FAP-Targeted Drugs for Cancer Treatment and Diagnosis

Abstract

A drug targeting FAP for anti-cancer use, comprising the chemical structure: FAPi-R 1 -FAPs-CT and R 1 = Formula (I) or Formula (II) or Formula (III), FAPi represents a FAP inhibitor, FAPs represents a FAP substrate, CT represents a cytotoxin, MG represents a radioisotope labeling group, TL represents a tris linker, and L1, L2, L3, L4, L5, and L6 represent bivalent linkers. [Formula 1] JPEG2025500410000065.jpg70154

Description

[Technical field]

[0001] The present invention relates to pharmaceutical compounds targeting fibroblast activation protein (FAP) for the treatment and diagnosis of cancer.

[0002] The compounds of the present invention have the structure [ka] having FAPi represents a FAP inhibitor, FAPs represents a FAP substrate, CT represents a cytotoxin, MG represents a radioisotope labeling group, TL represents a Tris linker, and L1, L2, L3, L4, L5, and L6 represent bivalent linkers. [Background technology]

[0003] Tumor Treatment and Diagnosis Cytotoxic drugs, such as doxorubicin, have been used in chemotherapy for decades. In conventional systemic chemotherapy, cytotoxic drugs are administered intravenously, orally or intraperitoneally at relatively high doses. Cytotoxic drugs damage not only cancer cells but also healthy tissues, especially cells with high dividing rates, causing severe, sometimes life-threatening side effects that often force the patient to discontinue treatment.

[0004] To reduce side effects, low doses of targeted cytotoxic drugs with high binding affinity to tumor cells have been used in the last few years. High tumor affinity is achieved by conjugating the cytotoxic active ingredient to a targeting vector. Targeting vectors usually contain agonists (substrates) or antagonists (inhibitors) of membrane-bound proteins that are significantly overexpressed in the cell wall of tumor cells compared to healthy cells. Targeting vectors can be simple organic compounds (small molecules), oligopeptides containing natural or derivatized amino acids, and aptamers or monoclonal antibodies (mAbs). Known compounds are configured to specifically target certain tumor cells and have a severely limited scope of application.

[0005] The compounds of the invention are intended for cytotoxic and / or radiotherapy of various tumor and cancer types, as well as for diagnostic imaging by positron emission tomography (PET) and single photon emission computed tomography (SPECT).

[0006] The FAP inhibitors and FAP substrates present in the compounds of the present invention target fibroblast activation protein (FAP).Since FAP is overexpressed in the tumor stroma of various tumors, the compounds of the present invention are suitable for the treatment and diagnosis of many cancers.

[0007] In nuclear medicine diagnostics, tumor cells or metastases are detected by radioisotopes, such as gallium-68 ( 68 Ga) or Technetium 99m ( 99m 1Tc) to visualize the tumor. In the case of metallic radioisotopes, it is preferable to use coordinate-bonding or complexing radiotracers. Radiotracers consist of, as essential chemical components, a chelating agent for effective and stable complexation of the metallic radioisotope, and one or more targeting vectors that bind to biological target structures in the tumor tissue. In general, the targeting vectors have a high affinity for transmembrane receptors, proteins, enzymes or other structures of tumor cells. In addition, fluorine-18 ( 18 F) or iodine-123( 123 I) and iodine-131( 131 Radioactive tracers containing non-metallic radioisotopes such as I) are used, which are covalently bound to the respective radiotracer.

[0008] After being injected intravenously into the bloodstream, the radioactive tracer accumulates on or within tumor cells or metastases. To minimize the radiation dose to healthy tissue, radioisotopes with short half-lives (hours to days) are used.

[0009] In contrast, in nuclear medicine therapy, high doses of radiation are used to maximize damage to the carcinogenic lesion. For this purpose, for example, lutetium-177 (177 Lu), Yttrium 90 ( 90 Y) and iodine-131 ( 131 I), or actinium 225 ( 225 Ac) or lead 212 (Pb 212 Alpha-emitting radioisotopes such as alpha-particles and beta-negative particles have short ranges in tissue, which gives them the advantage of selectively irradiating and damaging tumors or metastases while minimizing the radiation dose to surrounding healthy tissue.

[0010] In recent years, the combination of diagnosis and therapy, which is called theranostics by experts, has become increasingly important. Here, the radioactive tracers used for diagnosis and therapy are similar and preferably have the same chemical structure, except for the radioisotope. In PET diagnosis and radionuclide therapy, mainly gallium-68 and lutetium-177 are used, respectively, since both radioisotopes can be complexed with DOTA chelators. This fact allows 68 Diagnosis by Ga and 177 The same labeled precursors can be used for radioendoscopic therapy with Lu, allowing a direct translation from diagnostics to therapy.

[0011] In known methods, it must always be borne in mind that the radiolabeling group, e.g. a chelating agent, affects the chemical and pharmacokinetic properties of the radiotracer. Therefore, when exchanging the labeling group of the radiotracer or the labeling precursor thus modified, a reassessment is necessary. This relates mainly to the biochemical and pharmacokinetic properties of the radiotracer and, to some extent, also to the coordination or binding of the respective radioisotope. The labeling group has a significant influence on the biological and nuclear medicine efficacy of the respective labeling precursor.

[0012] In addition to high affinity, the radioactive tracer or labelled precursor must fulfil further requirements, such as: - Rapid and effective complexation of the respective radioisotope; -High selectivity for tumor cells and metastases compared to healthy tissue; - In vivo stability, i.e. biochemical stability in serum under physiological conditions.

[0013] Tumor stroma Malignant epithelial cells are components of many tumors and tumor types and form the tumor stroma that surrounds the tumor, measuring at least 1–2 mm in size.

[0014] The tumor stroma is composed of various non-malignant cell types that are part of the tumor microenvironment that surrounds tumor cells. The tumor stroma can account for up to 90% of the entire tumor. The tumor stroma plays an important role in tumor initiation, growth and metastasis, as well as in the supply of tumor cells.

[0015] The most important component of the tumor stroma is the extracellular matrix, which contains a variety of cytokines, endothelial cells, pericytes, macrophages, immunomodulatory cells and activated fibroblasts. The activated fibroblasts that surround the tumor are called cancer-associated fibroblasts (CAFs).

[0016] During the process of tumor growth, CAFs change their morphology and biological functions. These changes are caused by intercellular communication between cancer cells and CAFs. In the present context, CAFs form an environment that promotes the proliferation of cancer cells. Therapies that target only cancer cells have proven insufficient. Effective therapies must also include the tumor microenvironment, i.e., CAFs.

[0017] In more than 90% of all human epithelial cancers, CAFs overexpress fibroblast activation proteins (FAPs). Thus, FAPs are promising attack points for nuclear medicine diagnosis and therapy. A suitable affine biological targeting vector for FAP-labeled precursors is the FAP inhibitor (FAPI or FAPi). Although the in vivo role of FAP has not yet been fully elucidated, it is known to be an enzyme with unique catalytic activity. It has both dipeptidyl peptidase activity (DPP) and prolyl oligopeptidase activity (PREP). Therefore, useful inhibitors are those that inhibit the DPP and / or PREP activity of FAPs. The crucial factor is the selectivity of each inhibitor against related enzymes such as dipeptidyl peptidases DPPII, DPPIV, DPP8 and DPP9 and homologous prolyl oligopeptidases (PREPs). However, in the case of cancer types in which both FAP and PREP are overexpressed, it is possible to use inhibitors that are not very selective for PREP and FAP and inhibit both enzymes.

[0018] Since 2013, FAP inhibitors with high affinity and selectivity, consisting of a modified glycine-proline unit and a quinoline group attached to it, have been known. Two such FAP inhibitors with the chemical structure (S)-N-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide and its difluorinated derivative (abbreviated as "UAMC1110") are shown in Figure 1. [ka]

[0019] The difluorinated FAP inhibitor UAMC1110 is used in a known labeled precursor for nuclear medicine applications, termed "FAPI04" and shown in Figure 2. In addition to FAPI04, three more known labeled precursors, FAPI-21, FAPI46 and DOTA.SA.FAPI, are shown in Figure 2. In the case of DOTA.SA.FAPi, the pharmacophoric FAPi unit is conjugated to the DOTA chelator via a 4-aminobutoxy unit or an ethylenediamine squarate unit. [ka]

[0020] FIG. 3 shows the novel dimeric labeled precursors, termed "DOTA-2P(FAPI)2" and "DOTAGA.(SA.FAPi)2," each of which contains two structurally identical FAPi targeting vectors. [ka]

[0021] The radiotracers based on the labeled precursors shown in FIG. 3 are characterized by a significantly longer tumor retention time compared to radiotracers based on monomeric labeled precursors (see FIG. 2).

[0022] Furthermore, highly selective FAP substrates are known, as shown in FIG. 4, which, like the FAP inhibitors described above, have a 4,4'-difluoropyrrolidine ring. In contrast to the FAP inhibitors according to FIG. 1, the nitrile group of the FAP substrate in FIG. 4 is replaced by an amide bond. In the FAP substrate, various aromatic units, such as 7-amino-4-methylcoumarin (AMC) or p-nitroaniline (pNA), are linked via an amide bond. The substrates shown in FIG. 4 are enzymatically cleaved by FAPs, the glycine-proline unit of the substrate being cleaved by an endopeptidase present in the FAP. Otherwise, the substrates in FIG. 4 are only cleavable by prolyl endopeptidases (PREPs) with the appropriate enzymatic activity. [ka]

[0023] The prior art discloses a large number of labelled precursors for the treatment and diagnosis of cancer using radioisotopes.

[0024] WO2019 / 154886A1 discloses labeled precursors and radiotracers for visualization of epithelial cancers and tumor stroma, including the compound FAPI04 shown in FIG. 2.

[0025] Cytostatic drug delivery systems using low molecular weight targeting vectors targeting FAP are also known. For example, in the prior art, cytostatic doxorubicin is linked to a glycine-proline unit via an amide bond. Figure 5 shows two compounds used as prodrugs, FTPD (Z-Gly-Pro-doxorubicin) on the left and PhAc-ALGP-Doxo on the right. To release the cytotoxic active doxorubicin, the prodrug must first be cleaved. [ka]

[0026] In vivo studies in mice using prodrugs of this configuration have shown promising results.

[0027] Despite many advances in cancer diagnosis and treatment, - affinity and selectivity; -Cytotoxicity; -Pharmacokinetics; -Increased contrast or signal uptake value (SUV) in PET and SPECT images; -Ease of clinical use; and -Expanding patient population There is a continuing need for improved anticancer drugs.

[0028] It is therefore an object of the present invention to provide an anticancer drug having superior properties to known compounds. [ka] [FAPi stands for FAP inhibitor, FAPs stands for FAP substrate, CT stands for cytotoxin, MG stands for radioisotope labeling group, TL stands for tris linker, and L1, L2, L3, L4, L5, and L6 stand for bivalent linkers.] This is achieved by a compound having the formula:

[0029] Advantageous embodiments of the compounds of the invention are characterized by the following additional features in any combination, provided that the combined features are not contradictory: -FAP has any one of the structures [1] to

[20] : [ka] JPEG2025500410000010.jpg226137JPEG2025500410000011.jpg220146JPEG2025500410000012.jpg75146

[20] represents the amino acid sequence Ala-Pro-Gly; X=H or F; Y=H, CH3, CH(CH3)2, C(CH3)3 or (CH2) n CH3, n=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and Z is selected from the group comprising alcohol, amidine, amine, amide, carboxamide, thioamide, imide, imidoester, imine, urea, thiourea, guanidine, carbonate, carboxylic ester, carbamate, ether, thioether, ester, ketone, phosphate, phosphonate, phosphinate, sulfonate, sulfinate, sulfone, thiol, disulfide, boronic ester, silyl ether radicals and derivatives thereof; -FAPi is an inhibitor of fibroblast activation protein (FAP) and has the structure of any of the following:

[21] -

[46] [ka] JPEG2025500410000014.jpg227140JPEG2025500410000015.jpg213145JPEG2025500410000016.jpg157146X=H or F; Y=H, CH3, CH(CH3)2, C(CH3)3 or (CH2) n CH3, where n=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Z is selected from the group comprising alcohol, amidine, amine, amide, carboxamide, thioamide, imide, imidoester, imine, urea, thiourea, guanidine, carbonate, carboxylic ester, carbamate, ether, thioether, ester, ketone, phosphate, phosphonate, phosphinate, sulfonate, sulfinate, sulfone, thiol, disulfide, boronic ester, silyl ether radicals and derivatives thereof; - the linkers L1, L2, L3, L4, L5, L6 are independently [ka] Selected from the group comprising: - spacers S1, S2, S3, S4, S5, S6, S7, S8, S9, S10 are independently a monomer or oligomer consisting of m alkyl units, polyethylene glycol (-(CH2CH2O) n -), polypropylene glycol (-(CH2CH(CH3)2O) n -), polyalkylene glycol ether (-((CH2) n O)-), polyamines (-((CH2) n NH)-), polyamide (-((CH2) n CONH)-), polyester (-((CH2) n COO)-), polyurethane (-((CH2) n NHCOO)-), Polyurea (-((CH2) nNHCONH)-) and a peptide having m amino acids, where m=1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; - each of the spacers S1, S2, S3, S4, S5, S6, S7, S8, S9, S10 is independently an oligopeptide having m amino acids selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, GABA (gamma-aminobutyric acid), homoserine, DOPA (3,4-dihydroxyphenylalanine), citrulline, beta-alanine and thyroxine, where m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; the coupling groups K1, K2, K3, K4, K5 are independently selected from the group comprising radicals of alcohols, amidines, amines, amides, carboxamides, thioamides, imides, imidoesters, imines, ureas, thioureas, guanidines, carbonates, carboxylic esters, carbamates, ethers, thioethers, esters, ketones, phosphates, phosphonates, phosphinates, sulfonic esters, sulfinic esters, sulfones, thiols, disulfides, boronic esters, silyl ethers and their derivatives; and -Connected unit V is: -

[47] ~

[50] Structure: [ka] [

[47] represents a radical of squaric acid,

[48] represents a radical of squaric diamide,

[49] represents a radical of 1,4-disubstituted 1,2,3-triazole, and

[50] represents a radical of 1,3-disubstituted succinimidyl.] Selected from one of; - selected from the group comprising residues of amino acids such as Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, GABA (gamma-aminobutyric acid), homoserine, DOPA (3,4-dihydroxyphenylalanine), citrulline, beta-alanine, thyroxine; or -Benzene, phenol, cyclopentane, cyclohexane, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, piperazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, 1,2,4,5-tetrazine, thiazine, oxazine, pyrrole, pyrrolidine, pyrazole, imidazole, tetrahydroimidazole, 1,2,4-triazole, tetrazole, thiophene, furan, 1,2-thiazole, 1,3-thiazole, thiadiazo Radicals of 1,2-oxazole, 1,3-oxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, naphthalene, indene, indole, isoindole, indazole, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, phthalazine, tetrahydroquinoline, tetrahydroisoquinoline, quinolizidine, indolizidine, 2H-chromene, 4H-chromene, 2H-thiochromene, 4H-thiochromene, coumarin, purine and -Tris linker TL linker has the structure

[51] ~

[0115] : [ka] Selected from JPEG2025500410000020.jpg231152JPEG2025500410000021.jpg201148; -CT is -Antimetabolites such as cytarabine, fludarabine, fluorouracil (5-FU), gemcitabine, and methotrexate; -Alkylating cytotoxic agents such as adozelesin, bizelesin, carzelesin, dacarbazine (DTIC), melphalan (BCNU), temozolomide; - Mitotic inhibitors such as monomethylauristatin E (MMAE); -Antibiotics such as dactinomycin, daunorubicin, doxorubicin, duocarmycin A, duocarmycin B1, duocarmycin B2, duocarmycin C1, duocarmycin C2, duocarmycin D, duocarmycin SA, idarubicin, anthramycin, mitoxantrone; -Enzyme inhibitors such as L-asparaginase, motesanib; -PARP inhibitors such as rucaparib, olaparib, niraparib, veliparib, and iniparib: -Goserelin, leuprolide, metformin, NSC668394, tetrazole, alpha-solamargine, alpha-tomatine; -Tubulin inhibitors such as tubulysin B hydrazide; -Tyrosine kinase inhibitors such as imatinib -angiogenesis inhibitors such as Neovastat (AE-941); -Hedgehog signaling pathway inhibitors such as sonidegib; -VEGFR inhibitors such as sunitinib; - SERCA ATPase inhibitors such as thapsigargin and its derivatives 12ADT, A12ADT and S12ADT is a cytotoxin selected from: -MG is 43 Sc, 44 Sc, 47 Sc, 55 Co, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 89 Zr, 86 Y, 90 Y, 89 Zr, 90 Nb, 99m Tc, 111 In, 135 Sm,140 Pr, 159 Gd, 149 Tb, 160 Tb, 161 Tb, 165 Er, 166 Dy, 166 Ho, 175 Yb, 177 Lu, 186 Re, 188 Re, 211 At, 203 Pb, 212 Pb, 213 Bi, 225 Ac and 232 It is a chelating agent for complexation of radioisotopes of the group including Th; -MG is H4pypa, EDTA (ethylenediaminetetraacetate), EDTMP (diethylenetriaminepenta(methylenephosphonic acid)), DTPA (diethylenetriaminepentaacetate) and its derivatives, NOTA (nona-1,4,7-triamine-triacetate) and its derivatives, such as NODAGA (1,4,7-triazacyclononane, 1-glutaric acid, 4,7-acetate), TRAP (triazacyclononanephosphinic acid), NOPO (1,4,7-triazacyclononane-1,4-bis[methylene(hydrogen) [2-(1,4,7,10-tetraazacyclododecane-4,7,10)pentanedioic acid]-7-[methylene(2-carboxyethyl)phosphinic acid]), DOTA (dodeca-1,4,7,10-tetraaminetetraacetate), DOTAGA (2-(1,4,7,10-tetraazacyclododecane-4,7,10)pentanedioic acid) and other DOTA derivatives, TRITA (trideca-1,4,7,10-tetraaminetetraacetate), TETA (tetradeca-1,4,8,11-tetraaminetetraacetate) and its derivatives, PEPA (pentadeca-1,4,7,10,13-pentaaminetetraacetate) and its derivatives, hexaamine pentaacetate), HEHA (hexadeca-1,4,7,10,13,16-hexaamine hexaacetate) and its derivatives, HBED (N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetate) and its derivatives, such as HBED-CC (N,N'-bis[2-hydroxy-5-carboxyethyl)benzyl)ethylenediamine-N,N'-diacetate), DEDPA and its derivatives, such as H2-dedopa (1,2-[[6-(carboxyl)pyridin-2-yl]methylamine]ethoxylate), H4Octapan (1,2-[[6-(carboxyl)pyridin-2-yl]methylamine]ethane-N,N'-diacetate), DFO (deferoxamine) and its derivatives, trishydroxypyridinone (THP) and its derivatives, e.g. H3THP-Ac and H3THP-mal (YM103), TEAP (tetraadicyclodecane phosphinic acid) and its derivatives, AAZTA (6-amino-6-methylperhydro-1,4-diazepane-N,N,N',N'-tetraacetate) and its derivatives, e.g. AAZTA 5(5-[(6-amino)-1,4-diazepane]pentanoic acid-N,N,N',N'-tetraacetate), DATA (2,2'-(6-((carboxymethyl)(methyl)amino)-6-methyl-1,4-diazepane-1,4-diyl)diacetate) and its derivatives, such as DATA 5m (5-[[6-(N-methyl)amino]-1,4-diacetate-1,4-diazepane]pentanoic acid-N,N',N'-triacetate); sarcofagin SAR (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexazabicyclo[6.6.6]eicosane-1,8-diamine) and its derivatives, such as (NH2)2SAR (1,8-diamino-3,6,10,13,16,19-hexazabicyclo[6.6.6]eicosane-1,8-diamine); azabicyclo[6.6.6]eicosane), N4 (3-[(2'-aminoethyl)amino]-2-[(2''-aminoethyl)-aminomethyl]propionic acid) and other N4 derivatives, PnAO (6-(4-isothiocyanatobenzyl)-3,3,9,9-tetramethyl-4,8-diazaundecane-2,10-dione dioxime) and its derivatives, e.g. BMS181321 (3,3'-(1,4-butanedioxime) aryldiamino)-bis(3-methyl-2-butanone)dioxime), MAG2 (mercaptoacetylglycylglycine) and derivatives thereof, MAG3 (mercaptoacetylglycylglycine) and derivatives thereof, such as N3S adipate, MAS3 (mercaptoacetylserylserylserine) and derivatives thereof, MAMA (N-(2-mercaptoethyl)-2-[(2-mercaptoethyl)amino]acetamide) and derivatives thereof, EC (ethylenedicysteine) and derivatives thereof, dmsa (dimercaptosuccinic acid) and derivatives thereof, DADT (diaminodithiol), DADS (diaminodisulfide), N2S2 chelating agents and derivatives thereof, aminothiol and derivatives thereof; salts of the above-mentioned chelating agents; hydrazine nicotinamide (HYNIC) and hydrazine nicotinamide derivatives; -MG is DOTA (dodeca-1,4,7,10-tetraaminetetraacetic acid); -MG is DOTAGA (2-(1,4,7,10-tetraazacyclododecane-4,7,10)pentanedioic acid); -MG is DATA 5m (1,4-bis(carboxymethyl)-6-[methylcarboxymethylamino]-6-pentanoic acid-1,4-diazepane); -MG is AAZTA 5 (1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)amino]-6-pentanoic acid-1,4-diazepane); -MG is 18 F, 131 I or 211 is a labeling group for covalently attaching At; -MG is [ka] Selected from; -MG is 18 F, 131 I or 211 Has a leaving group X which is replaced by At [ka] and / or -MG comprises a leaving group X selected from bromine (Br), chlorine (Cl), iodine (I), tosyl (Ts), brosylate (Bs), nosylate (Nos), 2-(N-morpholino)ethanesulfonic acid (MES), triflate (Tf), and nonaflate (Non) radicals.

[0030] The present invention further relates to a radiotracer comprising one of the pharmaceutical compounds described above and a radioisotope complexed or bound thereto.

[0031] In an advantageous embodiment of the invention, the radiotracer comprises one of the pharmaceutical compounds described above and a radioisotope complexed therewith, the radioisotope being 44 Sc, 47 Sc, 55 Co, 62 Cu, 64Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 89 Zr, 86 Y, 90 Y, 89 Zr, 90 Nb, 99m Tc, 111 In, 135 Sm, 140 Pr, 159 Gd, 149 Tb, 160 Tb, 161 Tb, 165 Er, 166 Dy, 166 Ho, 175 Yb, 177 Lu, 186 Re, 188 Re, 211 At, 203 Pb, 212 Pb, 213 Bi, 225 Ac and 232 It is selected from the group including Th.

[0032] The radioactive tracer is preferably a radioisotope complexed with one of the pharmaceutical compounds described above. 68 Includes Ga.

[0033] In particular, the radioactive tracer may be a radioisotope complexed with one of the pharmaceutical compounds described above. 177 Includes Lu.

[0034] In a further advantageous embodiment of the invention, the radiotracer comprises one of the pharmaceutical compounds mentioned above and a radioisotope bound thereto, said radioisotope being 18 F, 131 I and 211 At.

[0035] The pharmaceutical compounds of the present invention include a FAP inhibitor, a FAP substrate and a cytotoxin, and optionally a radioisotope labeling group. The high affinity of known FAP inhibitors (antagonists) is combined with the action of FAP substrates to selectively deposit high doses of cytotoxins in the tumor stroma, and optionally in cancer-associated fibroblasts (CAFs) and carcinogenic cells via endocytosis. Fibroblast activation proteins (FAPs) are widely expressed in many cancers, and in the present invention, -As a biological target; - due to enzymatic degradation of FAP-cytotoxin complexes; -To release pharmacologically active forms of cytotoxins are used simultaneously.

[0036] The cytotoxin is then internalized and becomes cytotoxic active.

[0037] In an advantageous embodiment, the compounds of the invention are coupled to a diagnostic or therapeutic radioisotope labelling group, e.g. 68 Ga, 90 Y, 177 Lu or 225 Contains Ac. This allows - Near-direct translation of diagnosis to treatment; - combination of cytotoxicity and radiological damage to CAFs and carcinogenic cells; - Quantitative assessment of treatment success with downstream imaging becomes possible.

[0038] Simultaneous attack of CAFs and carcinogenic cells will enhance efficacy, expand the patient population, and greatly facilitate and improve clinical use and efficiency.

[0039] The FAP inhibitors (FAPi) used in the present invention have high binding affinity to fibroblast activation proteins (FAPs) that are overexpressed in cancer-associated fibroblasts (CAFs) of various cancers. In addition, FAP substrates (FAPs) are used that are linked to cytotoxins (CTs) via FAP-cleavable amide bonds. This allows the use of the pharmaceuticals of the present invention with the concept of targeted drug delivery. The pharmaceuticals of the present invention function here as prodrugs, from which the cytotoxins (CTs) are released and "activated" upon contact with FAPs. Due to the combination of FAPi and FAPs, the pharmaceuticals of the present invention have significantly improved affinity to FAPs compared to known targeted drug delivery systems using simple FAP substrates (FAPs). Thus, the pharmaceuticals of the present invention accumulate higher and more selectively in tumor tissues or stroma, which is associated with reduced accumulation in healthy tissues.

[0040] The linkers L1, L2, L3, L4, L5, L6 simultaneously function as spacers and chemical modulators, compensating for interference, e.g., steric hindrance, of the biochemical function of the targeting vector (binding affinity to the target) and the radiochemical function of the labeling group (e.g., stable complexation of the radionuclide with a chelator).

[0041] The Trislinker TL ensures that the labelling group MG - in particular the chelator - is covalently linked to the rest of the molecule exclusively via a functional group, as in known monomeric radiopharmaceuticals. Thus, the labelling properties are essentially unchanged compared to established radiotracers. This ensures high labelling efficiency and in vivo stability of the radiopharmaceuticals of the invention.

[0042] In an advantageous embodiment, the radiopharmaceutical of the present invention comprises a radioisotope 18 F, 123 I, 124 I, 125 I, 131 I and 211 Therefore, the labeling group MG contains a radioisotope 18 F, 123 I, 124 I,125 I, 131 I and 211 It contains a leaving group X substituted with any of At.

[0043] In a further advantageous embodiment, the radiopharmaceutical of the invention comprises a metallic radioisotope. 44 Sc, 47 Sc, 55 Co, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 89 Zr, 86 Y, 90 Y, 89 Zr, 90 Nb, 99m Tc, 111 In, 135 Sm, 140 Pr, 159 Gd, 149 Tb, 160 Tb, 161 Tb, 165 Er, 166 Dy, 166 Ho, 175 Yb, 177 Lu, 186 Re, 188 Re, 211 At, 203 Pb, 212 Pb, 213 Bi, 225 The labeling group MG is intended to label either Ac or Th. 44 Sc, 47 Sc, 55 Co, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 89 Zr, 86 Y, 90 Y, 89 Zr, 90 Nb, 99m Tc, 111 In, 135 Sm,140 Pr, 159 Gd, 149 Tb, 160 Tb, 161 Tb, 165 Er, 166 Dy, 166 Ho, 175 Yb, 177 Lu, 186 Re, 188 Re, 211 At, 203 Pb, 212 Pb, 213 Bi, 225 Ac and 232 The present invention includes chelating agents that form complexes with either Th or Th.

[0044] Chelating Agents The prior art discloses a number of chelating agents for complexation of the above-mentioned radioisotopes. Figure 5 shows examples of chelating agents that can be used in the present invention. [ka] JPEG2025500410000025.jpg229158JPEG2025500410000026.jpg231159JPEG2025500410000027.jpg217160JPEG20255004100 00028.jpg221162JPEG2025500410000029.jpg221151JPEG2025500410000030.jpg234167JPEG2025500410000031.jpg118156

[0045] Cytotoxicity (cell proliferation inhibition) CT The prior art discloses a large number of cytotoxic active ingredients for the treatment of cancer.

[0046] For example, rucaparib and some of its derivatives inhibit the enzyme PARP (poly ADP ribose polymerase), which is involved in the repair of single-strand breaks (SSBs) in DNA. The effect of PARP inhibitors is based on synthetically induced lethality. In healthy cells with intact DNA repair, PARP inhibition does not cause cell death because double-strand breaks (DSBs) in DNA caused by SSBs are repaired by homologous recombination (HR). In contrast, in HR-deficient cells, PARP inhibition causes cell death because DSBs accumulate in the cell and recruit apoptotic molecules. Two genes, BRCA1 and BRCA2 (breast cancer genes), are crucially involved in HR. Mutations in these genes lead to dysfunction of DNA repair and increase the risk of tumor formation.

[0047] In 20-25% of patients with mCRPC (metastatic castration-resistant prostate cancer), HR genes, including BRCA1 / 2, are mutated. These patients would benefit from treatment with PARP inhibitors, which have high tumor specificity. It is also possible to induce BRCA deficiency with drugs. The active ingredient enzalutamide, an inhibitor of the androgen receptor signaling pathway, can cause downregulation of the BRCA gene. After administration of enzalutamide, even patients without BRCA mutations can benefit from the selective tumor toxicity of rucaparib. Therefore, the patient population for PARP therapy can be expanded.

[0048] Temozolomide is a pharmacologically compatible active ingredient (prodrug) that, after metabolism and spontaneous hydrolytic cleavage, is converted to methylhydrazine (CH3(NH) n H2) and methylates DNA bases to induce apoptosis.

[0049] Monomethylauristatin E (MMAE) is an antitumor active ingredient that interrupts the cell cycle and induces apoptosis by inhibiting tubulin polymerization.

[0050] Table 1 shows cytotoxins (cytostatic agents) that can be used in the present invention. It is preferable to use cytotoxins that have a primary or secondary amino group and form an amide bond that can be cleaved by FAP. [Table 1] JPEG2025500410000033.jpg227164JPEG2025500410000034.jpg215164JPEG2025500410000035.jpg221165JPEG2025500410000036.jpg197164 JPEG2025500410000037.jpg222165JPEG2025500410000038.jpg235165JPEG2025500410000039.jpg220164JPEG2025500410000040.jpg117166

[0051] Amide Coupling In the present invention, functional groups such as labeling groups MG, FAPi, FAPs, bivalent linkers L1, L2, L3, L4, L5, L6 and tris linkers TL are preferably linked by amide coupling reaction.In an advantageous embodiment of the present invention, specifically, coupling groups K1, K2, K3, K4, K5 are configured as amide.

[0052] The most commonly used reaction in medicinal chemistry is the amide coupling that forms the backbone of proteins. A typical example of the amide coupling is shown in Figure 6. [ka]

[0053] Due to the virtually unlimited number of readily available carboxylic acid and amine derivatives, the amide coupling strategy opens up a straightforward route for the synthesis of new compounds. Those skilled in the art will recognize the numerous reagents and protocols for amide coupling. The most commonly used amide coupling strategy is based on the condensation of a carboxylic acid with an amine. For this purpose, the carboxylic acid is usually activated. Prior to activation, the remaining functional groups are protected. The reaction is carried out in one reaction medium (single pot), with the direct conversion of the activated carboxylic acid, or in two steps, with the isolation of the activated "trapped" carboxylic acid and its reaction with the amine.

[0054] Here, the carboxylic acid reacts with the coupling reagent to form a reactive intermediate, which can be isolated or reacted directly with the amine. Numerous reagents can be used to activate the carboxylic acid, such as acid halides (chlorides, fluorides), azides, anhydrides or carbodiimides. Furthermore, the reactive intermediate formed can be an ester, such as pentafluorophenyl ester or hydroxysuccinimide ester. Intermediates derived from acyl chlorides or azides are highly reactive. However, the harsh reaction conditions and high reactivity often pose a barrier to use with sensitive substrates or amino acids. Therefore, the amide coupling strategy using carbodiimides such as DCC (dicyclohexylcarbodiimide) and DIC (diisopropylcarbodiimide) opens up a wide range of applications. Additives are often used to improve the reaction efficiency, especially in the case of solid-phase synthesis. Aminium salts are very efficient peptide coupling reagents with short reaction times and minimal racemization. It is also possible to completely prevent racemization by using additives, such as HOBt. Aminium reagents are used in equimolar amounts with the carboxylic acid to prevent excessive reaction with the free amines of the peptide. Phosphonium salts react with carboxylates, which usually requires two equivalents of a base, e.g., DIEA. A major advantage of phosphonium salts over iminium reagents is that the phosphonium does not react with the free amino group of the amine component. This allows coupling of the acid and amine in equimolar ratios, which helps to avoid intramolecular cyclization of linear peptides and overuse of expensive amine components.

[0055] An extensive compilation of amide coupling reaction strategies and reagents can be found in the following reviews: -Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?; DG Brown, J. Bostroem; J. Med. Chem. 2016, 59, 4443-4458; -Peptide Coupling Reagents, More than a Letter Soup; A. El-Faham, F. Albericio; Chem. Rev. 2011, 111, 6557-6602; -Rethinking amide bond synthesis; VR Pattabiraman, JW Bode; Nature, Vol. 480 (2011) 22 / 29; -Amide bond formation: beyond the myth of coupling reagents; E. Valeur, M. Bradley; Chem. Soc. Rev., 2009, 38, 606-631

[0056] The meaning of some terms used in the context of the present invention is explained below. Theranostics: the diagnosis and treatment of cancer using nuclear medicine. Tracer: A synthetically produced radioactive labelled substance that is used in very small amounts and is transformed within an organism without affecting metabolism. Labeled precursor: A compound that contains a chelator or functional group for labeling with a radioisotope. Target: A biological target structure in an organism to which a targeting vector binds, in particular a (membrane-bound) receptor, protein, enzyme, or antibody. Targeting Vector: A chemical group or radical that functions as a ligand, agonist, antagonist or inhibitor for a biological target (e.g., a protein, enzyme or receptor) and has high binding affinity for the target. FAPi: A fibroblast activation protein (FAP) inhibitor that binds to and inhibits or inactivates FAP. FAP: A FAP substrate that binds to fibroblast activation protein (FAP) and preferably initiates endocytosis. Radiopharmaceutical: A radiolabeled compound or labeled precursor complexed with a radioisotope for nuclear medicine or therapeutic diagnosis. Tris-linker: A structural unit, group or radical that can be interconnected with three other chemical structural units. Linker: A structural unit, group or radical which in each case links two functional groups together, such as a FAP inhibitor (FAPi), a FAP substrate (FAPs), a cytotoxin (CT), a labeling group (MG) and optionally a Tris linker (TL). Spacer: A structural unit that acts as a spacer between two other chemical structural units and counteracts steric hindrance. Cytotoxin (cytostatic agent): A compound that attacks, damages, and / or destroys cells and is used in chemotherapy to treat cancer. Chelating agent: A structural unit capable of stably complexing a metallic radioisotope. Residue of a chelator: A chelator that is part of a compound of the invention. Targeted drug delivery system: A compound comprising a cytotoxic active moiety, a cleavable linker for releasing the cytotoxic active moiety, and a targeting vector for accumulation in tumor tissue, and optionally further linkers or spacers, and a chelating agent for labeling with a radioisotope. Active ingredient conjugate: a compound comprising a cytotoxin, a biological targeting vector and a cleavable linker. Dual active ingredient conjugate: a compound comprising a cytotoxin, a biological targeting vector, a chelator and a linker.

[0057] The following Figures 7 to 25 show examples of compounds of the present invention. [ka] JPEG2025500410000043.jpg185161JPEG2025500410000044.jpg228162JPEG2025500410000045.jpg190162 JPEG2025500410000046.jpg201162JPEG2025500410000047.jpg216161JPEG2025500410000048.jpg235162

Claims

1. A pharmaceutical compound for anticancer use, having the structure 【Chemistry 1】 CT represents a cytotoxin, MG represents a radioisotope labeling group, TL represents a Tris linker, and L1, L2, L3, L4, L5, and L6 represent bivalent linkers; -FAPs is a substrate of fibroblast activation protein (FAP) and has any one of the structures [1] to [20]: 【Chemistry 2】 【change】 【change】 【change】 [20] represents the amino acid sequence Ala-Pro-Gly; X=H or F; Y=H, CH ３ , CH(CH ３ ) ２ , C(CH ３ ) ３ Or (CH ２ ) ｎ CH ３ where n=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and Z is selected from the group comprising alcohol, amidine, amine, amide, carboxamide, thioamide, imide, imidoester, imine, urea, thiourea, guanidine, carbonate, carboxylic ester, carbamate, ether, thioether, ester, ketone, phosphate, phosphonate, phosphinate, sulfonate, sulfinate, sulfone, thiol, disulfide, boronic ester, silyl ether radicals and derivatives thereof; -FAPi is an inhibitor of fibroblast activation protein (FAP) and has the structure of any one of [21] to [46]: 【Chemistry 3】 【change】 【change】 【change】 X=H or F; Y=H, CH ３ , CH(CH ３ ) ２ , C(CH ３ ) ３ Or (CH ２ ) ｎ CH ３ where n=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Z is selected from the group comprising alcohol, amidine, amine, amide, carboxamide, thioamide, imide, imidoester, imine, urea, thiourea, guanidine, carbonate, carboxylic ester, carbamate, ether, thioether, ester, ketone, phosphate, phosphonate, phosphinate, sulfonic ester, sulfinic ester, sulfone, thiol, disulfide, boronic ester, silyl ether radicals and derivatives thereof; The pharmaceutical compound.

2. CT scan, - Antimetabolites such as cytarabine, fludarabine, fluorouracil (5-FU), gemcitabine, methotrexate; - alkylating cytotoxic agents such as adozelesin, bizelesin, carzelesin, dacarbazine (DTIC), melphalan (BCNU), temozolomide; - Mitotic inhibitors such as monomethylauristatin E (MMAE); - Antibiotics such as Dactinomycin, Daunorubicin, Doxorubicin, Duocarmycin A, Duocarmycin B1, Duocarmycin B2, Duocarmycin C1, Duocarmycin C2, Duocarmycin D, Duocarmycin SA, Idarubicin, Anthramycin, Mitoxantrone; - Enzyme inhibitors such as L-asparaginase, motesanib, etc.; - PARP inhibitors such as rucaparib, olaparib, niraparib, veliparib, iniparib; - goserelin, leuprolide, metformin, NSC 668394, tetrazole, α-solamargine, α-tomatine; - tubulin inhibitors such as tubulysin B hydrazide; - tyrosine kinase inhibitors such as imatinib; - Angiogenesis inhibitors such as Neovastat (AE-941); - Hedgehog pathway inhibitors such as sonidegib; - VEGFR inhibitors such as sunitinib; and - SERCA ATPase inhibitors such as thapsigargin and its derivatives 12ADT, A12ADT and S12ADT 2. The pharmaceutical compound of claim 1, which is a cytotoxin selected from:

3. MG is H ４ pypa, EDTA (ethylenediaminetetraacetate), EDTMP (diethylenetriaminepenta(methylenephosphonic acid)), DTPA (diethylenetriaminepentaacetate) and its derivatives, NOTA (nona-1,4,7-triamine-triacetate) and its derivatives, such as NODAGA (1,4,7-triazacyclononane, 1-glutaric acid, 4,7-acetate), TRAP (triazacyclononanephosphinic acid), NOPO (1,4,7-triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid]), DOTA (dodeca-1,4,7,10-tetraaminetetraacetate), DOTAGA (2-(1,4,7,10-tetraazacyclodo decane-4,7,10)pentanedioic acid) and other DOTA derivatives, TRITA (trideca-1,4,7,10-tetraaminetetraacetate), TETA (tetradeca-1,4,8,11-tetraaminetetraacetate) and its derivatives, PEPA (pentadeca-1,4,7,10,13-pentaaminepentaacetate), HEHA (hexadeca-1,4,7,10,13,16-hexaaminehexaacetate) and its derivatives, HBED (N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetate) and its derivatives, such as HBED-CC (N,N'-bis[2-hydroxy-5-carboxyethyl)benzyl)ethylenediamine-N,N'-diacetate), DEDPA and its derivatives, such as H ２ Dedopa (1,2-[[6-(carboxyl)pyridin-2-yl]methylamine]ethane) and H ４ Octapa (1,2-[[6-(carboxyl)pyridin-2-yl]methylamine]ethane-N,N'-diacetate), DFO (deferoxamine) and its derivatives, trishydroxypyridinone (THP) and its derivatives, e.g. ３ THP-Ac and H ３ THP-mal (YM103), TEAP (tetraadicyclodecane phosphinic acid) and its derivatives, AAZTA (6-amino-6-methylperhydro-1,4-diazepane-N,N,N',N'-tetraacetate) and its derivatives, e.g. AAZTA ５ (5-[(6-amino)-1,4-diazepane]pentanoic acid-N,N,N',N'-tetraacetate), DATA (2,2'-(6-((carboxymethyl)(methyl)amino)-6-methyl-1,4-diazepane-1,4-diyl)diacetate) and its derivatives, such as DATA ５ｍ (5-[[6-(N-methyl)amino]-1,4-diacetate-1,4-diazepane]pentanoic acid-N,N',N'-triacetate); sarcofagin SAR (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexazabicyclo[6.6.6]eicosane-1,8-diamine) and its derivatives, such as (NH ２ ) ２ SAR (1,8-diamino-3,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane), N4 (3-[(2'-aminoethyl)amino]-2-[(2''-aminoethyl)-aminomethyl]propionic acid) and other N ４ derivatives, PnAO (6-(4-isothiocyanatobenzyl)-3,3,9,9-tetramethyl-4,8-diazaundecane-2,10-dione dioxime) and its derivatives, for example BMS181321 (3,3'-(1,4-butanediyldiamino)-bis(3-methyl-2-butanone) dioxime), MAG2 (mercaptoacetylglycylglycine) and its derivatives, MAG3 (mercaptoacetylglycylglycylglycine) and its derivatives, for example N ３ S adipate, MAS3 (mercaptoacetylserylserylserine) and its derivatives, MAMA (N-(2-mercaptoethyl)-2-[(2-mercaptoethyl)amino]acetamide) and its derivatives, EC (ethylenedicysteine) and its derivatives, DMSA (dimercaptosuccinic acid) and its derivatives, DADT (diaminodithiol), DADS (diaminodisulfide), N ２ S ２ 3. The pharmaceutical compound according to claim 1 or 2, which is a chelating agent selected from the group consisting of chelating agents and derivatives thereof, aminothiols and derivatives thereof; salts of the above chelating agents; hydrazine nicotinamide (HYNIC) and hydrazine nicotinamide derivatives.

4. The pharmaceutical compound according to claim 1 or 2, wherein MG is DOTA (dodeca-1,4,7,10-tetraaminetetraacetate).

5. MG is DATA ５ｍ 3. The pharmaceutical compound according to claim 1 or 2, which is 1,4-bis(carboxymethyl)-6-[methylcarboxymethylamino]-6-pentanoic acid-1,4-diazepane.

6. 3. The pharmaceutical compound of claim 1 or 2, wherein MG is AAZTA (1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)amino]-6-pentanoic acid-1,4-diazepane).

7. M.G. １８ F. １３１ I or ２１１ 3. The pharmaceutical compound of claim 1 or 2, wherein At is a labeling group for covalent attachment.

8. M.G. 【Chemistry 4】 8. The pharmaceutical compound of claim 7, selected from:

9. M.G. １８ F. １３１ I or ２１１ having a leaving group X which is replaced by At 【Chemistry 5】 8. The pharmaceutical compound of claim 7, wherein the group is of the type:

10. 10. The pharmaceutical compound of claim 9, wherein MG comprises a leaving group X selected from the radicals of bromine (Br), chlorine (Cl) or iodine (I), tosyl (Ts), brosylate (Bs), nosylate (Nos), 2-(N-morpholino)ethanesulfonic acid (MES), triflate (Tf) and nonaflate (Non).

11. L1, L2, L3, L4, L5, and L6 are independently 【Chemistry 6】 Selected from the group comprising: -S1, S2, S3, S4, S5, S6, S7, S8, S9, and S10 each independently represent a monomer or oligomer consisting of m alkyl units, polyethylene glycol (-(CH ２ CH ２ O) ｎ -), polypropylene glycol (-(CH ２ CH (CH ３ ) ２ O) ｎ -), polyalkylene glycol ether (-((CH ２ ) ｎ O)-), polyamine (-((CH ２ ) ｎ NH)-), polyamide (-((CH ２ ) ｎ CONH)-), polyester (-((CH ２ ) ｎ COO)-), polyurethane (-((CH ２ ) ｎ NHCOO)-), polyurea (-((CH ２ ) ｎ NHCONH)-) and a peptide having m amino acids, where m=1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; - K1, K2, K3, K4, K5 are independently selected from the group comprising alcohol, amidine, amine, amide, carboxamide, thioamide, imide, imidoester, imine, urea, thiourea, guanidine, carbonate, carboxylic ester, carbamate, ether, thioether, ester, ketone, phosphate, phosphonate, phosphinate, sulfonic ester, sulfinic ester, sulfone, thiol, disulfide, boronate, silyl ether radicals and derivatives thereof; -V is - any one of structures [47], [48], [49] or [50]: 【Chemistry 7】 [[47] represents a radical of squaric acid, [48] represents a radical of squaric diamide, [49] represents a radical of 1,4-disubstituted 1,2,3-triazole, and [50] represents a radical of 1,3-disubstituted succinimidyl.] Selected from; - selected from the group comprising residues of amino acids such as Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val, Pyl, Sec, GABA (gamma-aminobutyric acid), homoserine, DOPA (3,4-dihydroxyphenylalanine), citrulline, beta-alanine, thyroxine; or -Benzene, phenol, cyclopentane, cyclohexane, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, piperazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, 1,2,4,5-tetrazine, thiazine, oxazine, pyrrole, pyrrolidine, pyrazole, imidazole, tetrahydroimidazole, 1,2,4-triazole, tetrazole, thiophene, furan, 1,2-thiazole, 1,3-thiazole, thiadiazole, 1,2-oxazine azole, 1,3-oxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, naphthalene, indene, indole, isoindole, indazole, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, phthalazine, tetrahydroquinoline, tetrahydroisoquinoline, quinolizidine, indolizidine, 2H-chromene, 4H-chromene, 2H-thiochromene, 4H-thiochromene, coumarin, purine radicals and derivatives thereof; A pharmaceutical compound according to any one of claims 1 to 10.

12. TL is a structure represented by any one of [51] to [115]: 【Chemistry 8】 【change】 【change】 The pharmaceutical compound according to any one of claims 1 to 11, which is selected from:

13. A radioactive tracer comprising the pharmaceutical compound according to any one of claims 1 to 12 and a radioisotope complexed therewith, the radioisotope being ４４ Sc, ４７ Sc, ５５ Co, ６２ Cu, ６４ Cu, ６７ Cu, ６６ G.A. ６７ G.A. ６８ G.A. ８９ Zr, ８６ Y. ９０ Y. ８９ Zr, ９０ Nb, ９９ｍ Tc, １１１ In, １３５ Sm, １４０ P.R. １５９ Gd, １４９ Tb, １６０ Tb, １６１ Tb, １６５ Er, １６６ Dy, １６６ Ho, １７５ Yb, １７７ Lu, １８６ Re, １８８ Re, ２１１ At, ２０３ Pb, ２１２ Pb, ２１３ Bi, ２２５ Ac and ２３２ The radioactive tracer is selected from the group consisting of: Th.

14. A radioactive tracer comprising the pharmaceutical compound according to any one of claims 1 to 12 and a radioisotope bound thereto, wherein the radioisotope is １８ F. １３ 1I and ２１１ The radioactive tracer is selected from the group consisting of:

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