Glycopeptide targeting tumor-related fibroblast activation protein, radionuclide marker and use thereof

Abstract

A FAP glycopeptide as represented by Formula (I), and a radionuclide marker thereof and the use thereof. The FAP glycopeptide is obtained by modifying a linker portion that forms a cyclic peptide on the basis of a polypeptide FAP-2286 structure, and further introducing mono- or di-saccharide molecules. After being marked with radionuclides, the glycopeptide shows superior tumor uptake and lower liver uptake compared to FAP-2286, resulting in better imaging outcomes, facilitating the development of candidate radionuclide pharmaceuticals with further research value, and contributing to the ultimate goal of developing FAP-targeted cyclic peptide radiopharmaceuticals with independent intellectual property rights. Drawing_references_to_be_translated

Description

A class of glycopeptides and radionuclide markers targeting tumor-associated fibroblast activation proteins and their applications Technical Field

[0001] This invention relates to the field of peptide technology that targets tumor-associated fibroblast activation protein (FAP), specifically to a class of FAP glycopeptides, their radionuclide labels, and their applications. Background Technology

[0002] The development of radiopharmaceuticals has become an important direction in new drug research and development both internationally and domestically, attracting the attention of numerous research institutions, enterprises, and the market. In particular, therapeutic radiopharmaceuticals targeting tumors, which can effectively diagnose and treat tumors with radionuclide therapy, represent a cutting-edge direction in current drug research. Examples include Lutathera (lutetium oxide octreotide), a radiolabeled peptide targeting the somatostatin receptor, and Pluvicto (formerly known as...), a radioactive small molecule targeting prostate-specific membrane antigen (PSMA). 177 Lu-PSMA-617 was also approved for marketing by the US FDA in 2018 and 2022, respectively.

[0003] Malignant tumors comprise both tumor cells and their surrounding microenvironment. The tumor microenvironment, also known as the tumor stroma, includes various non-malignant cells that collectively shape an environment conducive to tumor growth. Non-cancer stromal cells, through the production of various growth factors, chemokines, and cytokines, promote extracellular matrix remodeling, induce angiogenesis, induce cell migration, develop drug resistance, and evade immune surveillance, thereby promoting tumor invasion and metastasis. Studies have confirmed that cancer-associated fibroblasts (CAFs) are a major component of non-cancer stromal cells in the tumor microenvironment, and fibroblast activation protein (FAP) is widely expressed on the surface of CAFs, making it a highly promising tumor biomarker.

[0004] FAP is a membrane-bound glycoprotein belonging to the dipeptidyl peptidase 4 (DPP4) family. It possesses both dipeptidyl peptidase and endopeptidase activities and shares 52% protein homology with DPP4. This protein consists of 760 amino acids, including a short intracellular region (6 amino acids), a transmembrane region (20 amino acids), and a large extracellular region (734 amino acids). In normal tissues, FAP is generally not expressed or expressed at very low levels, but it is overexpressed in stromal fibroblasts (CAFs) and is also highly expressed in over 90% of epithelial tumors. It can directly promote the proliferation, migration, and invasion of mesenchymal fibroblasts and other cell types, leading to tumor angiogenesis, extracellular matrix degradation, and evasion of immune surveillance.

[0005] Recent studies have shown that FAP is a very promising target for radiotherapy-guided therapies for tumors. The University of Heidelberg in Germany has successfully developed a series of small molecule probes targeting FAP, such as FAPI-02 and FAPI-04, and has used them... 68 Ga and 177 Lu-labeled radiopharmaceuticals have become a form of integrated diagnostic and therapeutic radiopharmaceutical. Clemens Kratochwil et al. evaluated a total of 80 patients. 68 Ga-FAPI PET / CT scans were used by these patients. 18 F-FDG imaging or other traditional imaging methods cannot provide accurate diagnosis, but when drug administration is involved... 68 Following Ga-FAPI-04, 54 primary tumors and 229 metastatic lesions were detected among the 28 cancer types included in the analysis [Kratochwil C., et al.(68)Ga-FAPIPET / CT:Tracer Uptake in 28Different Kinds of Cancer.J Nucl Med,2019,60(6),801-805.]. 18 Compared to F-FDG, 68 Ga-FAPI-04 can detect more primary and metastatic tumor lesions. This probe can accurately diagnose and stage metastatic lesions of various tumors, showing great promise for application and potentially becoming a widely used screening and radionuclide therapy tool in clinical oncology. Furthermore, the imaging procedure of this probe is simplified, requiring no fasting or blood sugar control, making it more acceptable to patients.

[0006] FAP-2286, a cyclic peptide probe targeting FAP, consists of a 7-amino acid cyclic peptide and a metal ligand moiety, with an affinity ranging from 0.4 to 1.4 nM. It is compatible with small molecule FAP inhibitor probes. 177 Compared to the Lu-FAPI series 177 Lu-FAP-2286 still showed a high tumor uptake signal 72 hours after administration, while FAPI-46 showed only a weak signal in tumors. Therefore, radiotherapy drugs based on the cyclic peptide FAP-2286 have greater research and development potential in tumor treatment.

[0007] at present, 68 Ga-FAP-2286 and 177 The study of Lu-FAP-2286 is currently in Phase I / II clinical trials (NCT04939610). Although 68 Ga-FAP-2286 and 177Lu-FAP-2286 exhibits high uptake in tumors with high FAP expression, but its retention time in the kidneys is relatively long. At 3h, 24h, and 72h after administration, its uptake levels are 2.2% ID / g, 1.1% ID / g, and 0.6% ID / g, respectively, all higher than the small molecule probe FAPI-46, which can easily cause radiotoxic nephropathy or increase the renal burden [Zboralski D., et al. Preclinical evaluation of FAP-2286 for fibroblast activation protein targeted radionuclide imaging and therapy. Eur J Nucl Med Mol Imaging, 2022, 49(11), 3651-3667.]. Although radiopharmaceuticals themselves do not cause damage to normal tissues under normal use due to small dosages, when they accumulate in large quantities and remain for a long time, the cumulative effect of long-term radioactivity can cause radiation damage to normal tissues. Furthermore, most patients receiving radiotherapy are in the late stages of cancer and have undergone radiotherapy and chemotherapy, and may have some liver and kidney dysfunction or underlying diseases.

[0008] Therefore, radiopharmaceutical research requires special attention to liver accumulation and kidney retention time, and these are important directions to consider from the outset of drug design. Thus, structural modification of this molecule to reduce accumulation in liver and kidney metabolic organs while maintaining high tumor uptake, and the development of a "best-in-class" FAP-targeting cyclic peptide radiopharmaceutical with independent intellectual property rights, has very high clinical translational value and feasibility. Summary of the Invention

[0009] This invention modifies the linker portion forming the cyclic peptide based on the structure of peptide FAP-2286, and further introduces monosaccharide or disaccharide molecules to obtain a series of novel glycopeptides. After radiolabeling, these glycopeptides exhibit superior tumor uptake and lower liver uptake compared to FAP-2286, resulting in better imaging outcomes. This facilitates the development of candidate radionuclide therapeutics with further research value, and ultimately yields a "best-in-class" FAP-targeting cyclic peptide radiopharmaceutical with independent intellectual property rights.

[0010] In one aspect, the present invention provides a compound or a salt thereof represented by formula (I):

[0011] G can independently represent a monosaccharide, disaccharide, or trisaccharide group, or a phenyl group substituted with a monosaccharide, disaccharide, or trisaccharide group;

[0012] L represents a dipeptide or tripeptide linker;

[0013] M represents a metal chelating group that can bind to radioactive nuclides;

[0014] n is an integer from 1 to 3, especially 1 or 2.

[0015] In some embodiments, G independently represents a monosaccharide group or a phenyl group substituted with a monosaccharide group.

[0016] In some implementations, G is independently selected from the following groups:

[0017] In some implementations, G is independently selected from the following groups:

[0018] In some implementations, G is independently selected from the following groups:

[0019] In some implementations, G is independently selected from the following groups:

[0020] In some implementations, G is independently selected from the following groups:

[0021] In some implementations, G is independently selected from the following groups:

[0022] In some embodiments, G is a group consisting of:

[0023] In some embodiments, L is selected from the following groups:

[0024] In some embodiments, L is selected from the following groups:

[0025] In some embodiments, L is a group consisting of:

[0026] In some embodiments, M and L are linked by an amide bond (i.e., M is attached to the NH terminal of L), and M is selected from groups with the following structures:

[0027] In some embodiments, M is a group selected from the following structures:

[0028] In some embodiments, M is a group selected from the following structures:

[0029] More preferably, M is

[0030] More preferably, M is

[0031] More preferably, M is

[0032] Here, "---" indicates that the substituent is attached at this location.

[0033] In some implementations, n is an integer of 1 or 2; in some implementations, n is an integer of 1; in some implementations, n is an integer of 2.

[0034] In some implementations...

[0035] G is independently selected from the following groups:

[0036] L is selected from the following groups:

[0037] M is a group selected from the following structures:

[0038] n is an integer that is either 1 or 2.

[0039] In some implementations...

[0040] G is independently selected from the following groups:

[0041] L is selected from the following groups:

[0042] M is

[0043] n is an integer that is either 1 or 2.

[0044] In some implementations...

[0045] G is independently selected from the following groups:

[0046] L is selected from the following groups:

[0047] M is

[0048] n is an integer that is either 1 or 2.

[0049] In some implementations...

[0050] G is selected from the following groups:

[0051] L is selected from the following groups:

[0052] M is

[0053] n is an integer where n is 1.

[0054] In some implementations...

[0055] G represents the following groups:

[0056] L represents the following groups:

[0057] M is

[0058] In some embodiments, the compound of formula (I) is selected from:

[0059] In some embodiments, the compound of formula (I) is:

[0060] Another aspect of the present invention provides a radionuclide label comprising the compounds described herein or salts thereof, and a radionuclide.

[0061] In some embodiments, the radionuclide is selected from radiodiagnostic and radiotherapy radionuclides, but is not limited thereto. Radiodiagnostic radionuclide markers can be used for tumor imaging, which is beneficial for tumor diagnosis, while radiotherapy radionuclide markers can be used for the diagnosis and treatment of tumors.

[0062] In some embodiments, the radiodiagnostic nuclide is selected from... 86 Y、 18 F, 51 Mn, 52m Mn, 52g Mn, Al[ 18 F]、 64 Cu、 67 Ga、 68 Ga、 89 Zr、 99m Tc, 111 In、 123 I, 124 I, 125 I, 44 Sc、 47 Sc、 203 Any one or more of Pb; preferred 86 Y、 18F, 51 Mn, 52m Mn, 52g Mn, Al[ 18 F]、 64 Cu、 67 Ga、 68 Ga、 89 Zr、 99m Tc, 111 In、 123 I, 124 I, 125 I, 44 Sc、 47 Any one or more of Sc; preferred 86 Y, Al[ 18 F]、 64 Cu、 68 Ga、 89 Zr、 99 mTc, 124 I, 203 Any one or more of Pb; preferred 86 Y, Al[ 18 F]、 64 Cu、 68 Ga、 89 Zr、 99 mTc, 124 Any one or more of I; more preferably 68 Ga、 203 Pb or 64 Cu; more preferred 68 Ga or 64 Cu; more preferred 68 Ga; More preferred 203 Pb; more preferred 64 Cu.

[0063] In some implementations...

[0064] The radioactive nuclide is selected from... 67 Cu、 90 Y、 125 I, 131 I, 153 Sm、 166 Ho、 177 Lu、 186 Re、 188 Re、 211 At、 212 Pb, 212 Bi、 213 Bi、 223 Ra、 225 Ac、 227 Th、 161Tb, 149 Any one or more of Tb; preferred 67 Cu、 90 Y、 125 I, 131 I, 153 Sm、 166 Ho、 177 Lu、 186 Re、 188 Re、 211 At、 212 Pb, 212 Bi、 213 Bi、 223 Ra、 225 Ac、 227 Any one or more of Th; preferred 67 Cu、 90 Y、 125 I, 131 I, 177 Lu、 227 Th、 223 Ra、 225 Ac、 211 At、 161 Tb, 149 Any one or more of Tb; preferred 67 Cu、 90 Y、 125 I, 131 I, 177 Lu、 227 Th、 223 Ra、 225 Ac、 211 Any one or more of At; more preferably 227 Th、 177 Lu、 225 Ac or 212 Pb; more preferred 177 Lu、 225 Ac or 212 Pb; more preferred 177 Lu or 212 Pb; more preferred 177 Lu; More preferred 212 Pb.

[0065] In some embodiments, the radionuclide label is:

[0066] In some embodiments, the radionuclide label is:

[0067] Another aspect of the present invention provides the use of the above-mentioned compounds or their salts or their radionuclide labels in the preparation of tumor imaging agents or antitumor drugs.

[0068] In some embodiments, the tumor is a tumor that highly expresses FAP, such as a solid tumor (especially a solid tumor that highly expresses FAP); in particular, the tumor is an epithelial tumor, sarcoma, or mesothelioma; in particular, the tumor is selected from, but is not limited to, sarcoma, mesothelioma, esophageal tumor, glioblastoma, melanoma, colorectal cancer, pancreatic cancer, lung cancer, breast cancer, gastric cancer, kidney cancer, cervical cancer, liver cancer, prostate cancer, or glottic cancer.

[0069] In some embodiments, the tumor is an epithelial tumor, preferably a sarcoma, mesothelioma, esophageal tumor, glioblastoma, colorectal tumor, pancreatic cancer, lung cancer, breast cancer, or gastric cancer.

[0070] Another aspect of the present invention relates to a compound of formula (II) or a salt thereof.

[0071] The definitions of M, L, and n are as described in this article.

[0072] In some embodiments, the compound of formula (II) is selected from:

[0073] Another aspect of the present invention relates to compounds of the following formula or salts thereof:

[0074] The compounds according to the present invention can be prepared by those skilled in the art using the synthesis methods described in the examples in combination with existing techniques. Attached Figure Description

[0075] Figure 1 is 68 PET / CT images of Ga-labeled FAP-2286 at 30 min, 1 h, and 2 h in the U87 tumor mouse model.

[0076] Figure 2 is 68 PET / CT images of Ga-labeled compound g4 at 30 min, 1 h, and 2 h in the U87 tumor mouse model.

[0077] Figure 3 is 177 Stability data for Lu-g4.

[0078] Figure 4 is 177 Lu-g4 uptake increased in HEK293-hFAP cells.

[0079] Figure 5 is 177 Tumor growth curve of Lu-g4 in HT1080-hFAP tumor-bearing mice.

[0080] Figure 6 is 177 HE sections of the liver and kidneys were obtained 21 days after Lu-g4 administration.

[0081] Figures 7A-7H show intravenous injection. 68 After Ga-labeling compound g4, whole-body PET / CT images of the human body showed that the molecules of the present invention were distributed in various tumors. Detailed Implementation

[0082] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.

[0083] Unless otherwise specified, the raw materials, reagents, and methods used in the embodiments are all conventional raw materials, reagents, and methods in the art.

[0084] Experimental materials and analytical instruments:

[0085] H-Cys(Trt)-2-Chlorotrityl Resin was purchased from Jier Biochemical (Shanghai) Co., Ltd.

[0086] C18 reversed-phase chromatography preparative system: preparative liquid chromatograph (LC-20AR), C18 column is XBridge BEH C18 column (4.6 mm x 150 mm);

[0087] The MALDI-TOF mass spectrometer is a matrix-assisted laser desorption / ionization time-of-flight mass spectrometer.

[0088] The Sep-Pak C18 column is WAT023501SEP-PAK LIGHT C18;

[0089] The biomolecular interaction instrument is model Biacore T200;

[0090] The protein is a Sino Biological Recombinant Human FAP Protein;

[0091] All reagents used for chip coupling and regeneration were purchased from Cytivo.

[0092] The instrument used to determine the radioactivity of tissue biodistribution counters is the WIZARD2 2-Detector gamma counter, model number 2470-0020;

[0093] All other reagents were purchased from Sinopharm.

[0094] Abbreviations: DCM: Dichloromethane; DMF: N,N-Dimethylformamide; HBTU: Benzotriazole-N,N,N,N-Tetramethylurea hexafluorophosphate; DIEA: N,N-Diisopropylethylamine; TFA: Trifluoroacetic acid; EDT: 1,2-Ethylenedithiol; ddH2O: Deuterium water; TIS: Triisopropylsilane; tBu-DOTA: Tri-tert-butyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.

[0095] Example 1: Synthesis of Compound a

[0096] S1: Place 0.6g of HL-Cys(Trt)-2-Chlorotrityl Resin with a degree of substitution of 0.336mmol / g into a peptide synthesizer (CS Bio, CS336X) and set the program;

[0097] S2: Resin swelling: Add about 10 mL of DMF to the reaction flask and shake for 30 min;

[0098] S3: Deprotection twice, each time adding 10 mL of DMF solution containing 20% ​​volumetric piperidine and reacting for 15 min, then washing the resin with DMF three times and DCM three times;

[0099] S4: Add the first amino acid Fmoc-L-Phe-OH: Add 4 times the molar amount of Fmoc-L-Phe-OH, 4 times the molar amount of HBTU, and 8 times the molar amount of DIEA based on the resin. Perform the condensation reaction for 3 hours, rinse the resin 3 times with DMF, and rinse the resin 3 times with DCM.

[0100] S5: Repeat S3 to S4, and connect Fmoc-L-Gln(Trt)-OH, Fmoc-L-Thr(tBu)-OH, Fmoc-L-Pro-OH, Fmoc-L-Pro-OH, and Fmoc-L-Cys(Trt)-OH in sequence;

[0101] S6: Deprotect twice, each time adding 10 mL of DMF solution containing 20% ​​piperidine and reacting for 15 min, then washing the resin with DMF three times and DCM three times.

[0102] S7: Remove the solvent and condense the mixture in 5 mL of DMF solution containing 4 times the molar amount of hexanoic acid.

[0103] S8: Resin removal: Remove the solvent, add 20 mL of lysis buffer with a volume ratio of TFA:TIS:EDT:ddH2O = 95%:2.5%:1.25%:1.25%, and react for 2.5 h;

[0104] S9: Cutting completed, solvent is removed by rotary evaporator to obtain crude peptide dissolved in TFA;

[0105] S10: Precipitation of peptides: Transfer the crude peptide dissolved in TFA to a centrifuge tube, add 10 times the volume of ice-cold ether, and then centrifuge at 4°C and 8000g to remove the solvent, and obtain the precipitated crude peptide.

[0106] S11: Dissolve 10 mg of crude polypeptide in a 1:3 (v / v) mixture of acetonitrile and dd water (ddH2O). Collect 0.5 mg of the sample in a C18 reversed-phase chromatography system to obtain the target peak solution. Set the HPLC parameters as follows: Wavelength: 210 nm and 254 nm; Flow Rate: 3 mL / min; Inj. Vol: 1 mL; Column Temp: 25 °C; Phase A: 0.1% TFA aqueous solution; Phase B: acetonitrile. Lyophilize the target peak solution to obtain compound a, which is a precursor of FAP-2286, and store at -20 °C.

[0107] Example 2: Synthesis of compounds b and b1-b4

[0108] S1: Place 0.5g of HL-Cys(Trt)-2-Chlorotrityl Resin with a degree of substitution of 0.336mmol / g into a peptide synthesizer (CS Bio, CS336X) and set the program;

[0109] S2: Resin swelling: Add about 10 mL of DMF to the reaction flask and shake for 30 min;

[0110] S3: Deprotection twice, each time adding 20% ​​piperidine DMF solution (10 mL) and reacting for 15 min, then washing the resin with DMF three times and DCM three times;

[0111] S4: Add the first amino acid Fmoc-L-Lys(Boc)-OH: Add 4 times the molar amount of Fmoc-L-Lys(Boc)-OH, 4 times the molar amount of HBTU and 8 times the molar amount of DIEA based on the resin, condense for 3 hours, rinse the resin 3 times with DMF, and rinse the resin 3 times with DCM.

[0112] S5: Repeat S3 to S4, connecting Fmoc-L-Val-OH and Fmoc-L-Met-OH in sequence;

[0113] S6: Deprotect twice, each time adding 10 mL of DMF solution containing 20% ​​piperidine and reacting for 15 min. Rinse the resin three times with DMF and three times with DCM.

[0114] S7: Remove the solvent and condense the solution into a pre-prepared DMF solution of 4 times the molar volume of tBu-DOTA.

[0115] S7: Resin removal: Remove the solvent, add pyrolysis buffer with a volume ratio of TFA:TIS:EDT:ddH2O = 95%:2.5%:1.25%:1.25%, and react for 3 hours;

[0116] S8: Cutting completed, solvent is removed by rotary evaporator to obtain crude peptide dissolved in TFA;

[0117] S7: Precipitation of peptides: Transfer the crude peptide dissolved in TFA to a centrifuge tube, add 10 times the amount of ice-cold ether, and then centrifuge at 4°C and 8000g to remove the solvent, and obtain the precipitated crude peptide.

[0118] S8: Dissolve 10 mg of crude polypeptide in a 1:3 (v / v) mixture of acetonitrile and water. Collect 0.5 mg of the sample in a C18 reversed-phase chromatography system to obtain the target peak solution. Set the HPLC parameters as follows: Wavelength: 210 nm and 254 nm; Flow Rate: 3 mL / min; Inj. Vol: 1 mL; Column Temp: 25 °C; Phase A: 0.1% TFA aqueous solution; Phase B: acetonitrile. Freeze-dry the target peak solution to obtain compound b, and store at -20 °C.

[0119] Except for replacing the amino acids to be linked in step S5 with the amino acids in Table 1 below, compounds b1 to b4 are obtained in the same manner.

[0120] Table 1

[0121] Example 3 Synthesis of compound b5

[0122] S1: 1.55 g of HL-Cys(Trt)-2-Chlorotrityl Resin with a degree of substitution of 0.322 mmol / g was placed in a polypeptide sand core reaction column;

[0123] S2: Resin swelling: Add about 10 mL of DMF to the reaction flask and purge with air for 30 min;

[0124] S3: Deprotection twice, each time adding 20% ​​piperidine DMF solution (10 mL) and reacting for 15 min, then washing the resin with DMF three times and DCM three times;

[0125] S4: Add the first amino acid Fmoc-L-Lys(Dde)-OH: Add 4 times the molar amount of Fmoc-L-Lys(Dde)-OH, 4 times the molar amount of HBTU and 8 times the molar amount of DIEA based on the resin, condense for 3 hours, rinse the resin with DMF 3 times, and rinse the resin with DCM 3 times.

[0126] S5: Repeat S3 to S4, connecting Fmoc-L-Phe-OH and Boc-Gly-OH in sequence;

[0127] S6: Remove Dde twice, each time adding 10 mL of DMF solution containing 5% hydrazine hydrate and reacting for 15 min. Rinse the resin three times with DMF and three times with DCM.

[0128] S7: Synthesis of 4-isothiocyanate phenyl-A-D-mannoside: Remove solvent, add 4-isothiocyanate phenyl-A-D-mannoside and 2 molar amounts of DIEA, and condense for 3 hours;

[0129] S8: Resin removal: Remove the solvent, add pyrolysis buffer with a volume ratio of TFA:TIS:ddH2O:anisole = 90%:2.5%:2.5%:5%, and react for 3.5 hours;

[0130] S9: Cutting completed, solvent is removed by rotary evaporator to obtain crude peptide dissolved in TFA;

[0131] S10: Precipitation of peptides: Transfer the crude peptide dissolved in TFA to a centrifuge tube, add 10 times the amount of ice-cold ether, and then remove the solvent by centrifugation to obtain the precipitated crude peptide.

[0132] S11: Dissolve 200 mg of crude polypeptide in a 1:3 (v / v) mixture of acetonitrile and water. Collect 20 mg of the sample in a C18 reversed-phase chromatography system to obtain the target peak solution. Set the HPLC parameters as follows: Wavelength: 214 nm and 254 nm; Flow Rate: 25 mL / min; Inj. Vol: 5 mL; Column Temp: 25 °C; Phase A: 0.05% TFA aqueous solution; Phase B: 0.05% TFA acetonitrile solution. Freeze-dry the target peak solution to obtain compound b5 and store at -20 °C.

[0133] Example 4 Synthesis of compound d

[0134] Compound a (3 mg, 3.363 μmol) and compound c (1 mg, 4.036 μmol) were dissolved in a 1:1 mixture of acetonitrile and dd water. Saturated sodium bicarbonate was added to adjust the pH to approximately 8. The reaction was carried out at room temperature for 3 hours, quenched with formic acid, and concentrated with nitrogen to remove excess solvent. The target peak solution was collected using a C18 reversed-phase chromatography preparative system. The HPLC parameters were set as follows: Wavelength: 210 nm and 254 nm; Flow Rate: 3 mL / min; Inj. Vol: 1 mL; Column Temp: 25 °C; Mobile phase A: 0.1% TFA aqueous solution; Mobile phase B: acetonitrile, to obtain compound d.

[0135] Example 5: Synthesis of compounds e and e1 to e4

[0136] Compound d (1 mg, 0.876 μmol) and compound b (0.8 mg, 0.876 μmol) were dissolved in 500 μL acetonitrile and 500 μL dd water. The pH was adjusted to approximately 8 with the addition of saturated sodium bicarbonate. The reaction was carried out overnight at room temperature, quenched with formic acid, and the solvent was removed by concentration. The target peak solution was collected in a C18 reversed-phase chromatography preparative system. The HPLC parameters were set as follows: Wavelength: 210 nm and 254 nm; Flow Rate: 3 mL / min; Inj. Vol: 1 mL; Column Temp: 25 °C; Mobile phase A: 0.1% TFA aqueous solution, Mobile phase B: acetonitrile, to obtain compound e.

[0137] Compounds e1 to e4 were synthesized in the same manner, except that compounds b1 to b4 were used to replace compound b, respectively.

[0138] Example 6 Synthesis of compound e5

[0139] Compound d (80 mg, 0.07 mmol) and compound b5 (53 mg, 0.07 mmol) were dissolved in 2 mL of acetonitrile and 8 mL of dd water. Saturated sodium bicarbonate was added to adjust the pH to approximately 8. The reaction was carried out overnight at room temperature, quenched with formic acid, and the solvent was removed by concentration. The target peak solution was collected in a C18 reversed-phase chromatography preparative system. The HPLC parameters were set as follows: Wavelength: 214 nm and 254 nm; Flow Rate: 25 mL / min; Inj. Vol: 5 mL; Column Temp: 25 °C; Phase A: 0.05% TFA aqueous solution; Phase B: 0.05% TFA acetonitrile solution, to obtain compound e5.

[0140] Example 7 Synthesis of compounds g and g1-10

[0141] Compound e (0.5 mg, 0.249 μmol) and compound f (0.234 mg, 0.747 μmol) were dissolved in DMF, and DIEA (0.161 mg, 1.245 mmol) was added. The mixture was reacted overnight at room temperature, diluted with dd water, and the target peak solution was collected in a C18 reversed-phase chromatography preparative system. The HPLC parameters were set as follows: Wavelength: 210 nm and 254 nm; Flow Rate: 3 mL / min; Inj. Vol: 1 mL; Column Temp: 25 °C; Mobile phase A: 0.1% TFA aqueous solution, Mobile phase B: acetonitrile, to obtain compound g.

[0142] According to Table 2 below, replace compound e with compounds e1-e4, and replace compound f with f1, f2 or f3 as follows, to obtain the corresponding compounds g1-g10 in the same way.

[0143] Table 2

[0144] Example 8: Synthesis of compound g11

[0145] Compound e5 (67 mg, 0.035 mmol, 1 eq) and compound p-NCS-Bn-TCMC (102 mg, 0.175 mmol, 3-5 eq) were dissolved in DMF, and DIEA (45 mg, 0.35 mmol, 10 eq) was added. The mixture was reacted overnight at room temperature, diluted 10 times with dd water (or the DMF was evaporated to dryness), and the target peak solution was collected in a C18 reversed-phase chromatography preparative system. The HPLC parameters were set as follows: Wavelength: 214 nm and 254 nm; Flow Rate: 25 mL / min; Inj. Vol: 5 mL; Column Temp: 25 °C; Phase A: 0.05% aqueous acetic acid; Phase B: 0.05% acetic acid in acetonitrile solution, to obtain compound g11.

[0146] Table 3 shows the MALDI-TOF data of the synthesized compounds.

[0147] Table 3

[0148] Comparative Example 1 FAP-2286

[0149] FAP-2286 (purchased from MedChemExpress) was used as a comparative example.

[0150] Example 9 68 Preparation of Ga-labeled compounds

[0151] The compounds of the present invention were prepared by the following method. 68 Ga-labeled compounds, for example, radiolabeled compounds prepared using compounds g, g4, and FAP-2286 as precursor compounds, respectively. 68 Ga-g, 68 Ga-g4 and 68 Ga-FAP-2286.

[0152] S1: Take 1 μL of the precursor compound dissolved in dd water (concentration of 10 μg / μL) into an EP tube, and add 180 μL of 3M sodium acetate to adjust the pH to 4-5;

[0153] S2: Add 400 μL of 0.6 M radioactive material. 68 Ga was reacted in an EP tube at 95°C for 10 min;

[0154] S3: After the reaction, paper chromatography was performed to determine the purity. The developing solvent was methanol:1M ammonium formate = 1:1. If the purity was not above 90%, purification was performed using a Sep-Pak C18 column. The specific procedure was as follows: first, activate with 20 mL of anhydrous ethanol, then rinse once with 20 mL of dd water. Load the radioactive sample, wash away free Ga with 20 mL of dd water, and then elute with 75% ethanol. Discard the first 500 μL of product. Each 100 μL tube was used as one tube. The radioactive dose was measured, and the tube with the highest radioactive dose was taken as the final product. 68 Ga-labeled products.

[0155] Radiolabeled compounds can be prepared using compounds g1, g2, g3, g5, g6, g7, g8, g9, g10, and g11 as precursor compounds, respectively, following the same method. 68 Ga-g1, 68 Ga-g2, 68 Ga-g3, 68 Ga-g5, 68 Ga-g6, 68 Ga-g7, 68 Ga-g8、 68 Ga-g9, 68 Ga-g10 and 68 Ga-g11.

[0156] Example 10 177 Preparation of Lu-labeled compounds

[0157] The compounds of the present invention were prepared by the following method. 177 Lu-labeled compounds, for example, preparing radiolabeled compounds using compound g4 as a precursor compound. 177 Lu-g4.

[0158] Dissolve 1 μg of precursor compound g4 in 100 μL of ultrapure water and vortex until fully dissolved; add 10 μL of sodium acetate solution (pH 5.0-5.5) to the above solution; inject 1 μL of solution containing... 177 The LuCl3 eluent (radioactivity 1-5 mCi) was immediately vortexed to mix; the mixture was incubated at 80-95℃ for 10-15 minutes; labeling results: iTLC labeling rate 100%.

[0159] Radiolabeled compounds can be prepared using compounds g, g1, g2, g3, g5, g6, g7, g8, g9, g10, and g11 as precursor compounds, respectively, following the same method. 177 Lu-g、 177 Lu-g1、 177 Lu-g2, 177 Lu-g3, 177 Lu-g5, 177 Lu-g6, 177 Lu-g7, 177 Lu-g8, 177 Lu-g9, 177 Lu-g10 and 177 Lu-g11.

[0160] Example 11 212 Preparation of Pb-labeled compounds

[0161] The compounds of the present invention were prepared by the following method. 212 Pb-labeled compounds, for example, radiolabeled compounds prepared using compound g11 as a precursor compound. 212 Pb-g11.

[0162] Take compound g11 dissolved in labeling buffer (1-4M sodium acetate, pH 5-6), and add 10-50 MBq. 212 PbCl2 solution, maintaining pH 4.5–5.5; react the mixture at 37–80℃ for 15–40 min. After the reaction, add a reagent buffer (ascorbic acid, ethanol, etc.), and adjust the pH to 6.0–7.5 with PBS (pH 7.2) buffer and NaOH. Take samples for analysis of properties, pH, nuclide identification (HPGe), radiochemical purity analysis (i-TLC), and radioactivity concentration.

[0163] Radiolabeled compounds can be prepared using compounds g, g1, g2, g3, g4, g5, g6, g7, g8, g9, and g10 as precursor compounds, respectively, following the same method. 212 Pb-g, 212 Pb-g1, 212 Pb-g2, 212 Pb-g3, 212 Pb-g4, 212 Pb-g5, 212 Pb-g6, 212 Pb-g7, 212 Pb-g8, 212 Pb-g9 and 212 Pb-g10.

[0164] Example 12 203 Preparation of Pb-labeled compounds

[0165] The compounds of the present invention were prepared by the following method. 203 Pb-labeled compounds, for example, radiolabeled compounds prepared using compound g11 as a precursor compound. 203 Pb-g11.

[0166] Take g11 of the compound dissolved in labeling buffer (1-4M sodium acetate, etc., containing 5-15% vol ethanol, pH 5-6), and add 50-200 MBq of [unspecified substance]. 203 PbCl2 solution, maintaining pH 4–6; react the mixture at 37–80℃ for 15–40 min. After the reaction, add a formulation buffer (ascorbic acid, ethanol, etc.), and adjust the pH to 6.0–7.5 with PBS (pH 7.2) buffer and NaOH. Samples are taken for analysis of properties, pH, radiochemical purity (radio-HPLC), and radioactivity concentration. The yield (RCY, radiochemical yield) is 90–99%, and the radiochemical purity (RCP, radiochemical purity) is >99%, as measured by radio-HPLC.

[0167] Radiolabeled compounds can be prepared using compounds g, g1, g2, g3, g4, g5, g6, g7, g8, g9, and g10 as precursor compounds, respectively, following the same method. 203 Pb-g, 203 Pb-g1, 203 Pb-g2, 203 Pb-g3, 203 Pb-g4, 203 Pb-g5, 203 Pb-g6, 203 Pb-g7, 203 Pb-g8, 203 Pb-g9 and 203 Pb-g10.

[0168] Example 13 225 Preparation of Ac-labeled compounds

[0169] The compounds of the present invention were prepared by the following method. 225 Ac-labeled compounds, for example, preparing radiolabeled compounds using compound g4 as a precursor compound. 225 Ac-g4.

[0170] Dissolve 10 μg of compound g4 in sodium acetate buffer (pH 4-6), and then react with...225 Ac hydrochloric acid solution (activity ≥ 50 MBq / μL) was heated at 90-100 degrees Celsius for 15-20 min in a buffer system with pH 7-8; after the reaction, the sample was analyzed by thin-layer chromatography (iTLC) using sodium citrate buffer.

[0171] Radiolabeled compounds can be prepared using compounds g, g1, g2, g3, g5, g6, g7, g8, g9, g10, and g11 as precursor compounds, respectively, following the same method. 225 Ac-g, 225 Ac-g1, 225 Ac-g2、 225 Ac-g3, 225 Ac-g5, 225 Ac-g6, 225 Ac-g7, 225 Ac-g8, 225 Ac-g9, 225 Ac-g10 and 225 Ac-g11.

[0172] Example 14 68 PET imaging methods for Ga-labeled compounds in the glioblastoma model U87

[0173] Prepared using Example 9 68 Ga-g4 and 68 Ga-FAP-2286 was used as a radiolabeled compound in imaging experiments.

[0174] Approximately 150 μCi of radiolabeled compound was injected into mice with a glioblastoma model (U87 cells) via the tail vein. After 10 minutes, the mice were anesthetized with isoflurane and placed in a Siemens mouse PET / CT scanner for a 10-minute CT scan and a 15-minute PET scan.

[0175] The results are shown in Figures 1 and 2, respectively. Figure 1 shows the injection. 68 Imaging images at 30 min, 1 h, and 2 h after Ga-FAP-2286 injection. Figure 2 shows the injection... 68 Imaging images of Ga-g4 at 30 min, 1 h, and 2 h. Comparing the results in Figures 1-2, it can be seen that... 68 Compared to Ga-FAP-2286, 68 PET / CT imaging at 30 min showed higher uptake by the tumor and lower uptake by the liver in Ga-g4; secondly, due to 68 Ga-g4 metabolic ratio 68 Ga-FAP-2286 is faster and can better reduce radiation damage in the body.

[0176] The uptake rate of the radiolabeled compound was obtained by directly quantifying the imaging results using software, and the results are shown in Table 4.

[0177] Table 4. Uptake rates of tumors, liver, and kidneys

[0178] As shown in Table 4, the present invention 68 Ga-g4 uptake in tumors after injection is superior to 68 Ga-FAP-2286 has lower uptake by the liver and kidneys, resulting in better imaging results and reduced radiation damage in the body.

[0179] Example 15 177 In vitro stability of Lu-labeled compounds

[0180] Will 177 Lu-g4 was mixed with equal volumes of fetal bovine serum and phosphate-buffered saline (PBS, pH 7.4) and incubated at 25±1℃ for 0 h (baseline), 24 h, 48 h, and 72 h, respectively. At each time point, the labeling reaction was immediately terminated by quenching with buffer containing 50% (v / v) PBS or 50% (v / v) FBS. Real-time thin-layer chromatography (iTLC) analysis was performed on the samples.

[0181] As shown in Figure 3. 177 Lu-g4 was stable in both incubation systems at room temperature for 24h, 48h, and 72h.

[0182] Example 16 177 Lu-labeled compounds on SPECT images of tumor-bearing mice

[0183] HEK293-hFAP cells were resuspended in PBS, mixed with an equal volume of matrix gel, and subcutaneously inoculated into female BALB / c nude mice. Tumor volume was 200-300 mm². 3 At that time, a tail vein injection diluted with physiological saline was administered. 177 Lu-FAP-2286 or 177 Lu-g4 was used to delineate tumor uptake (SUVmax) in mice at 1 hr, 4 hr, and 24 hr after injection.

[0184] As shown in Table 5 177 Lu-g4 showed significant tumor uptake in HEK293-hFAP tumor-bearing mice, and remained in the tumor for an extended period of time.

[0185] Table 5, 177 Lu-tagged molecules in mouse tumors SUVmax

[0186] Example 17 177 Cellular uptake assay of Lu-labeled compounds in tumor-bearing mice

[0187] HEK293-hFAP cells were resuspended in complete DMEM medium with 10% FBS, seeded into 6-well plates pretreated with Poly-D-Lysine, and cultured overnight in a 5% CO2, 37°C cell culture incubator. The culture supernatant was then discarded, and each well was filled with... 177 Lu-g4, 177 Lu-FAP-2286 cells were incubated in an incubator for 1 hour and 4 hours. After incubation, the supernatant was removed, and the cells were washed twice with PBS. 0.4 mL of 1M NaOH solution was added to each well, and the cells were lysed by incubation at room temperature for 10 minutes. The lysates were collected. The culture wells were then washed twice with PBS, and the PBS wash buffer was collected. The total radioactivity count in the NaOH lysis buffer and PBS wash buffer was detected using a γ-counter.

[0188] As shown in Figure 4 177 Lu-g4 increased cell uptake by 20% in HEK293-hFAP cells over 4 hours compared to 1 hour. 177 The cell uptake rate of Lu-FAP-2286 in HEK293-hFAP cells remained essentially unchanged after 4 hours compared to 1 hour.

[0189] Example 18 177 Pharmacodynamic studies of Lu-labeled compounds in tumor-bearing mice

[0190] HT1080-hFAP cells were resuspended in PBS, mixed with an equal volume of matrix gel, and subcutaneously seeded into BALB / c nude mice. After grouping the tumor-bearing mice (N=4), each mouse received a single intravenous injection of 40 MBq of physiological saline. 177 Lu-g4 or 177 Lu-FAP-2286. Mice were given free access to sterile water and pellets. Tumor volume was measured every two days after administration. The tumor volume was calculated using the formula: Tumor volume (mm²) 3 = 0.5 × tumor long diameter × tumor short diameter 2 Collect the medication after 21 days. 177 The kidneys and livers of mice in the Lu-g4 administration group were stained with hematoxylin and eosin (HE).

[0191] As shown in Figure 5, 40 MBq 177 Lu-g4 or 177 Lu-FAP-2286 can significantly inhibit tumor growth. 177 Lu-g4 has a better effect on inhibiting tumor growth than 177Lu-FAP-2286.

[0192] As shown in Figure 6 177 After 21 days of Lu-g4 administration, the liver and kidney tissue structures remained normal.

[0193] Example 19 225 Distribution of Ac-labeled compounds in tumor-bearing mice tissues

[0194] HT080-hFAP cells were resuspended in PBS, mixed with an equal volume of matrix gel, and subcutaneously inoculated into female BALB / c nude mice. Tumor volume was 200-300 mm². 3 At that time, a tail vein injection diluted with physiological saline was administered. 225 Four hours after Ac-g4 injection, kidney and tumor tissues from mice were collected, washed with physiological saline, blotted dry with absorbent paper, and weighed. The radioactivity count of each tissue was determined using a γ-counter, and the percentage injection dose rate per gram of tissue (%ID / g) was calculated.

[0195] As shown in Table 6, the tissue biodistribution data... 225 Ac-g4 uptake in tumor tissues is greater than in the kidneys over 4 hours.

[0196] Table 6. 225 Tissue biodistribution of Ac-g4 in HT080-hFAP tumor-bearing mice

[0197] Example 20 212 Distribution of Pb-labeled compounds in tumor-bearing mice

[0198] HEK293-hFAP cells were resuspended in PBS, mixed with an equal volume of matrix gel, and subcutaneously inoculated into female BALB / c nude mice. Tumor volume was 200-300 mm². 3 At that time, a tail vein injection diluted with physiological saline was administered. 212 Pb-g11 (N=4) was injected, and mice were euthanized by cervical dislocation at 1 hr, 4 hr, and 24 hr. Liver, kidney, bone, muscle, and tumor tissues were collected, washed with physiological saline, blotted dry with absorbent paper, and weighed. The radioactivity count of each tissue was determined using a γ-counter, and the percentage injection dose rate per gram of tissue (%ID / g) was calculated.

[0199] As shown in Table 7 212Pb-g11 showed significant uptake in tumors, with average ID / g values ​​of 8.81%, 8.57%, and 4.73% over 1, 4, and 24 hours, respectively. It was rapidly cleared from the bloodstream, with average ID / g values ​​of 1.81%, 0.73%, and 0.04% over 1, 4, and 24 hours, respectively. In the kidneys, the average ID / g values ​​were 33.80%, 27.17%, and 15.05% over 1, 4, and 24 hours, respectively. Uptake in other tissues was low.

[0200] Table 7. 212 Pb-g11 uptake in key organs of HEK293-hFAP tumor-bearing mice

[0201] Example 21: Determination of affinity Kd for SPR surface plasmon resonance

[0202] The affinity Kd between FAP protein and FAP-2286, compounds g, and g1 was determined by surface plasmon resonance (SPR).

[0203] The experiment was conducted in a Biacore T200 device (GE) according to the operating manual. CM5 series chips with carboxyl groups were used. The coupling conditions were selected as pH 5.5, and the regeneration conditions as Glycine-HCl pH 2.0. The obtained affinity data are shown in Table 8.

[0204] Table 8

[0205] The results in Table 8 show that compounds g, g1 and FAP-2286 have the same order of magnitude affinity, and g1 is even better than FAP-2286, proving that the g series of compounds has a good affinity for human FAP protein.

[0206] Example 22 SA sensor chip for determining affinity Kd

[0207] Biotinylated FAP protein at concentrations of 10-50 μg / ml was immobilized on the surface of an SA sensor chip. Subsequently, different concentrations of analyte molecules or corresponding control samples were injected onto the chip surface. A mobile phase composed of running buffer (HEPES pH 7.4, NaCl, P2O, DMSO, etc.) was used, with binding occurring at 90 s and dissociation at 1800 s. Binding kinetics data for different analyte molecules were analyzed using Biacore 8K analysis software. Raw data were fitted globally using a 1:1 Langmuir binding model, and the kinetic parameters binding rate (kon) and dissociation rate (koff) were calculated, with KD = koff / kon.

[0208] The affinity results are shown in Table 9.

[0209] Table 9: SPR Results

[0210] The results in Table 9 show that compounds g4 and g11 have significantly better affinity for FAP-2286 than FAP-2286, demonstrating that the compounds of this invention have better affinity for human FAP protein.

[0211] Example 23 68 Imaging of Ga-labeled molecules in the human body

[0212] Administer imaging drugs intravenously at a dose of 0.03–0.05 mCi / kg. 68 After administration of the Ga-g4 labeled molecule, the patient rested for 60 minutes before undergoing a whole-body PET / CT scan (uEXPLORER, combined imaging). The scan range was from the top of the skull to the soles of the feet, using one bed, and lasted 5 minutes. Images were reconstructed using the Ordered Subset Expectation Maximization (OSEM) method. The scan results are shown in Figures 7A-7H, where 7A represents esophageal cancer, 7B cervical cancer, 7C lung cancer, 7D gastric cancer, 7E renal cancer, 7F liver cancer, 7G colon cancer, and 7H prostate cancer. The results indicate that the radionuclide marker of this invention is distributed in various tumors.

Claims

1. The compound or its salt represented by formula (I): G can independently represent a monosaccharide, disaccharide, or trisaccharide group, or a phenyl group substituted with a monosaccharide, disaccharide, or trisaccharide group; L represents a dipeptide or tripeptide linker; M represents a metal chelating group that can bind to radioactive nuclides; n is an integer from 1 to 3.

2. The compound of claim 1 or a salt thereof, wherein, G independently represents a monosaccharide group or a phenyl group substituted with a monosaccharide group; Preferably, each of G is independently selected from the following groups: Preferably, each of G is independently selected from the following groups: Preferably, each of G is independently selected from the following groups: Preferably, each of G is independently selected from the following groups: Preferably, G is a group consisting of the following:

3. The compound or a salt thereof according to claim 1 or 2, wherein, L is selected from the following groups: Preferably, L is selected from the following groups: Preferably, L is selected from the following groups:

4. The compound or a salt thereof according to any one of claims 1-3, wherein, M is a group selected from the following structures: Preferably, M is Preferably, M is Preferably, M is 5. The compound or a salt thereof according to any one of claims 1-4, wherein, n is an integer of 1 or 2; preferably, n is an integer of 1.

6. The compound of claim 1 or a salt thereof, wherein, G is independently selected from the following groups: L is selected from the following groups: M and L are linked by an amide bond and are groups selected from the following structures:

7. The compound of claim 1 or a salt thereof, wherein, G is independently selected from the following groups: M is 8. The compound of claim 1 or a salt thereof, wherein, G is independently selected from the following groups: L is selected from the following groups: M is a group selected from the following structures: n is an integer that is either 1 or 2.

9. The compound of claim 1 or a salt thereof, wherein, G is independently selected from the following groups: L is selected from the following groups: M is n is an integer that is either 1 or 2.

10. The compound of claim 1 or a salt thereof, wherein, G is independently selected from the following groups: L is selected from the following groups: M is n is an integer that is either 1 or 2.

11. The compound of claim 1 or a salt thereof, wherein, G is selected from the following groups: L is selected from the following groups: M is n is an integer where n is 1.

12. The compound of claim 1 or a salt thereof, wherein, G represents the following groups: L represents the following groups: M is n is an integer where n is 1.

13. The compound of claim 1 or a salt thereof, wherein the compound is preferably selected from:

14. A radionuclide label comprising the compound or a salt thereof as described in any one of claims 1-13, and a radionuclide; Preferably, wherein, The radionuclide is selected from radiodiagnostic radionuclides and radiotherapy radionuclides; Preferably, The radioactive diagnostic nuclide is selected from... 86 Y、 18 F, 51 Mn, 52m Mn, 52g Mn, Al[ 18 F]、 64 Cu、 67 Ga、 68 Ga、 89 Zr、 99m Tc, 111 In、 123 I, 124 I, 125 I, 44 Sc、 47 Sc、 203 Any one or more of Pb; preferred 86 Y、 18 F, 51 Mn, 52m Mn, 52g Mn, Al[ 18 F]、 64 Cu、 67 Ga、 68 Ga、 89 Zr、 99m Tc, 111 In、 123 I, 124 I, 125 I, 44 Sc、 47 Any one or more of Sc; preferred 86 Y, Al[ 18 F]、 64 Cu、 68 Ga、 89 Zr、 99 mTc, 124 I, 203 Any one or more of Pb; preferred 86 Y, Al[ 18 F]、 64 Cu、 68 Ga、 89 Zr、 99 mTc, 124 Any one or more of I; more preferably 68 Ga、 203 Pb or 64 Cu; more preferred 68 Ga or 64 Cu; more preferred 68 Ga; More preferred 203 Pb; more preferred 64 Cu; Preferably, The radioactive nuclide is selected from... 67 Cu、 90 Y、 125 I, 131 I, 153 Sm、 166 Ho、 177 Lu、 186 Re、 188 Re、 211 At、 212 Pb, 212 Bi、 213 Bi、 223 Ra、 225 Ac、 227 Th、 161 Tb, 149 Any one or more of Tb; preferred 67 Cu、 90 Y、 125 I, 131 I, 153 Sm、 166 Ho、 177 Lu、 227 Th, 186 Re、 188 Re、 211 At、 212 Pb, 212 Bi、 213 Bi、 223 Ra、 225 Ac、 227 Any one or more of Th; preferred 67 Cu、 90 Y、 125 I, 131 I, 177 Lu、 227 Th、 223 Ra、 225 Ac、 211 At、 161 Tb, 149 Any one or more of Tb; preferred 67 Cu、 90 Y、 125 I, 131 I, 177 Lu、 227 Th、 223 Ra、 225 Ac、 211 Any one or more of At; more preferably 227 Th、 177 Lu、 225 Ac or 212 Pb; more preferred 177 Lu、 225 Ac or 212 Pb; more preferred 177 Lu or 212 Pb; more preferred 177 Lu; More preferred 212 Pb.

15. The radionuclide marker of claim 14, wherein the radionuclide marker is selected from:

16. The radionuclide marker of claim 14, wherein the radionuclide marker is selected from:

17. The radionuclide marker of claim 14, wherein the radionuclide marker is selected from:

18. The radionuclide marker of claim 14, wherein the radionuclide marker is selected from:

19. Use of the compound of any one of claims 1-13 or its salt, or the radionuclide label of any one of claims 14-18, in the preparation of tumor imaging agents or antitumor drugs.

20. The use as described in claim 19, wherein, The tumor is a tumor that highly expresses FAP, such as a solid tumor (especially a solid tumor that highly expresses FAP); in particular, the tumor is an epithelial tumor, sarcoma, or mesothelioma; in particular, the tumor is selected from sarcoma, mesothelioma, esophageal tumor, glioblastoma, melanoma, colorectal cancer, pancreatic cancer, lung cancer, breast cancer, gastric cancer, kidney cancer, cervical cancer, liver cancer, prostate cancer, or glottic cancer.

21. The use as described in claim 19, wherein, The tumor is an epithelial tumor, preferably a sarcoma, mesothelioma, esophageal tumor, glioblastoma, colorectal tumor, pancreatic cancer, lung cancer, breast cancer, or gastric cancer.

22. The compound shown in formula (II) or its salt: in, The definitions of M, L, and n are respectively defined in any one of claims 1-13; Specifically, the compound of formula (II) is selected from:

23. The compound shown in formula d or its salt:

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