FAP-targeting dimeric compound, probe thereof, and use thereof

Abstract

A FAP-targeting dimeric compound, a probe thereof, and use thereof. The FAP-targeting dimeric compound has a structure represented by formula (I). The derived radionuclide probe, compared to radionuclide-labeled conventional FAPI-based probes, has a higher tumor uptake and an excellent in vivo pharmacokinetic profile.

Description

A dimer compound targeting FAP, its probe, and its applications Technical Field

[0001] This invention relates to a dimeric compound targeting FAP, its probe, and its applications, belonging to the field of radiopharmaceuticals. Background Technology

[0002] Fibroblast activation protein-α (FAP) is a type II serine protease with dipeptidyl peptidase and endopeptidase activities, specifically expressed by activated fibroblasts. In the tumor stroma, tumor-associated fibroblasts (CAFs) stably express FAP in large quantities and play a crucial role in promoting tumor growth, invasion, metastasis, and immunosuppression. CAF overexpression of FAP promotes tumor development and metastasis by influencing extracellular matrix remodeling, intracellular signal transduction, angiogenesis, epithelial-mesenchymal transition, and immunosuppression. FAP is overexpressed in malignant tumors such as breast cancer, colorectal cancer, pancreatic cancer, gastric cancer, lung cancer, bladder cancer, and ovarian cancer, while it is not expressed or is expressed at low levels in normal tissues. For example, in women with a high incidence of breast cancer, CAFs account for 50-70% of the cells in the tumor microenvironment. Given the widespread high expression of FAP in tumor tissues and its important physiological role, FAP has become a high-potential target for tumor diagnosis and treatment.

[0003] Radionuclide-labeled quinoline-based fibroblast activating protein inhibitors (FAPIs) have made significant progress in the field of precision tumor imaging. For example, [ 68 Ga]-FAPI-02、[ 68 Ga]FAPI-04、[ 68 Ga]FAPI-46 and [ 18 PET / CT imaging agents such as FAPI-74 have enabled tumor-specific imaging of over 30 different types. However, existing radionuclide-labeled FAPIs suffer from rapid clearance but low tumor uptake, hindering the development of targeted radiotherapy drugs. 18 F-labeled FAPI nuclide probes have poor pharmacokinetic properties, for example... 18 F-FAPI-42 has a high hepatobiliary metabolic rate, which can affect the imaging results of abdominal tumors. 18 F-FAPI-74 (clinical phase II) also presents with hepatobiliary and intestinal metabolic issues, which negatively impacts the detection of related lesions. Existing... 177 Lu-labeled FAPI-based small molecule probes generally suffer from rapid clearance rates, which is highly detrimental to therapeutic drugs.

[0004] Homodimerization can enhance probe affinity, enabling tumor cells to achieve high specificity and internalization rates, and prolonging retention time. This is an effective strategy for developing targeted radiotherapy drugs. Although many research groups have made numerous attempts, physiological high uptake by the kidneys, blood pools, liver, salivary glands, or pancreas often exists, affecting the detection rate at lesion sites and hindering the development of targeted radiotherapy drugs. Therefore, it is necessary to develop novel radionuclide-labeled dimeric FAPI inhibitors, optimize their pharmacokinetic properties, reduce non-physiological uptake, improve tumor uptake and retention time, and develop novel probes suitable for clinical imaging and treatment. Currently, no highly effective solutions have been proposed to address the problems in these technologies.

[0005] Summary of the Invention

[0006] Purpose of the invention: The technical problem to be solved by the present invention is to provide a dimeric compound targeting FAP with high tumor uptake rate and excellent in vivo metabolic kinetic properties, as well as its probe and application.

[0007] Technical Solution: To solve the above-mentioned technical problems, the present invention provides a dimer compound targeting FAP or its pharmaceutically acceptable salt, hydrate, solvate, isomer, or corresponding radioactive element labeling compound, wherein the FAP-targeting dimer compound has the following structure:

[0008] R1 and R2 are independently selected from hydrogen, deuterium, or fluorine;

[0009] R3 is selected from cyano, dihydroxyboron, or chloroacetyl;

[0010] R4 is selected from hydrogen, deuterium, methyl, ethyl, or cyclopropyl;

[0011] Ar is selected from optionally substituted 4-quinolone or 4-quinolone aromatic ring 4-, 5-, or 6-membered aliphatic ring hydrocarbon (heterocyclic) ring, wherein the 4-quinolone aromatic ring is optionally substituted with hydrogen, halogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, hydroxy or phenyl.

[0012] R5, R6, R7, and R8 are each independently selected from hydrogen, fluorine, chlorine, or methyl;

[0013] L1 and L2 are independently selected from -NH- or based on -(CH2). n- substitution structures, where n is an integer from 1 to 20, wherein each -CH2- is individually replaced with or without -O-, -NH-, -(CO)-, -NH(CO)-, -CH(NH2)-, -(CO)O-, -(CO)NH-, the condition for substitution is that no two adjacent -CH2- groups are replaced, and side chains spliced ​​together by different reactions are included;

[0014] Y is selected from any of the following:

[0015] Where Q is based on -(CH2) p - substitution structure, where p is an integer from 1 to 20, wherein each -CH2- is individually replaced with or without -O-, -NH-, -(CO)-, -NH(CO)-, -CH(NH2)-, -(CO)O-, -(CO)NH-, and the condition for substitution is that no two adjacent -CH2- groups are replaced;

[0016] Z represents the bifunctional chelating group portion of the nuclide, and the bifunctional chelating agent is selected from […]. 18 F, 64 Cu、 68 Ga、 89 Zr、 90 Y、 111 In、 177 Lu、 188 Re、 212 Bi、 211 At、 212 Pb, 225 Ac can be any group that performs bifunctional chelation coordination.

[0017] Wherein, the Ar is selected from the substituted 4-quinolone group, which is selected from any of the following structures:

[0018] Wherein, L1 and L2 are independently selected from any of the following structures:

[0019] Z is selected from DOTA, DOTAGA, NOTA, NODA, NOTAGA, DOTP, TETA, ATSM, PTSM, EDTA, EC, HBEDCC, DTPA, BAPEN, Df, DFO, TACN, NO2A, NOMAM, CB-DO2A, Cyclen, DO3A, DO3AP, MAS3, MAG3, or isonitriles.

[0020] Z is selected from any of the following structures:

[0021] The compound described herein has any of the following structures:

[0022] The present invention also provides a method for preparing the radionuclide-labeled targeted FAP dimer compound, comprising the following steps: reacting the targeted FAP dimer compound of the present invention with a compound containing a radionuclide according to an existing wet or lyophilized labeling method, thereby preparing the radionuclide-labeled targeted compound.

[0023] The radioactive nuclide is selected from isotopes that emit alpha rays, isotopes that emit beta rays, isotopes that emit gamma rays, isotopes that emit Auger electrons, or isotopes that emit X-rays.

[0024] Further preferably, the radionuclide is selected from... 18 F, 51 Cr 64 Cu、 67 Cu、 67 Ga、 68 Ga、 89 Zr、 111 In、 186 Re、 188 Re、 139 La、 140 La、 175 Yb、 153 Sm、 166 Ho、 86 Y、 90 Y、 149 Pm, 165 Dy、 169 Er、 177 Lu、 47 Sc、 142 Pr, 159 Gd, 212 Bi、 213 Bi、 72 As、 72 Se、 97 Ru、 109 Pd, 105 Rh、 101m Rh、 119 Sb, 128 Ba、 123 I, 124 I, 131 I, 197 Hg, 211 At、 151 Eu、 153 Eu、 169 Eu、201 TI, 203 Pb, 212 Pb, 198 Au、 225 Ac、 227 Th or 199 Any one of Ag.

[0025] More preferably, the radioactive nuclide is 18 F, 64 Cu、 68 Ga、 89 Zr、 90 Y、 111 In、 177 Lu、 188 Re or 225 Ac.

[0026] The present invention also provides a radionuclide-labeled dimer compound targeting fibroblast activation proteins, which is obtained by labeling the compound with a radionuclide; wherein the radionuclide is selected from isotopes that emit alpha rays, isotopes that emit beta rays, isotopes that emit gamma rays, isotopes that emit Auger electrons, or isotopes that emit X-rays.

[0027] The present invention also provides a kit comprising the FAP-targeting dimer compound or any pharmaceutically acceptable tautomer, racemate, hydrate, solvate, or salt thereof, or the FAP-targeting dimer compound labeled with the radionuclide.

[0028] The present invention also provides the use of the aforementioned FAP-targeting dimer compound, the aforementioned radionuclide-labeled fibroblast activation protein-targeting dimer compound, or the aforementioned kit in the preparation of medicaments or reagents for diagnosing and / or treating diseases characterized by fibroblast activation protein overexpression.

[0029] The diseases characterized by overexpression of fibroblast activation proteins include cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling, or scarring.

[0030] Preferably, the disease is selected from breast cancer, pancreatic cancer, thyroid cancer, small intestine cancer, colon cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, liver cancer, esophageal cancer, stomach cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma, bladder cancer, bile duct cancer, kidney cancer, neuroendocrine tumors, carcinogenic osteomalacia, sarcoma, primary unknown cancer, thymic cancer, glioma, astrocytoma, cervical cancer, prostate cancer, and testicular cancer.

[0031] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: 1. The present invention provides 18F-labeled radioactive probe, in conjunction with 18 In head-to-head experiments, F-FAPI-74 showed significantly superior performance compared to other drugs in terms of tumor uptake and in vivo pharmacokinetic properties. 18 The effects of F-FAPI-74; 2. 18 The tumor uptake rate of the F-labeled radioactive probe is 18 It is twice that of F-FAPI-74 and is mainly excreted by the kidneys, with good metabolism in the body, making it very promising for clinical translation; 3. Derived from the novel framework of this invention 68 Ga-labeled radionuclide probes also exhibit high tumor uptake rates and good in vivo metabolic kinetics; 4. The invention provides... 177 The novel FAPI dimer compound with Lu-labeled backbone has a relatively higher tumor uptake rate and tumor retention time; 5. The radionuclide probe derived from the novel FAPI backbone provided by this invention has higher tumor uptake and superior in vivo metabolic kinetic properties compared with traditional FAPI-based probes labeled with radionuclides. Attached Figure Description

[0032] Figure 1 shows the mass spectrum of compound a7;

[0033] Figure 2 is the mass spectrum of compound a9;

[0034] Figure 3 is the mass spectrum of compound 1;

[0035] Figure 4 is the mass spectrum of compound 6;

[0036] Figure 5 shows the mass spectrum of compound b5;

[0037] Figure 6 is the mass spectrum of compound b6;

[0038] Figure 7 is the mass spectrum of compound 7;

[0039] Figure 8 is the mass spectrum of compound 8;

[0040] Figure 9 is the mass spectrum of compound 9;

[0041] Figure 10 is the mass spectrum of compound 10;

[0042] Figure 11 is 18 F-labeled compound 6 and 18 Head-to-head comparison of F-FAPI-74 MicroPET images: A: Intravenous injection 18 MicroPET images of U87MG tumor-bearing mice at different time points after F-labeled compound 6, B: intravenous injection. 18 MicroPET images of U87MG tumor-bearing mice at corresponding time points after F-FAPI-74;

[0043] Figure 12 is 68 Ga-labeled compound 4 in a MicroPET image of a U87MG tumor-bearing mouse;

[0044] Figure 13 is 177 MicroSPECT image of Lu-labeled compound 3 in U87MG tumor-bearing mice. Detailed Implementation

[0045] The technical solution of the present invention will be further described below with reference to the accompanying drawings. Compounds a1, a3, a6, a8, b1, and b4 were purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd., a10 and b7 were purchased from Xi'an Kangfuno Biotechnology Co., Ltd., and compound b2 was purchased from Jiangsu Aikon Biomedical R&D Co., Ltd.

[0046] Example 1: Preparation of Compound 1:

[0047] Synthesis route:

[0048] 1. Synthesis of compound a2:

[0049] Dissolve 319 mg (1 mmol) of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazin-3-quinolinecarboxylic acid a1 in 20 mL of tetrahydrofuran solution (tetrahydrofuran:water = 1:1, v / v), add 0.65 mL of 2 M NaOH solution, stir at room temperature until clear, add (Boc)2O (226.8 mg, 1.05 mmol), and stir overnight at room temperature. After the reaction is complete, concentrate under vacuum to remove THF, adjust the pH to 7 with citric acid, and a white solid precipitates. Filter, wash three times with 10 mL of water, and dry under vacuum to obtain 410 mg of white solid (a2), yield 98%.

[0050] 2. Synthesis of compound a4:

[0051] Dissolve a2 (41.9 mg, 0.1 mmol), (S)-4,4-difluoro-1-glycylpyrrolidine-2-carboxynitrile a3 (20.8 mg, 0.11 mmol) in 1 mL of N,N-dimethylformamide (DMF), add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 49.4 mg, 0.13 mmol) and N-ethyldiisopropylamine (DIPEA, 69.5 μL, 0.4 mmol), and react at room temperature for 2 h. The reaction was monitored by TLC until complete, and the reaction solution was concentrated. The solution was dissolved in ethyl acetate, washed successively with water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The solution was then purified by column chromatography using a wet loading method to obtain compound a4 (38.4 mg, 65% yield).

[0052] 3. Synthesis of compound a5:

[0053] a4 (59.0 mg, 0.1 mmol) was added to a mixed solution (TFA:DCM = 1:2, v / v), and reacted at room temperature for 1 h. The reaction solution was concentrated and purified by C18 reversed-phase liquid chromatography (10% acetonitrile aqueous solution was increased to 50% proportionally, the acetonitrile content was increased by 1% per minute, and the flow rate was 2 mL / min). The solution was then freeze-dried to obtain compound a5 (46.6 mg, yield 95%).

[0054] 4. Synthesis of compound a7:

[0055] Dissolve a5 (49.0 mg, 0.1 mmol) and tert-butyloxycarbonyl 6-aminohexanoic acid a6 (25.4 mg, 0.11 mmol) in 1 mL of dimethyl sulfoxide (DMSO), add HATU (49.4 mg, 0.13 mmol) and DIPEA (69.5 μL, 0.4 mmol), and react at room temperature for 2.5 h. The reaction was monitored by TLC until complete, and the reaction solution was concentrated. The solution was dissolved in ethyl acetate, washed successively with water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The solution was then subjected to wet loading and column chromatography for purification, yielding a solid compound. The solid compound was added to a mixed solution (TFA:DCM = 1:2, v / v), reacted at room temperature for 1 h, the reaction solution was concentrated, and purified by C18 reversed-phase liquid chromatography (10% acetonitrile aqueous solution was increased proportionally to 50%, with an acetonitrile content increased by 1% per minute, flow rate 2 mL / min). The solution was then freeze-dried to give compound a7 (38.0 mg, yield 63%). MS: [M+H] + =604.37. The mass spectrum of compound a7 is shown in Figure 1.

[0056] 5. Synthesis of compound a9:

[0057] Dissolve a7 (132.7 mg, 0.22 mmol) and Boc-L-glutamic acid a8 (24.8 mg, 0.1 mmol) in 1 mL DMSO, add HATU (49.4 mg, 0.13 mmol) and DIPEA (69.5 μL, 0.4 mmol), and react at room temperature for 3 h. The reaction was monitored by TLC until complete, and the reaction solution was concentrated. Ethyl acetate was added to dissolve the compound, and the mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The mixture was then loaded onto a wet plate and purified by column chromatography to obtain a solid compound. The solid compound was added to a mixed solution (TFA:DCM = 1:2, v / v), reacted at room temperature for 1 h, and the reaction solution was concentrated. The mixture was then purified by C18 reversed-phase liquid chromatography (10% acetonitrile aqueous solution was increased proportionally to 50%, with an acetonitrile content increasing by 1% per minute at a flow rate of 2 mL / min). The purified compound was lyophilized to obtain compound a9 (81.6 mg, yield 62%). MS: M / 2 = 660.33. The mass spectrum of compound a9 is shown in Figure 2.

[0058] 6. Synthesis of Compound 1:

[0059] Dissolve a9 (131.7 mg, 0.1 mmol) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid 1-(2,5-dioxo-1-pyrrolyl) ester a10 (50.1 mg, 0.1 mmol) in 1.5 mL of DMSO, add DIPEA (69.5 μL, 0.4 mmol), and react at room temperature for 4 h. Purify by C18 reversed-phase liquid chromatography (10% acetonitrile aqueous solution increased proportionally to 50%, acetonitrile content increased by 1% per minute, flow rate 2 mL / min), and freeze-dry to obtain compound 1 (136.4 mg, yield 80%). MS: M / 2 = 853.61. The mass spectrum of compound 1 is shown in Figure 3.

[0060] Example 2: Preparation of compound 7:

[0061] Synthesis route:

[0062] 1. Synthesis of compound b3:

[0063] 3-tert-butoxycarbonylaminoglutaric acid b1 (24.7 mg, 0.1 mmol) and amino-pentaethylene glycol-azide b2 (52.4 mg, 0.2 mmol) were dissolved in 1 mL of DMF. HATU (98.8 mg, 0.26 mmol) and DIPEA (104.3 μL, 0.6 mmol) were added, and the mixture was reacted at room temperature for 4 h. The reaction was monitored by TLC until complete, and the reaction solution was concentrated. Ethyl acetate was added to dissolve the compound, and the mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The mixture was then loaded onto a wet plate and purified by column chromatography to obtain a solid compound. The solid compound was added to a mixed solution (TFA:DCM = 1:2, v / v), and the mixture was reacted at room temperature for 1 h. The reaction solution was concentrated, purified by C18 reversed-phase liquid chromatography, and lyophilized to obtain compound b3 (41.32 mg, 65% yield).

[0064] 2. Synthesis of compound b5:

[0065] Compound a5 (49.0 mg, 0.1 mmol) and 4-pentynoic acid b4 (10.8 mg, 0.11 mmol) were dissolved in 1 mL of DMSO. HATU (49.4 mg, 0.13 mmol) and DIPEA (69.5 μL, 0.4 mmol) were added, and the mixture was reacted at room temperature for 4 h. The mixture was purified by C18 reversed-phase liquid chromatography and freeze-dried to give compound b5 (41.04 mg, 72% yield). MS: [M+H] + =571.46. The mass spectrum of compound b5 is shown in Figure 5.

[0066] 3. Synthesis of compound b6:

[0067] Prepare Cu by mixing CuSO4·5H2O and sodium vitamin C. + Aqueous solution. Dissolve b3 (63.6 mg, 0.1 mmol) and b5 (114.1 mg, 0.2 mmol) in 1.5 mL of DMSO solution (DMSO:H2O = 1:1, v / v), and add a catalytic amount of Cu. + The aqueous solution was reacted overnight at room temperature. The reaction was confirmed to be complete by TLC. The compound was purified by C18 reversed-phase liquid chromatography and freeze-dried to give compound b6 (138.6 mg, yield 78%). MS: MS / 2 = 889.60. The mass spectrum of compound b6 is shown in Figure 6.

[0068] 4. Synthesis of Compound 7:

[0069] Compound b6 (177.6 mg, 0.1 mmol) and Nota-NHS ester b7 (40.0 mg, 0.1 mmol) were dissolved in 1 mL of DMSO, and DIPEA (69.5 μL, 0.4 mmol) was added. The mixture was reacted at room temperature for 4 h. After purification by C18 reversed-phase liquid chromatography, compound 1 (156 mg, 85% yield) was obtained by freeze-drying. The mass spectrum of compound 7 is shown in Figure 7.

[0070] Example 3: Preparation of compounds 2-6, 8-10:

[0071] Compounds 2-6 were prepared according to Example 1, using methods well-known in the art, replacing the 6-aminohexanoic acid linker with equimolar amounts of polyethylene glycol and glycine linkers, and replacing the DOAT-NHS ester with equimolar amounts of NOA-NHS ester, under the same reaction time, temperature, and post-treatment process, to obtain compounds 2-6. The mass spectrum of compound 6 is shown in Figure 4.

[0072] Compounds 8-10 were prepared according to Example 2, by replacing NOAT-NHS ester with equimolar amounts of NOAT-NHS ester and DOTA-NHS ester using methods well-known in the art, under the same reaction time, temperature, and post-treatment process, to obtain compounds 8-10. The mass spectra of compounds 8-10 are shown in Figures 8-10.

[0073] Example 4: Radioactivity 18 Preparation of F-labeled complexes:

[0074] 2-10GBq 18 F-ions (Nanjing Atomic High-Tech Pharmaceutical Co., Ltd.) were dissolved in 4 mL of water and captured on an anion exchange column (Waters Accel Plus QMA Light cartridge, pre-activated with 5 mL of 0.5 M NaOAc (pH 3.9) and 10 mL of water). 18 F-ions were then eluted with 0.30 mL of 0.5 M NaOAc (pH 3.9). This solution was incubated with 6 μL of AlCl3 aqueous solution (10 mM) and 300 μL of DMSO at room temperature for 5 minutes, followed by the addition of 20 μL of compound 6 solution (4 mM). The reaction was carried out at 95 °C for 15 minutes, cooled to room temperature, diluted with water to 5 mL, and processed by solid-phase extraction (Waters Oasis HLB Plus Light cartridge). The final product was eluted with 0.5 mL of ethanol and 5 mL of 0.9% physiological saline, and after addition of phosphate buffer, sterilized and filtered to obtain radioactive... 18 F-labeled complex 6.

[0075] Example 5: Radioactivity 68 Preparation of Ga-labeled complexes:

[0076] By using 1.00 mL 68 Ge / 68 Ga generator eluent (China Isotope & Radiation Corporation) (0.6M hydrochloric acid; 1.2 GBq) was added to a mixture of 15 μL of Compound 4 solution (4 mM aqueous solution), 310 μL of sodium acetate (2.5 M aqueous solution), and 0.50 mL of ethanol, achieving [the desired effect]. 68 The chelation of Ga was performed. After incubation at room temperature for 15 minutes, the reaction was carried out according to the solid-phase extraction method described in Example 4 to obtain radioactive Ga. 68 Ga-labeled complex 4.

[0077] Example 6: Radioactivity 177 Preparation of Lu-labeled complexes:

[0078] Dissolve 100 μg of compound 3 in 1 mL of 0.25 M sodium acetate solution; then dissolve the compound in 0.05 M HCl solution. 177 LuCl3 solution (100 mCi) was diluted to 4 mL and reacted in a reaction flask at 90 °C for 30 min. After cooling, the liquid in the reaction flask was forced into a waste bottle through a C18 column (pre-activated: rinsed with 5 mL of 70% ethanol followed by 5 mL of 0.9% NaCl). The reaction flask was then rinsed with 5 mL of physiological saline, and the rinsing solution was forced into the waste bottle through a C18 column. The product was then washed: 1 mL of 60% ethanol was injected into the product bottle through a C18 column and a sterile filter membrane, followed by 5 mL of physiological saline, yielding a radioactive product. 177 Lu-labeled complex 3.

[0079] Example 7: Radioactivity 90 Preparation of Y-labeled complexes:

[0080] Take 40 μg of compound 3 into a 2 mL vial, and add 0.2 mL of 4 M sodium acetate buffer (pH 4.5) and 0.1 mL of... 90 YCl3 solution (50 mCi, 0.01 M hydrochloric acid solution). The reaction mixture was placed in a metal bath at 95 °C and reacted for 20 min. After the reaction was completed, the reaction was processed according to the solid-phase extraction method described in Example 6. The labeled substance was diluted with 2 mL of physiological saline and filtered through a 0.22 μm microporous membrane before being stored in a sterile vacuum bottle for later use.

[0081] Example 8: Application Effect Analysis:

[0082] The product prepared according to the method in Example 4 18F-labeled complex 6 (0.1 mCi) was injected intravenously into U87MG tumor-bearing mice (Jiangsu Huachuang Xinno Pharmaceutical Technology Co., Ltd.). MicroPET-CT imaging was then performed at 0.5 h, 1 h, and 2 h post-administration under 1.5% isoflurane anesthesia. Figure 11A shows the intravenous injection... 18 MicroPET images of U87MG tumor-bearing mice at different time points after F-labeled compound 6, Figure 11B shows intravenous injection. 18 MicroPET images of U87MG tumor-bearing mice at the corresponding time points after F-FAPI-74. Figure 11 shows that in the head-to-head experiment... 18 The F-labeled compound 6 is rapidly and efficiently taken up at tumor sites, but is taken up in very low amounts in most normal organs, and is primarily cleared by the kidneys. This contrasts with compounds currently used in phase II clinical trials. 18 Compared to F-FAPI74, 18 The F-labeled compound 6 showed a tumor uptake rate of 22% ID / g in U87MG tumor-bearing mice after 1 hour, while the corresponding 18 F-FAPI-74 showed an uptake rate of only 10.5% ID / g in tumors. Furthermore... 18 F-FAPI-74 exhibits significant biliary and intestinal metabolism, resulting in a high abdominal background, which affects the detection of related lesions. The invention provides... 18 Novel F-labeled scaffold compounds exhibit higher tumor uptake rates and superior in vivo metabolic kinetics, demonstrating potential for clinical application.

[0083] The product prepared according to the method in Example 5 68 Ga-labeled complex 4 was injected intravenously into U87MG tumor-bearing mice (0.1 mCi), followed by MicroPET-CT imaging at 0.5 h, 1 h, and 2 h post-administration under 1.5% isoflurane anesthesia. Figure 12 shows the mouse images after intravenous injection. 68 MicroPET images of U87MG tumor-bearing mice at different time points after administration of Ga-labeled compound 4, showing the novel scaffold derived from this invention. 68 Ga-labeled nuclide probes exhibit very low uptake in most normal organs and are rapidly cleared primarily by the kidneys. They also show high tumor uptake rates (18% ID / g in mice at 1 hour) and favorable in vivo metabolic kinetics.

[0084] The product prepared according to the method in Example 6 177 Lu-labeled complex 3 was injected intravenously into U87MG tumor-bearing mice (0.5 mCi), followed by MicroSPECT imaging at 1 h, 2 h, 12 h, 24 h, 48 h, and 72 h post-administration under 1.5% isoflurane anesthesia. Figure 13 shows mouse images after intravenous injection.177 MicroSPECT images of U87MG tumor-bearing mice at different time points after Lu-labeled compound 3, derived from the novel scaffold of this invention. 177 Lu-labeled radionuclide probes exhibit highly high tumor targeting and very low background signal, are rapidly cleared primarily by the kidneys, and also demonstrate high tumor uptake rates (15% ID / g in mice after 1 hour) and favorable in vivo metabolic kinetics. They possess potential for clinical therapeutic applications.

Claims

1. A dimeric compound targeting FAP, characterized in that, The compound is any of the following structures:

2. A radionuclide labeled FAP-targeting dimeric compound, characterized in that, which is labeled with a radionuclide selected from the group consisting of 18 F, 68 Ga or 177 Lu.

3. A kit or pharmaceutical composition, characterized in that, which comprises the FAP-targeting dimeric compound of claim 1 or the radionuclide-labeled FAP-targeting dimeric compound of claim 2.

4. Use of the FAP-targeting dimeric compound of claim 1, the radionuclide-labeled FAP-targeting dimeric compound of claim 2 or the pharmaceutical composition of claim 3 for the preparation of a diagnostic agent for a disease characterized by overexpression of fibroblast activation protein; the disease characterized by overexpression of fibroblast activation protein includes liver cancer, lung cancer, colorectal cancer, cholangiocarcinoma, pancreatic islet cancer, esophageal cancer, gastric cancer, thyroid cancer, head and neck cancer, breast cancer, cervical cancer.

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