C 1-6 -alkyl, alkenyl, heteroalkenyl, cycloalkenyl, cycloheteroalkenyl, alkynyl, aryl, and -C 1-6 -aralkyl, each of said - C 1-6 -alkyl being optionally substituted with from 1 to 3 substituents selected from -OH, oxo, halo and optionally connected to Q, R, U, V, W, Y or Z;
  • R 5 is selected from the group consisting of -H, halo and C 1-6 -alkyl
  • R 6 , and R 7 are independently selected from the group consisting of-H, under the proviso that R and R are not at the same time H, preferably R 6 is attached to the 7- or 8-quinolyl position and R 7 is attached to the 5- or 6- quinolyl position; more preferably R 6 is attached to the 7-quinolyl position and R 7 is attached to the 6-quinolyl position, wherein L is a linker, wherein D, A, E, and B are individually present or absent, preferably wherein at least A, E, and B are present, wherein when present:
  • D is a linker
  • A is selected from the group consisting of NR 4 , O, S, and CH2;
  • E is selected from the group consisting of C 1-6 -alkyl, wherein i is 1, 2, or 3; wherein j is 1, 2, or 3; wherein k is 1, 2, or 3; wherein m is 1, 2, or 3; more preferably, E is C 1-6 -alkyl, most preferably, E is C3 or C4 alkyl;
  • B is selected from the group consisting of S, NR 4 , NR 4 -0, NR 4 -C I - 6 -alkyl, NR 4 -C 1-6 -alkyl-NR 4 , and a 5- to 10-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms, preferably wherein NR 4 -C 1 - 6 -alky 1-NR 4 and the N-containing heterocycle is substituted with 1 to 3 substituents selected the group consisting of C 1-6 -alkyl, aryl, Ci- 6 -aralkyl; and
  • R 8 is selected from the group consisting of radioactive moiety, chelating agent, fluorescent dye, a contrast agent and combinations thereof; is a 1-naphtyl moiety or a 5 to 10- membered N-containing aromatic or non- aromatic mono- or bicyclic heterocycle, wherein there are 2 ring atoms between the N atom and X; said heterocycle optionally further comprising 1, 2 or 3 heteroatoms selected from O, N and S; and X is a C atom; or a pharmaceutically acceptable tautomer, racemate, hydrate, solvate, or salt thereof.
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • a and E together form a group consisting of a C 3 , C 4 , C 5 , C 6 , C 7 and Cx monocyclic, preferably C 5 or C 6 monocyclic, or C 7 , C 8 , C 9 , C 10 , C1 or C 12 bicyclic, preferably C 7 , C 8 , C 9 and C 10 bicyclic heterocycloalkyl, preferably comprising 1, 2, 3, or 4, more preferably 1 or 2 heteroatoms independently selected from the group consisting of N, O and S, preferably N and O, most preferably 1 or 2 N.
  • Preferred monocyclic heterocycloalkyls are selected from the group consisting of pyrrolidinyl, piperidinyl, imidazolidinyl, 1,2-diazacyclohexanyl, 1,3- diazacyclohexanyl, piperazinyl, 1-oxo-2-azacyclohexanyl, 1-oxo-3-azacyclohexanyl, or morpholinyl, preferably piperidinyl, piperazinyl, and pyrrolidinyl.
  • Preferred bicyclic heterocycloalkyls are selected from the group consisting of bicyclo[2.2.1] 2,5-diazaheptanyl, 3,6-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.2.2]nonyl, octahydropyrrolo[2,3- b]pyrrolyl, octahydropyrrolo[3,2-b]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, 9-methyl-3,7,9-triazabicyclo[3.3.1]nonanyl.
  • the bond between the heterocycle formed by A and E and B on one hand and/or R 6 or R 7 on the other is preferably through the heteroatom, preferably through N.
  • heterocycle formed by A and E are selected from the group consisting of In a preferred embodiment of the first aspect of the present invention,
  • Q, R, U are CH2 and are individually present or absent; preferably, Q and R are absent;
  • W is NR 4 ; preferably, W is NH;
  • Y is HCR 4 ; preferably, Y is CH2; and
  • V is CH 2 ;
  • W is NH
  • R 1 and R 2 are independently selected from the group consisting of -H and halo; preferably, R 1 and R 2 are halo; more preferably, R 1 and R 2 are F;
  • R 3 is selected from the group consisting of -H, -CN, and -B(OH)2; preferably, R 3 is -CN or - B(OH)2; more preferably, R 3 is -CN;
  • R 4 is selected from the group consisting of -H and -C 1-6 -alkyl, wherein the -C 1-6 -alkyl is optionally substituted with from 1 to 3 substituents selected from -OH.
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert- butyl, pentyl and hexyl.
  • V is CH 2 ;
  • W is NH
  • Y is CH 2 ;
  • R 1 and R 2 are independently selected from the group consisting of -H and halo; preferably, R 1 and R 2 are halo; more preferably, R 1 and R 2 are F;
  • R 3 is selected from the group consisting of -H, -CN, and -B(OH)2; preferably, R 3 is -CN or - B(OH)2; more preferably, R 3 is -CN;
  • R 4 is selected from the group consisting of -H and -C 1-6 -alkyl, wherein the -C 1-6 -alkyl is optionally substituted with from 1 to 3 substituents selected from -OH.
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert- butyl, pentyl and hexyl.
  • W is CH 2 ;
  • Y is NH
  • R 1 and R 2 are independently selected from the group consisting of -H and halo; preferably, R 1 and R 2 are halo; more preferably, R 1 and R 2 are F;
  • R 3 is selected from the group consisting of -H, -CN, and -B(OH) 2 ; preferably, R 3 is -CN or - B(OH) 2 ; more preferably, R 3 is -CN;
  • R 4 is selected from the group consisting of -H and -C 1-6 -alkyl, wherein the -C 1-6 -alkyl is optionally substituted with from 1 to 3 substituents selected from -OH.
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert- butyl, pentyl and hexyl.
  • first aspect of the present invention optionally further comprising 1 or 2 heteroatoms selected from O, N, and S.
  • first aspect of the present invention optionally further comprising 1 or 2 heteroatoms selected from O, N, and S.
  • R , and R are independently selected from the group consisting of-H, and under the proviso that R 6 and R 7 are not at the same time H and preferably R 6 and R 7 are attached on positions 5, 6 or 7. In a preferred embodiment, is selected from the group consisting of
  • R 5 and R 6 are H;
  • R 7 is , preferably R 7 is attached to the 5- or 6-quinolyl position; more preferably R 7 is attached to the 6-quinolyl position, wherein D is absent;
  • A is O, S, CH 2 , NH, NC3 ⁇ 4;
  • E is C 1-6 -alkyl or , wherein m is 1, 2, or 3;
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl; more preferably, E is C 1-6 -alkyl, most preferably, E is C3 or C4 alkyl; or
  • a and E together form a group selected from:
  • B is NR 4 -C 1 - 6 -alkyl or a 5- to 10-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms, preferably wherein the N-containing heterocycle is substituted with 1 to 3 substituents selected the group consisting of C 1-6 -alkyl, aryl, Ci- 6 -aralkyl.
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • R 5 and R 6 are H
  • R 7 is , preferably R 7 is attached to the 5- or 6-quinolyl position; more preferably R 7 is attached to the 6-quinolyl position, wherein D is absent;
  • A is O
  • E is C 1-6 -alkyl or , wherein m is 1, 2, or 3;
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl; more preferably, E is C 1-6 -alkyl, most preferably, E is C3 or C4 alkyl;
  • B is NR 4 -C I - 6 -alkyl or a 5- to 10-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms, preferably wherein the N-containing heterocycle is substituted with 1 to 3 substituents selected the group consisting of C 1-6 -alkyl, aryl, Ci- 6 -aralkyl.
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • R 5 and R 6 are H
  • R 7 is , preferably R 7 is attached to the 5- or 6-quinolyl position; more preferably R 7 is attached to the 6-quinolyl position, wherein D is absent;
  • A is S
  • E is C 1-6 -alkyl or , wherein m is 1, 2, or 3;
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl; more preferably, E is C 1-6 -alkyl, most preferably, E is C3 or C4 alkyl;
  • B is NR 4 -C 1 - 6 -alkyl or a 5- to 10-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms, preferably wherein the N-containing heterocycle is substituted with 1 to 3 substituents selected the group consisting of C 1-6 -alkyl, aryl, C 1-6 -aralkyl.
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • R 5 and R 6 are H
  • R is preferably R is attached to the 5- or 6-quinolyl position; more preferably R 7 is attached to the 6-quinolyl position, wherein D is absent;
  • A is CH 2 ;
  • E is C 1-6 -alkyl or , wherein m is 1, 2, or 3;
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl; more preferably, E is C 1-6 -alkyl, most preferably, E is C3 or C4 alkyl;
  • B is NR 4 -C 1 -6 -alkyl or a 5- to 10-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms, preferably wherein the N-containing heterocycle is substituted with 1 to 3 substituents selected the group consisting of C 1-6 -alkyl, aryl, Ci- 6 -aralkyl.
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • R 5 and R 6 are H
  • R 7 is preferably R 7 is attached to the 5- or 6-quinolyl position; more preferably R 7 is attached to the 6-quinolyl position, wherein D is absent;
  • A is H
  • E is C 1-6 -alkyl or wherein m is 1, 2, or 3;
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl; more preferably, E is C 1-6 -alkyl, most preferably, E is C3 or C4 alkyl;
  • B is NR 4 -C 1 -6 -alkyl or a 5- to 10-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms, preferably wherein the N-containing heterocycle is substituted with 1 to 3 substituents selected the group consisting of C 1-6 -alkyl, aryl, Ci- 6 -aralkyl.
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • R 5 and R 6 are H
  • R is preferably R is attached to the 5- or 6-quinolyl position; more preferably R 7 is attached to the 6-quinolyl position, wherein D is an amino acid, preferably carrying a charged side chain;
  • A is O
  • E is C 1-6 -alkyl or , wherein m is 1, 2, or 3;
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl; more preferably, E is C 1-6 -alkyl, most preferably, E is C3 or C4 alkyl;
  • B is NR 4 -C I - 6 -alkyl or a 5- to 10-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms, preferably wherein the N-containing heterocycle is substituted with 1 to 3 substituents selected the group consisting of C 1-6 -alkyl, aryl, Ci- 6 -aralkyl.
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • R 5 and R 6 are H
  • R 7 is preferably R 7 is attached to the 5- or 6-quinolyl position; more preferably R 7 is attached to the 6-quinolyl position, wherein D is an amino acid, preferably carrying a charged side chain;
  • A is S
  • E is C 1-6 -alkyl or , wherein m is 1, 2, or 3;
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl; more preferably, E is C 1-6 -alkyl, most preferably, E is C3 or C4 alkyl;
  • B is NR 4 -C 1 -6 -alkyl or a 5- to 10-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms, preferably wherein the N-containing heterocycle is substituted with 1 to 3 substituents selected the group consisting of C 1-6 -alkyl, aryl, Ci- 6 -aralkyl.
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • R 5 and R 6 are H
  • R 7 is , preferably R 7 is attached to the 5- or 6-quinolyl position; more preferably R 7 is attached to the 6-quinolyl position, wherein D is an amino acid, preferably carrying a charged side chain;
  • A is CH 2 ;
  • E is C 1-6 -alkyl or , wherein m is 1, 2, or 3;
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl; more preferably, E is C 1-6 -alkyl, most preferably, E is C3 or C4 alkyl;
  • B is NR 4 -C 1 -6 -alkyl or a 5- to 10-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms, preferably wherein the N-containing heterocycle is substituted with 1 to 3 substituents selected the group consisting of C 1-6 -alkyl, aryl, C 1-6 -aralkyl.
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • R 5 and R 6 are H
  • R 7 is , preferably R 7 is attached to the 5- or 6-quinolyl position; more preferably R 7 is attached to the 6-quinolyl position, wherein D is an amino acid, preferably carrying a charged side chain;
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl; more preferably, E is C 1-6 -alkyl, most preferably, E is C3 or C4 alkyl;
  • B is NR 4 -C 1 - 6 -alkyl or a 5- to 10-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms, preferably wherein the N-containing heterocycle is substituted with 1 to 3 substituents selected the group consisting of C 1-6 -alkyl, aryl, Ci- 6 -aralkyl.
  • C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl.
  • R 5 and R 6 are H
  • R 7 is preferably R 7 is attached to the 5- or 6-quinolyl position; more preferably R 7 is attached to the 6-quinolyl position, wherein D is absent;
  • A is O
  • E is C 1-6 -alkyl or , wherein m is 1, 2, or 3;
  • E is C1-6- alkyl and C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl; more preferably, E is C 1-6 -alkyl, most preferably, E is C3 or C4 alkyl;
  • B is a 5- to 10-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 nitrogen atoms.
  • R 5 and R 6 are H
  • R 7 is , preferably R 7 is attached to the 5- or 6-quinolyl position; more preferably R 7 is attached to the 6-quinolyl position, wherein D is absent;
  • A is O
  • E is C3 or C4 alkyl; more preferably, E is propyl or butyl; B is a 5- to 10-membered N-containing aromatic or non-aromatic mono- or bicyclic heterocycle, preferably further comprising 1 or 2 nitrogen atoms.
  • R 5 and R 6 are H;
  • R 5 and R 6 are H;
  • R 7 is and B is a 5- to 10-membered N-containing aromatic or non- aromatic mono-or bicyclic heterocycle, preferably further comprising 1 or 2 heteroatoms selected from O, N, and S, preferably further comprising 1 or 2 nitrogen atoms.
  • the N-containing heterocycle comprised in B is an aromatic or non-aromatic monocyclic heterocycle:
  • heterocycle optionally further comprises 1 or 2 heteroatoms selected form O, N and S, optionally further comprises 1 nitrogen; is attached to position 1, 2, or 3, preferably to position 2;
  • 1 is 1 or 2.
  • the N-containing heterocycle comprised in B is an aromatic or non-aromatic monocyclic heterocycle:
  • heterocycle optionally further comprises 1 or 2 heteroatoms selected form O, N and S, optionally further comprises 1 nitrogen; is attached to position 1, 2, or 3, preferably to position 2;
  • N-containing heterocycle is substituted with a C 1-6 -alkyl.
  • the N-containing heterocycle comprised in B is selected from the group consisting of: wherein the N-containing heterocycle is substituted with a C 1-6 -alkyl wherein if the N-containing heterocycle comprised in B is the heterocycle optionally further comprises 1 or 2 heteroatoms selected from O, N and S, optionally further comprises 1 nitrogen, optionally compromises one or more (e.g. amino acid derived) side chains; is attached to position 1, 2, or 3, preferably to position 2; o is 1 or 2; preferably, if the N-containing heterocycle comprised in B is , the N- containing heterocycle comprised in B is selected from the group consisting of
  • the N-containing heterocycle comprised in B is selected from the group consisting of: the heterocycle optionally further comprises 1 or 2 heteroatoms selected from O, N and S, optionally further comprises 1 nitrogen, optionally compromises one or more (e.g. amino acid derived) side chains; is attached to position 1, 2, or 3, preferably to position 2; o is 1 or 2; preferably, if the N-containing heterocycle comprised in B is , the N- containing heterocycle comprised in B is selected from the group consisting of ; more preferably, if the N-containing heterocycle comprised in B is , the N-containing heterocycle comprised in B is
  • the N-containing heterocycle comprised in B is selected from the group consisting of:
  • the N-containing heterocycle comprised in B is selected from the group consisting of: wherein B is substituted with a C 1-3 alkyl.
  • R 5 and R 6 are H;
  • R 7 is preferably R 7 is attached to the 6-quinolyl position, wherein
  • D is absent; A is O;
  • E is propyl or butyl
  • Q, R, U are absent
  • W isNH
  • Y is CH 2 ;
  • R 3 is -CN
  • R 5 and R 6 are H
  • R is , preferably R is attached to the 6-quinolyl position, wherein
  • A is O
  • E is C 1-6 -alkyl or , wherein m is 1, 2, or 3; preferably, E is C 1-6- alkyl; preferably, C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i- propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl; more preferably, E is C 1-6 -alkyl, most preferably, E is C3 or C4 alkyl;
  • B is NH- C 1-6 -alkyl preferably, C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert-butyl, pentyl and hexyl; preferably, B is ; and
  • Q, R, U are absent
  • R 1 and R 2 are the same and are selected from the group consisting of -H and F; R 3 is -CN;
  • R 5 and R 6 are H; R 7 is preferably R is attached to the 6-quinolyl position, wherein
  • A is O, S, CH 2 , NH, NOE;
  • E is methyl, ethyl, propyl or butyl; A and E together form a group selected from: B is optionally B is substituted with a C1-3 alkyl; preferably, B is ; and
  • Q, R, U are absent
  • W is NH
  • Y is CH 2 ;
  • R 1 and R 2 are the same and are selected from the group consisting of -H and F; R 3 is -CN;
  • R 5 and R 6 are H; R 7 is preferably R is attached to the 6-quinolyl position, wherein
  • D is absent;
  • A is O;
  • E is methyl, ethyl, propyl or butyl;
  • B is preferably, B is and
  • Q, R, U are absent
  • W isNH
  • Y is CEE
  • R 1 and R 2 are the same and are selected from the group consisting of -H and F;
  • R 3 is -CN
  • R 5 and R 6 are H
  • R 7 is , R is attached to the 6-quinolyl position, wherein D is absent;
  • A is O
  • E is methyl, ethyl, propyl or butyl
  • Ci-6-alkyl is selected from the group consisting of methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert- butyl, pentyl and hexyl.
  • C1-3-alkyl is selected from the group consisting of methyl, ethyl, propyl and i-propyl.
  • C1-6- aralkyl is selected from the group consisting of benzyl, phenyl-ethyl, phenyl-propyl, and phenyl-butyl.
  • the compound is selected from the compounds of table 1. More preferably, the compound of the first aspect of the invention is selected from the compounds of table 2. More preferably, the compound of the first aspect of the invention is selected from the group consisting of FAPI-02 and FAPI-04. Most preferably, the compound of the first aspect of the invention is FAPI-04.
  • the compound is selected from the compounds of table 1 and/or table 3. More preferably, the compound of the first aspect of the invention is selected from the compounds of table 2 and/or table 4. More preferably, the compound of the first aspect of the invention is selected from the group consisting of FAPI-02, FAPI-04, FAPI-46, FAPI-34, FAPI-42, FAPI-52, FAPI-69, FAPI-70, FAPI-71, F API-72 and FAPI-73.
  • Table 1 Preferred compounds of the first aspect of the invention.
  • Table 2 Compounds of special interest.
  • Q, R, U, D are absent;
  • R 1 and R 2 are located at the 4- pyrrolidine position;
  • R 5 , R 6 are H;
  • R 7 is attached to the 6- quinolyl position;
  • W is NH;
  • Y is CH2;
  • R 3 is -CN;
  • B is 1,4-piperazine;
  • E is 1,3-propane;
  • A O.
  • Table 3 Further preferred compounds of the first aspect of the invention.
  • Table 4 Compounds of special interest.
  • Q, R, U, D are absent;
  • R 1 and R 2 are fluorine atoms located at the 4-pyrrolidine position;
  • R 5 , R 6 are H;
  • R 7 is attached to the 6-quinolyl position;
  • W is NH;
  • Y is CH2;
  • R 3 is -CN;
  • B is 1,4-piperazine;
  • E is 1,3-propane;
  • A is O.
  • Table 5 Preferred precursors for radiolabelling with ⁇ F-18; $ Cu-64; € Ga-68; £ Tc-99m, Re- 188; * Y-90, Sm-153, Lu-177.
  • R 8 is a radioactive moiety, wherein the radioactive moiety is a fluorescent isotope, a radioisotope, a radioactive drug or combinations thereof.
  • the radioactive moiety is selected from the group consisting of alpha radiation emitting isotopes, beta radiation emitting isotopes, gamma radiation emitting isotopes, Auger electron emitting isotopes, X-ray emitting isotopes, fluorescence emitting isotopes, such as 68 Ga, U C, 18 F, 51 Cr, 67 Ga, m In, 99m Tc, 186 Re, 188 Re, 1 39 La, 140 La, 175 Yb, 153 Sm, 166 Ho, 88 Y, 90 Y, 149 Pm, 16 Dy, 169 Er, 177 Lu, 47 Sc, 142 Pr, 159 Gd, 21 Bi, 2 13 Bi, 72 As, 72 Se, 97 RU
  • R 8 is a fluorescent dye select from the group consisting of the following classes of fluorescent dyes: Xanthens, Acridines, Oxazines, Cynines, Styryl dyes, Coumarines, Porphines, Metal-Ligand- Complexes, Fluorescent proteins, Nanocrystals, Perylenes, Boron-dipyrromethenes and Phtalocyanines as well as conjugates and combinations of these classes of dyes.
  • R 8 is a chelating agent which forms a complex with divalent or trivalent metal cations.
  • the chelating agent is selected from the group consisting of 1,4,7, 10-tetraazacyclododecane- N,N',N,A'-tetraacetic acid (DOTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7- triazacyclononane-1,4,7-triacetic acid (NOTA), triethylenetetramine (TETA), iminodiacetic acid, diethylenetriamine-N,N,N',N',N"-pentaacetic acid (DTPA), bis- (carboxymethylimidazole)glycine and 6-Hydrazinopyridine-3-carboxylic acid (HYNIC).
  • DOTA 1,4,7, 10-tetraazacyclododecane- N,N',N,A'-tetraacetic acid
  • EDTA ethylenediaminetetraacetic acid
  • NOTA 1,
  • R 8 is a contrast agent which comprises or consists of a paramagnetic agent, preferably, wherein the paramagnetic agent comprises or consists of paramagnetic nanoparticles.
  • R 8 is selected from any R 8 of tables 1 to 5.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising or consisting of at least one compound of the first aspect, and, optionally, a pharmaceutically acceptable carrier and/or excipient for the in vivo diagnosis of ischemia, preferably coronary ischemia.
  • ischemia in particular coronary ischemia, is in a prodromal stage.
  • the present invention relates to a kit comprising or consisting of the compound of the first aspect or the pharmaceutical composition of the second aspect and instructions for the in vivo diagnosis of ischemia, preferably coronary ischemia.
  • ischemia in particular coronary ischemia, is in a prodromal stage.
  • Fibroblast activation protein plays an important role in cardiac wound healing and remodeling. Although initially developed as a theranostic ligand for metastasized cancer, FAPI tracers have recently been used to study cardiac remodeling following myocardial infarction in small animal models. Disclosed herein is the evaluation of the activity of fibroblast activation protein via FAP inhibitor (FAPI) PET-CT scans in human hearts.
  • FAP inhibitor FAPI
  • FAPI-PET-CT (Siemens Biograph, Siemens Healthcare Diagnostics, Eschbom, Germany) scans were performed according to a standard protocol ([4], Giesel et al. 2019, J Nucl Med 2019;60:386-392).
  • 122 to 336 mBq of Ga-68 labelled fibroblast activation protein inhibitor (F API-04; see table 1 and 5 above) were administered intravenously 60 minutes before the examination.
  • F API-04 labelled fibroblast activation protein inhibitor
  • a 3-D emission scan (matrix 200 x 200) was performed, subsequently using FlowMotion (Siemens). The emission data was corrected for randoms, scatter and decay. Reconstruction was performed with an ordered subset expectation maximization (OSEM) algorithm with 2 iterations / 21 subsets and Gauss-filtered to atransaxial resolution of 5 mm at full-width at half-maximum (FWHM) and analyzed using regions of interest (ROI) measuring standardized uptake values (SUV). Signals were measured in the free left ventricular wall, the blood pool, the aorta, the gluteus muscle, the liver, the lung and the brain. The mean SUV of the region of interest (ROI) was reported. The ROI was selected in an area of homogenous signal intensity based on the anatomical structures depicted in the CT.
  • OEM ordered subset expectation maximization
  • FWHM full-width at half-maximum
  • SUV regions of interest
  • Patient characteristics included age, sex, cancer entity, body mass index (BMI), glomerular filtration rate (GFR-CDK-EPI), thyroid stimulating hormone (TSH), cardiovascular risk factors (CvRF), diabetes mellitus (DM), arterial hypertension (aHT), known coronary artery disease (CAD), known atrial fibrillation (aFib), previous radiation to the chest, chemotherapy (anthracyclines, platin derivatives, alkylating agents, antimetabolites, taxanes, topoisomerase inhibitors), checkpoint inhibitor use, FAPI signal pattern, cardiac medication (statins, aspirin, angiotensin converting enzyme inhibitor (ACEi) or angiotensin-receptor- blocker (ARB) and betablocker use).
  • BMI body mass index
  • GFR-CDK-EPI glomerular filtration rate
  • TSH thyroid stimulating hormone
  • CvRF cardiovascular risk factors
  • DM diabetes mellitus
  • aHT arterial hypertension
  • CAD known coronary artery disease
  • FAPI PET-CT scans from representative patients were selected using the next neighbor algorithm. Applicable patients with the smallest distance to the median were chosen.
  • Non-normal distributed values are reported as median ⁇ interquartile range (IQR) and were compared using Wilcoxon rank sum tests unless stated otherwise. Normal distributed values are reported as mean ⁇ standard deviation (SD). An analysis of variance test was performed to test for differences within the groups. Tukey’s honest significant difference method was applied for p-level adjustment.
  • SUVs did not follow a standard distribution
  • SUVs were compared with a pairwise Wilcoxon rank sum test using Holm’s method for p-value adjustment.
  • Holm a pairwise Wilcoxon rank sum test using Holm’s method for p-value adjustment.
  • repetitive measurements were displayed for each patient.
  • SUVs were logarithmised to achieve normal distribution.
  • Univariate logistic regression models were established using a signal intensity cut-off of 1.3, which was determined calculating the mean signal intensity and adding 1 ⁇ 2 of its standard deviation. Odds ratios, and 95% confidence intervals were calculated.
  • P level adjustment was carried out using the Holm-Bonferroni method. Multivariate models were created selecting the variables according to Akaike’s information criterion in a step-down approach.
  • the model was applied to the confirmatory cohort. Standardized residuals were calculated. Outliers in the second cohort were identified using the same values as cut-off for residuals as in the first cohort.
  • Multivariate regression models were established following model optimization using Akaike’s information criterion as described in the method section.
  • This model revealed a positive correlation of left ventricular signals with TSH levels above 4 pU/ml (OR: 8.6, p ⁇ 0.05), a BMI above 25kg/m 2 (OR: 2.6, p ⁇ 0.05), previous radiation to the chest (OR: 3.5, p ⁇ 0.05), previous intake of platin derivatives (OR: 3.0, p ⁇ 0.05) and a history of diabetes (OR: 2.9, p ⁇ 0.05) while checkpoint inhibitor use was associated with a decreased signal intensity (OR: 0.17, p ⁇ 0.05) (see Figure 1).
  • Multivariate linear prediction model and outlier analysis reveals doxorubicin therapy as potentially relevant variable in cardiac FAP-activity
  • the inventors further created a linear multivariate regression model based on the results of the logistic regression analyses. This model was used to find outliers in the dataset by selecting 5% of patients with the highest residuals (cut-off: 1.64).
  • a permutation test with 100.000 permutations revealed that patients with ovarian and prostate cancer patients (p ⁇ 0.01), as wells as patients receiving anthracyclines (p ⁇ 0.05) and/or alkylating agents (p ⁇ 0.05) were significantly overrepresented in the outlier cohort of patients with unexpectedly high cardiac FAPIsignals.
  • the prediction model was confirmed in another cohort of 44 consecutive patients, which were scanned after the first cohort.
  • the inventors were not able to find any outliers using the same metrics as in the first cohort (see Figure 1).
  • the standard deviation was even slightly smaller in the second cohort.
  • Patient characteristics of the confirmatory cohort are reported in Table 6. Focal signal enrichment and increased signal intensity associated with cardiovascular risk and disease
  • FAPI signal increases with cardiovascular risk factors associated with metabolic disease and cardiac remodeling.
  • the inventors report a correlation between fibroblast activation (FAP) density measured by fibroblast activation protein inhibitor PET-CT scans and cardiovascular disease and risk factors, particularly in cancer patients.
  • FAP fibroblast activation
  • An increase in signal intensity was associated with metabolic stress such as hypothyroid metabolic state, overweight, diabetes, the use of platin derivatives, and radiation to the chest while a focal enrichment pattern was correlated with cardiovascular disease as indicated by the presence of cardiovascular risk factors or aspirin intake.
  • Western blot analyses, microarrays, cardiac sections and most recently FAPI-PET-CT scans in small animal models showed that FAP expression in fibroblast is significantly increased in affected segments following myocardial infarction [8,9] So far, there is currently no method established to image the activation of fibroblasts in the human heart.
  • FAP is mainly expressed in granulation tissue, reactive stromal fibroblasts and malignant cells, it cannot be rule out completely that other cell types might contribute to the cardiac FAPI signal [25] Inflammation induced FAP activation in cardiomyocytes, fibroblasts or even endothelial cells as seen in vascular disease might be a contributory factor in some of the patients especially since CRP levels are increased in the outlier cohort [26]
  • FAPI PET- CT scans of the present invention display active cardiac remodeling and not fibrotic scars. Analyzing patients before and after myocardial infarction, the inventors noted increased FAPI signals just before the event while signals disappeared months to years after. In addition, a patient scanned while receiving chest radiation due to esophageal cancer showed high FAPI signals in the segments affected ( Figures 10 and 11).
  • a patient displayed high FAPI signals while on pazopanib treatment (patient 14, Figure 9).
  • a follow-up scan revealed normal signal intensities once the medication was stopped due to hypertension and hematotoxic side effects.
  • arterial hypertension was associated with an increase in signal intensity in general, the signal enrichment exhibited in this patient exceeded the expected effect of arterial hypertension alone.
  • off-target inhibition of fibroblast growth factors and other kinases might have led to this FAPI up-flare indicative of cardiac remodeling [27]
  • the present invention discloses the use of F APIs in in vivo diagnosis, which might be particularly suitable to find previously undetected cardiovascular disease or identify cardiotoxic effects of therapies, such as anti-cancer therapy.
  • the present invention could also be used to evaluate e.g.
  • Soetaert K. shape Functions for Plotting Graphical Shapes, Colors 2018.

Abstract

La présente invention concerne un composé, une composition pharmaceutique comprenant ledit composé ou constituée de celui-ci, un kit comprenant ledit composé ou constitué de celui-ci ou une composition pharmaceutique et l'utilisation du composé ou de la composition pharmaceutique pour une utilisation dans le diagnostic ou le traitement in vivo de l'ischémie.
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