Precursors and radiotracers targeting fibroblast activation proteins

Abstract

Precursor compounds and radiotracers for targeting a fibroblast activating protein, the precursor compounds and radiotracers comprising a chelating agent Ch and a ligand TV, where Ch = # imgabs0 #, where R =-CH3 or-CH2COOH; and TV is equal to # imgabs 1 #.

Description

SUMMARY OF THE INVENTION

[0001] The present invention relates to a precursor compound for imaging expression of fibroblast activation protein (FAP) and a radioactive tracer derived therefrom. The precursor compound of the present invention has the structure Ch-L1-B-L2-TV, wherein

[0002] Ch= , where R= or ;

[0003] TV= ;

[0004] L1 is a bifunctional linker part;

[0005] L2 is a bifunctional linker part;

[0006] B is absent or B is a bifunctional linker moiety;

[0007] L1 is configured to covalently bind to Ch and L2, or to Ch and B if B is present;

[0008] If B is present, B is configured to be covalently bound to L1 and to L2; and

[0009] L2 is configured to be covalently bound to L1 and TV, or to TV and B if B is present. Background Art

[0010] use 68 Nuclear Medicine Diagnosis of Tumors Involving Ga

[0011] Using gallium-68 (Ga-68 or 68Positron emission tomography (PET) with the aid of Ga-68 combined with computed tomography (CT) is a well-established nuclear medicine test today. The U.S. Food and Drug Administration and the European Medicines Agency have approved Ga-68 labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotide (DOTATATE) and DOTA(0)-d-Phe(1)-Tyr(3)-octreotide, or DOTATOC, for localization of somatostatin receptor-positive neuroendocrine tumors (NETs) in adult and pediatric patients (in the United States) and in adult patients thought to have so-called well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) (in Europe). Recently, the prostate-specific membrane antigen inhibitor PSMA-11 was approved for imaging and staging of metastatic prostate cancer. The diagnostic value of PET / CT depends primarily on sensitivity, specificity, and accuracy. Sensitivity measures the proportion of positives that are correctly identified (true positives divided by the sum of true positives and false negatives). Specificity measures the proportion of negatives that are correctly identified (true negatives divided by the sum of true negatives and false positives). Diagnostic accuracy refers to the ability of a test to distinguish between the target condition and health. This discriminatory potential can be quantified by sensitivity and specificity, target-to-background ratios, or the area under the receiver operating characteristic curve (ROC curve).

[0012] Fibroblast activation protein (FAP) is a membrane-bound serine protease that is currently receiving increasing attention in nuclear medicine because of the use of FAP-specific radiolabeled agents to target different cancer types for diagnosis and treatment. FAP is overexpressed by cancer-associated fibroblasts (CAFs), which are present in large numbers in more than 90% of common human epithelial tumors. CAFs are myofibroblast phenotypes that are located in the tumor stroma. Stromal cells contain up to 90% of the total tumor mass. FAP can also be expressed by fibroblasts present in wound healing, chronic inflammation, cirrhosis, rheumatoid arthritis, pulmonary fibrosis, osteosarcoma, and soft tissue sarcomas. However, in healthy tissues, FAP expression is almost non-existent. Therefore, radiopharmaceuticals targeting FAP are very suitable for molecular imaging by PET or SPECT, as well as for internal radiation therapy of cancer tumors and metastases.

[0013] Quinoline-glycine-4,4-difluoro-2-cyanopyrrolidine FAP inhibitor

[0014] The potent FAP inhibitor (FAPi), commonly named UAMC1110, is based on the quinoline-glycine-4,4-difluoro-2-cyanopyrrolidine skeleton. UAMC1110 has a low nanomolar affinity for FAP and is highly selective relative to enzymes of the dipeptidyl peptidase (DPP) family and the prolyl oligopeptidase (PREP) family. The high FAP selectivity of UAMC1110 is particularly attractive for targeted tumor therapy when considering the nearly ubiquitous expression of DPP and PREP in the human body. Since PREP exhibits the same endopeptidase activity as FAP and is abundant in healthy organs and healthy tissues, high FAP specificity is essential for a potent FAP ligand. UAMC1110 has FAP affinity in the low nM range and PREP and DPP4 affinity in the μM range. Therefore, FAPi-radiopharmaceuticals based on UAMC1110 have recently been applied in nuclear medicine.

[0015]

[0016] Figure 1: FAP inhibitor UAMC1110

[0017] Chelating agents in radiopharmaceuticals containing radioactive metals

[0018] The following properties are associated with the precursors and the radiotracers derived therefrom:

[0019] - Rapid and efficient complexation of diagnostic or therapeutic radioisotopes with labeling groups;

[0020] -High affinity and selectivity for tumor cells and metastases relative to healthy tissues;

[0021] - in vivo stability, i.e. biochemical persistence in serum under physiological conditions;

[0022] -Highly absorbed in tumors and metastases for precise diagnosis and effective treatment;

[0023] - Rapid clearance from healthy tissues and blood to minimize systemic dose and systemic toxicity.

[0024] According to the current knowledge in this field:

[0025] - Chelators and radioisotopes greatly affect the affinity and pharmacokinetics of radiotracers;

[0026] -DOTA can severely affect the affinity of targeting ligands;

[0027] - Chelators, radioisotopes and targeting ligands interact unpredictably in either a synergistic or antagonistic manner.

[0028] Fani et al. reported that the chelator portion and radiometal of the radiotracer can strongly affect the affinity of the targeting ligand. Reubi et al. showed that the binding of the targeting ligand to DOTA can significantly reduce its affinity for the targeted cell receptor. The data presented by Reubi et al. show that the combination of chelators, radiometals and targeting ligands can produce unpredictable synergistic or antagonistic effects. In general, the binding of the targeting ligand to linkers and large chelator portions is unhelpful and severely weakens its affinity for the targeted cell receptor.

[0029] For example, the chelator DOTA is not suitable for complexing the relatively small (radioactive) metal gallium, and the reaction temperature must be increased, which is unfavorable for many antibodies and heat-sensitive biomolecules. 68 Ga-DOTA chelate requires time to cool before intravenous injection due to 68 The half-life of Ga is short, only 67.7 minutes, which limits its clinical application.

[0030] "Hybrid" chelating agent frameworks DATA and AAZTA

[0031] DATA (1,4-bis(carboxymethyl)-6-[methyl-carboxymethyl-amino]-1,4-diazepane) and AAZTA (1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)-amino]-1,4-diazepane) exhibit cyclic, acyclic and hybrid properties and are found to be 68 Ga provides advantageous labeling properties. In particular, DATA can be rapidly and quantitatively detected at ambient temperature and over a wide pH range. 68 Ga marker. In addition, [ 68 Ga]Ga-DATA chelates are effective for transchelation (DTPA and apotransferrin) and transmetallation (Fe III ) immunity, and it is stable in a physiological environment. DETAILED DESCRIPTION OF THE INVENTION

[0032] The aim of the present invention is to improve nuclear theranostics of endothelial carcinoma tumors and metastases showing elevated FAP expression.

[0033] This object is achieved by a precursor compound having the structure Ch-L1-B-L2-TV, wherein

[0034] Ch= , where R= or ;

[0035] TV= , or ;

[0036] L1 is a bifunctional linker part;

[0037] L2 is a bifunctional linker part;

[0038] B is absent or B is a bifunctional linker moiety;

[0039] L1 is configured to covalently bind to Ch and L2, or to Ch and B if B is present;

[0040] If B is present, B is configured to be covalently bound to L1 and to L2; and

[0041] L2 is configured to be covalently bound to L1 and TV, or to TV and B if B is present.

[0042] Advantageous embodiments of the precursor compounds of the invention are characterized by one of the following features, or a combination of two or more of the following features, provided that the combined features are not mutually exclusive or contradictory, and according to the following features:

[0043] -TV= ;

[0044] -TV= ;

[0045] -TV= ;

[0046] -L1= , where m = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0047] -L2= , where n=1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0048] -m=4;

[0049] -n=4;

[0050] -L1 has the structure

[0051]

[0052] in

[0053] -For each P i , 1≤i≤k when P i Exists, when i>k, P i does not exist, where k = 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0054] - If P s exists, where s = 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each P sEach independently selected from -CH2-, -CH2CH2O-, -N(H)-, -C(O)- and -C(CH3)-;

[0055] -L2 has the structure

[0056]

[0057] in

[0058] -For each Q j , Q when 1≤j≤h j Exists, j>h when Q j does not exist, where h = 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0059] - If Q s exists, where s = 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each Q s Each independently selected from -CH2-, -CH2CH2O-, -N(H)-, -C(O)- and -C(CH3)-;

[0060] -B=does not exist, , , or ;

[0061] -B= ;

[0062] -B= ;

[0063] -B= ;

[0064] -B= ;

[0065] -B does not exist;

[0066] -The precursor compound has the structure

[0067] ;

[0068] -The precursor compound has the structure

[0069] ;

[0070] -The precursor compound has the structure

[0071] ;

[0072] -The precursor compound has the structure

[0073] ;

[0074] -The precursor compound has the structure

[0075] .

[0076] It is a further object of the present invention to provide radiotracers that provide improved nuclear theranostics of endothelial carcinoma tumors and metastases showing elevated FAP expression.

[0077] This object is achieved by a radioactive tracer comprising the above-mentioned precursor compound and a radioactive isotope complexed with the above-mentioned precursor compound. 68 Ga.

[0078] Other advantageous embodiments of the invention relate to:

[0079] - a radiopharmaceutical kit comprising one of the above-mentioned precursor compounds or a salt thereof;

[0080] - a radiopharmaceutical kit comprising one of the above-mentioned precursor compounds or a salt thereof and a solvent selected from the group consisting of water, 0.45% NaCl aqueous solution, 0.9% NaCl aqueous solution, Ringer's solution (Ringer's lactate solution), 5% dextrose aqueous solution and ethanol aqueous solution;

[0081] - A radiopharmaceutical kit comprising

[0082] - a vial containing one of the above-mentioned precursor compounds or a salt thereof;

[0083] - A radiopharmaceutical kit comprising

[0084] - a vial containing one of the above-mentioned precursor compounds or a salt thereof and a lyophilization buffer selected from the group consisting of sodium acetate, gentisic acid, ascorbic acid, succinic acid, HEPES, sodium carbonate, sodium bicarbonate, and salts thereof;

[0085] - A radiopharmaceutical kit comprising

[0086] - a first vial containing one of the above-mentioned precursor compounds or a salt thereof, and

[0087] - A second vial containing

[0088] - a solvent selected from water, 0.45% NaCl aqueous solution, 0.9% NaCl aqueous solution, Ringer's solution (Ringer's lactate solution), 5% dextrose aqueous solution and ethanol aqueous solution, or

[0089] - A buffer solution configured to adjust the pH between 3 and 7.4.

[0090] The following synonymous compound names are used in this invention:

[0091] (A)

[0092] "DATA 5m .NH.FAPi”

[0093] (S) 2,2'-(6-((carboxymethyl)(methyl)amino)-6-(5-((4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-5-oxopentyl)-1,4-diazepane-1,4-diyl)diacetic acid

[0094] (B)

[0095] "DATA 5m .Pipz.FAPi”

[0096] (S) 2,2'-(6-((carboxymethyl)(methyl)amino)-6-(5-(4-(2-((4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)piperazin-1-yl)-5-oxopentyl)-1,4-diazepane-1,4-diyl)diacetic acid

[0097] (C)

[0098] "DATA 5m .Pipd-N-Me.FAPi”

[0099] (S) 2,2'-(6-((carboxymethyl)(methyl)amino)-6-(5-(4-((2-((4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)(methyl)amino)piperidin-1-yl)-5-oxopentyl)-1,4-diazepane-1,4-diyl)diacetic acid

[0100] (D)

[0101] "DATA 5m .NH-Pyr.FAPi”

[0102] 2,2'-(6-((Carboxymethyl)(methyl)amino)-6-(5-(((S)-1-(2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)pyrrolidin-3-yl)amino)-5-oxopentyl)-1,4-diazepane-1,4-diyl)diacetic acid

[0103] (E)

[0104] "DATA 5m .Pyr-N-Me.FAPi”

[0105] 2,2'-(6-((Carboxymethyl)(methyl)amino)-6-(5-((S)-3-((2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)(methyl)amino)pyrrolidin-1-yl)-5-oxopentyl)-1,4-diazepane-1,4-diyl)diacetic acid

[0106] (F)

[0107] "DATA 5m .SA.FAPi”

[0108] 2,2'-(6-((Carboxymethyl)(methyl)amino)-6-(5-((S)-3-((2-((4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)oxy)butyl)amino)-2-oxoethyl)(methyl)amino)pyrrolidin-1-yl)-5-oxopentyl)-1,4-diazepane-1,4-diyl)diacetic acid

[0109] (G)

[0110] "UAMC1110"

[0111] (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide Example

[0112] Example 1: DATA 5m Precursor Chelating Agent ( Synthesis of prochelator

[0113] Figure 2 illustrates DATA 5mSynthesis of precursor chelators (see J. Seemann, B. Waldron, D.Parker, F. Roesch; DATATOC: a novel conjugate for kit-type 68 Ga labelling of TOC at ambient temperature; EJNMMI Radiopharmacy and Chemistry (2016) 1:4, DOI 10.1186 / s41181-016-0007-3).

[0114] 5-(1,4-Dibenzyl-6-nitro-[1,4]diazepan-6-yl)pentanoic acid methyl ester (1)

[0115] 2-Nitrocyclohexanone (0.608 g, 4.3 mmol) was added to EtOH containing Amberlyst A21 (1.216 g, 2 mass equivalents) and stirred at 60°C for 2 hours under argon. N,N′-dibenzyl-ethylenediamine (1.020 g, 4.3 mmol) and paraformaldehyde (0.446 g, 14.9 mmol) were added and the reaction was stirred at 60°C overnight. The mixture was purified by Celite ® Filter and remove the solvent under reduced pressure. The obtained residue is redissolved in CHCl3 (40 mL), washed with K2CO3 aqueous solution (2×30 mL, 0.1 M) and H2O (30 mL) in sequence, dried with MgSO4, filtered, and the solvent is removed under reduced pressure. Purification by silica gel column chromatography (DCM) gives the title compound (1.607 g, 85%) as a yellow oil. Rf=0.80 (DCM).

[0116] 5-(1,4-dibenzyl-6-nitro-[1,4]diazepan-6-yl)pentanoic acid methyl ester)(2)

[0117] A catalytic amount of Pd(OH)2 / C and acetic acid (50 μL, 0.87 mmol) was added to MeOH (20 mL) containing the protected triamine 1 (0.10 g, 0.29 mmol), and the mixture was stirred under a hydrogen atmosphere for 3 hours (1 standard atmosphere of H2). TLC (DCM) was used to confirm the complete reduction of the nitro group and the cleavage of the N-substituent on the benzyl group. Celite ® The Pd(OH)2 / C was removed by filtration. The solvent was removed under reduced pressure to give a yellow oil (0.065 g, 97%).

[0118] 5-[1,4-Bis-tert-butoxycarbonylmethyl-6-(tert-butoxycarbonylmethyl-amino)-[1,4]diazepan-6-yl]-pentanoic acid methyl ester (3)

[0119] Tert-butyl bromoacetate (0.567 g, 2.91 mmol) was added to MeCN (25 mL) containing 2 (0.208 g, 0.91 mmol) and K2CO3 (0.377 g, 2.73 mmol) and stirred at 368 K under argon for 24 h. The reaction was monitored by TLC (hexane / ethyl acetate; 1:1) for the formation of the tetraalkylated derivative. The solvent was removed under reduced pressure, and the resulting oil was redissolved in CHCl3 (25 mL), washed successively with aqueous K2CO3 solution (2×25 mL, 0.1 M) and H2O (25 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification by silica gel column chromatography (hexane / ethyl acetate, 2:1→1:1) gave a yellow oil (0.229 g, 44%). Rf=0.35 (hexane / ethyl acetate; 2:1).

[0120] 5-[1,4-Bis-tert-butoxycarbonylmethyl-6-(tert-butoxycarbonylmethyl-methyl-amino)-[1,4]diazepan-6-yl]-pentanoic acid methyl ester (4)

[0121] Iodomethane (0.023 g, 0.16 mmol) was added to DCM / MeCN (3:1) cooled in an ice bath containing 3 (0.104 g, 0.18 mmol) and K2CO3 (0.025 g, 0.18 mmol). The reaction mixture was allowed to warm to room temperature and left overnight. The solvent was removed under reduced pressure, and the resulting oil was redissolved in CHCl3 (20 mL), and washed with K2CO3 aqueous solution (2 × 20 mL, 0.1 M) and H2O (20 mL) in turn, dried with MgSO4, filtered, and the solvent was removed under reduced pressure. Purification by silica gel column chromatography (hexane / ethyl acetate, 3:1 → 2:1) gave a yellow oil (0.043 g, 46%). Rf = 0.38 (hexane / ethyl acetate; 2:1).

[0122] 5-[1,4-Bis-tert-butoxycarbonylmethyl-6-(tert-butoxycarbonylmethyl-methyl-amino)-[1,4]diazepan-6-yl]-pentanoic acid (5)

[0123] LiOH (0.009 g, 0.039 mmol) dissolved in H2O (0.5 mL) was added to THF (0.5 mL) containing 4 (0.010 g, 0.023 mmol), and the mixture was stirred at 298 K. LC-ESI MS was used to monitor the ester cleavage of the reaction. Once completely cleaved, the solvent was removed by freeze drying. H2O (5 mL) was added and removed by freeze drying, and this step was repeated twice. The resulting solid was washed with ice-cold DCM (0.5 mL) and vacuum dried to obtain a waxy yellow solid (0.009 g, 70%).

[0124]

[0125] Figure 2: 3 t Bu-protected DATA 5m Synthesis of precursor chelates (i) Amberlyst-21, EtOH; (ii) CH2O, EtOH; (iii) CH3COOH, Pd(OH)2 / C, H2, EtOH; (iv) BrCH2COO t Bu, K2CO3, MeCN; (v) CH3I, K2CO3, DCM:MeCN; (vi) LiOH, THF:H2O.

[0126] Example 2: Synthesis of FAP-targeting ligands

[0127] Figures 3 to 5 illustrate the synthesis of ligands that target FAP (see K. Jansen, L. Heirbaut, R.Verkerk, JD Cheng, J. Joossens, P. Cos, L. Maes, A.-M. Lambeir, I. DeMeester, K. Augustyns, P. Van der Veken; Extended Structure−ActivityRelationship and Pharmacokinetic Investigation of (4-Quinolinoyl)glycyl-2-cyanopyrrolidine Inhibitors of Fibroblast Activation Protein (FAP); J. Med. Chem. 2014 Apr 10; 57(7): 3053–74, DOI 10.1021 / jm500031w).

[0128]

[0129] Scheme 3: Synthesis of (S)-4,4-difluoro-1-(aminoacetyl)pyrrolidone-2-carbonitrile (a) TEMPO (0.02 equiv), 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione, DCM, 1 hour, 0°C, 74%; (b) DAST, DCM, 16 hours, 61%; (c) KOH, MeOH, 16 hours, 86%; (d) DCC, HONSu, NH3, DCM, 2 hours, 72%; (e) TFA, DCM, 1 hour, 90%; (f) HATU, Boc-Gly-OH, DIPEA, DCM, 3 hours, 77%; (g) TFAA, pyridine, THF, -15°C, 70%; (h) TsOH; MeCN; 24 hours, 90%.

[0130]

[0131] Figure 4: Synthesis of 6-methoxyquinoline-4-carboxylic acid (a) PBr3, DMF, 3 hours, 63%; (b) Zn(CN)2, Pd / C, Zn ++ (COO-)2, dppf, 110℃, 3 hours, 72%; (c) NaOH, H2O / EtOH, reflux, 94%.

[0132]

[0133] Scheme 5: Conjugation of (S)-4,4-difluoro-1-(aminoacetyl)pyrrolidone-2-carbonitrile with 6-methoxyquinoline-4-carboxylic acid.

[0134] Example 3: Affinity for FAP and PREP

[0135] The precursor compounds and radiotracers of the present invention have high targeting affinity and excellent selectivity for FAP, i.e., low binding to PREP. Therefore, they provide high image contrast for the diagnosis of endothelial tumors and metastases using Gallium-68 PET / CT.

[0136] Table 1 below shows the measured affinities of the inventive precursor compounds 1 to 4 and reference compound 5, as well as the original FAP inhibitor UAMC1110, which is the current gold standard, to FAP and PREP.

[0137] Table 1: Affinity for FAP and PREP

[0138]

[0139] *S=PREP IC 50 / FAP IC 50

[0140] **SF =S relative to UAMC1110

[0141] The precursor compounds (A), (B), (D) and (E) of the present invention exhibit higher affinity for FAP than the reference compound (F) and the gold standard UAMC1110 (G). Compared with the references (F) and (G), compounds (A), (D) and (E) exhibit reduced binding to non-target PREPs. Compound (B) has a PREP affinity comparable to that of compounds (F) and (G). Compared with the reference (F) and the gold standard (G), all compounds (A), (B), (D) and (E) have significantly higher selectivity for FAP than PREP. The selectivity of compound (B) is similar to that of compound (G). The selectivity of compound (E) is 2 times that of compound (G). The selectivity of compound (D) is 3 times that of compound (G). The selectivity of compound (A) is 6 times that of compound (G). As expected, due to the chemical modification, DATA 5m - The conjugated reference compound (F) has lower affinity and selectivity for FAP than compound (G).

[0142] The radioactive tracer of the present invention can be conveniently provided as a kit that can be used directly. The kit contains a freeze-dried precursor compound or a salt thereof, a buffer for pH adjustment, an antioxidant as a free radical scavenger to prevent radiolysis, and a freeze-dried bulking agent. According to the European Pharmacopoeia monograph "Gallium (68Ga) chloride solution", by adding [ 68 The corresponding radioactive tracer was prepared by the hydrochloric acid solution of Ga]GaCl3.

[0143] Example 4: Using [ 68 Ga]Ga-DATA 5m PET MIP of .Pip.FAPi

[0144] Figure 1 The use of the radiotracer of the present invention [ 68 Ga]Ga-DATA 5m .Pip.FAPi, PET MIP images of a 52-year-old male patient with radioiodine-refractory differentiated thyroid cancer. Multiple pancreatic (1), lung (2), and lymph node (3) metastases were detected.

[0145] Example 5: Using [ 68 Ga]Ga-DATA 5m PET MIP of .NH.FAPi

[0146] Figure 2 The use of the radiotracer of the present invention [ 68 Ga]Ga-DATA 5m.NH.FAPi, PET MIP images of a 40-year-old male patient with radioiodine-refractory differentiated thyroid cancer. Multiple liver (1), lung (2), and lymph node (3) lesions were detected.

[0147] Example 6: Coronal PET / CT Imaging

[0148] Figure 3 Describes the use of the radiotracer of the present invention [ 68 Ga]Ga-DATA 5m .NH-Pyr.FAPi coronal PET / CT patient image of a male patient with metastatic gastroesophageal cancer. Multiple skeletal metastases were detected.

[0149] Figure 3 The comments in

[0150] Li: Liver

[0151] Ki: kidney

[0152] Bl: bladder

[0153] L1: Bone tumor lesions, pelvis

[0154] L2: Bone tumor lesion, pelvis

[0155] L3: bone tumor lesions, ribs

[0156] L4: Tumor lesions

[0157] L5: Tumor lesions

[0158] L6: Bone tumor lesion, vertebra

[0159] L7: Bone tumor lesions, shoulder

[0160] L8: Multiple bone tumor lesions, pelvis

[0161] L9: Tumor lesion, pelvis

[0162] L10: Multiple bone tumor lesions, vertebrae

[0163] L11: Multiple bone tumor lesions, pelvis

[0164] L12: Bone tumor lesions, ribs

Claims

1. A precursor compound for a radioactive tracer having the structure Ch-L1-B-L2-TV, wherein Ch= , where R= or ; TV= , or ； L1 is a bifunctional linker part; L2 is a bifunctional linker part; B is absent or B is a bifunctional linker moiety; L1 is configured to covalently bind to Ch and L2, or to Ch and B if B is present; If B is present, B is configured to be covalently bound to L1 and to L2; and L2 is configured to be covalently bound to L1 and TV, or to TV and B if B is present.

2. The precursor compound according to claim 1, characterized in that TV= 。 3. The precursor compound according to claim 1 or 2, characterized in that B=does not exist, , , or .

4. The precursor compound according to claim 1, 2 or 3, characterized in that L1= , where m=1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

5. The precursor compound according to claim 4, characterized in that m=4。 6. The precursor compound according to any one of claims 1 to 5, characterized in that L2= , where n=1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

7. The precursor compound according to claim 6, characterized in that n=4。 8. The precursor compound according to any one of claims 1 to 7, characterized in that B= 。 9. The precursor compound according to any one of claims 1 to 7, characterized in that B= 。 10. The precursor compound according to any one of claims 1 to 7, characterized in that B= 。 11. The precursor compound according to any one of claims 1 to 7, characterized in that B= 。 12. The precursor compound according to claim 1, characterized in that It has the structure 。 13. The precursor compound according to claim 1, characterized in that It has the structure 。 14. The precursor compound according to claim 1, characterized in that It has the structure 。 15. The precursor compound according to claim 1, characterized in that It has the structure 。 16. The precursor compound according to claim 1, characterized in that It has the structure 。 17. A radioactive tracer comprising a precursor compound according to any one of claims 1 to 16 and a radioactive isotope complexed with the precursor compound 68 Ga.

Images