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 kind of targeting tumor-related fibroblast activation protein glycopeptide, radionuclide label and its application TECHNICAL FIELD

[0001] The present application relates to the technical field of polypeptides targeting tumor-related fibroblast activation protein (FAP), specifically to a kind of FAP glycopeptide and its radionuclide label and application. BACKGROUND

[0002] The development of radiopharmaceuticals has become an important development direction of new drug research at home and abroad, attracting the attention of many research institutions, enterprises and markets. In particular, the diagnosis and treatment of tumor-targeted radiopharmaceuticals can effectively diagnose and treat radionuclides, and is currently the forefront of drug research. The radiolabeled polypeptide Lutathera (lutetium octreotate) targeting somatostatin receptor and the radiopharmaceutical Pluvicto (formerly Lu-PSMA-617) targeting prostate-specific membrane antigen (PSMA) were approved for marketing by the US FDA in 2018 and 2022, respectively. 177 Lu-PSMA-617).

[0003] Malignant tumors include tumor cells and the microenvironment in which tumor cells exist. The tumor microenvironment is also known as the tumor stroma, which includes various non-malignant cells that collectively shape the environment suitable for tumor growth. Among them, non-cancer stromal cells promote extracellular matrix remodeling, induce angiogenesis, cell migration, drug resistance and immune surveillance evasion, thereby promoting tumor invasion and metastasis, by producing various growth factors, chemotactic factors and cytokines. Studies have shown that cancer-associated fibroblasts (CAFs) are the main components of non-cancer stromal cells in the tumor microenvironment, and fibroblast activation protein (FAP) is universally expressed on the surface of CAFs, making it a very promising tumor biomarker.

[0004] FAP is a membrane-bound glycoprotein belonging to the Dipeptidyl peptidase 4 (DPP4) family, with dipeptidyl peptidase and endopeptidase activity, and has 52% homology with DPP4 at the protein level. The protein is composed 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). FAP is generally not expressed or expressed in small amounts in normal tissues, but is overexpressed in CAFs and is highly expressed in more than 90% of epithelial tumors. It can directly promote the proliferation, migration and invasion of stromal fibroblasts and other cell types, leading to tumor angiogenesis, extracellular matrix degradation and evasion of immune surveillance, etc.

[0005] Recent studies have shown that FAP is a very promising target for tumor radiotherapy and diagnosis. A series of small molecule probes targeting FAP have been successfully developed by Heidelberg University in Germany, such as FAPI-02 and FAPI-04, and 68 Ga and 177 Lu labeled as diagnosis and treatment integrated radiopharmaceuticals. Clemens Kratochwil et al. evaluated 80 patients with 68 Ga-FAPI PET / CT scans, and these patients were diagnosed by 18 F-FDG imaging or other traditional imaging methods, but after administration of 68 Ga-FAPI-04, among the 28 cancer types included in the analysis, 54 primary tumors and 229 metastases were detected [Kratochwil C., et al. (68)Ga-FAPI PET / CT: Tracer Uptake in 28 Different Kinds of Cancer. J Nucl Med, 2019, 60(6), 801-805.]. Compared with 18 F-FDG, 68 Ga-FAPI-04 can detect more primary tumors and metastases. This probe can accurately diagnose and stage metastases of various tumors and has very high application prospects, and may become a widely used screening and radionuclide therapy tool in clinical oncology. In addition, the imaging procedure of this probe is simplified, and there is no need for fasting and sugar control, making it more acceptable to patients.

[0006] FAP-2286 is a cyclic peptide probe targeting FAP, and its structure includes a cyclic peptide composed of 7 amino acids and a metal ligand part, with an affinity in the range of 0.4-1.4 nM. Compared with the small molecule inhibitor probe 177 Lu-FAPI series, 177 Lu-FAP-2286 still has high tumor uptake signal 72 hours after administration, while FAPI-46 has only weak signal in the tumor, so the radiotherapy drug based on cyclic peptide FAP-2286 has higher research potential in tumor treatment.

[0007] Currently, 68 Ga-FAP-2286 and 177 Lu-FAP-2286 research is in clinical I / II phase (NCT04939610). Although 68 Ga-FAP-2286 and 177Lu-FAP-2286 has high uptake in FAP-high tumors, but its retention time in the kidney is longer, with 2.2% ID / g, 1.1% ID / g and 0.6% ID / g at 3h, 24h and 72h after administration, respectively, which is higher than the small molecular probe FAPI-46, and is easy to cause radioactive nephrotoxicity or aggravate kidney 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 the radiopharmaceutical itself does not cause damage to normal tissues due to the small amount used, when it is enriched and retained for a long time, it will cause radioactive damage to normal tissues due to the accumulation of radioactive amount for a long time. In addition, patients treated with radiotherapy are mostly in the advanced stage of cancer, and most of them have undergone radiotherapy and chemotherapy, and their liver and kidney functions may be damaged or have underlying diseases.

[0008] Therefore, special attention should be paid to the liver accumulation and kidney retention time of radiopharmaceuticals, and it is an important direction that should be concerned at the beginning of drug design. Therefore, the structure of the molecule is modified to maintain high tumor uptake while reducing enrichment in liver and kidney metabolic organs, and to develop a "best-in-class" FAP-targeting cyclic peptide radiopharmaceutical with independent intellectual property rights, which has very high clinical transformation value and feasibility. SUMMARY

[0009] The present application modifies the linker part forming the cyclic peptide based on the structure of the polypeptide FAP-2286, and further introduces a monosaccharide or disaccharide molecule to obtain a series of new glycopeptides. The radiolabeled glycopeptides show better tumor uptake and lower liver uptake than FAP-2286, have better imaging results, are beneficial to obtain candidate radiolabeled diagnostic and therapeutic drugs with further research value, and ultimately obtain a "best-in-class" FAP-targeting cyclic peptide radiopharmaceutical with independent intellectual property rights.

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

[0011] G each independently represents 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 which can bind to a radionuclide;

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

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

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

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

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

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

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

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

[0022] In some embodiments, each G is the following group:

[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 the following group:

[0026] In some embodiments, M is connected to L through an amide bond (i.e. M is connected to the NH connection end of L), M is selected from the following groups of 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 where the substituent is attached.

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

[0034] In some embodiments,

[0035] G is each 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 of 1 or 2.

[0039] In some embodiments,

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

[0041] L is selected from the following groups:

[0042] M is

[0043] n is an integer of 1 or 2.

[0044] In some embodiments,

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

[0046] L is selected from the following groups:

[0047] M is

[0048] n is an integer of 1 or 2.

[0049] In some embodiments,

[0050] G is selected from the following groups:

[0051] L is selected from the following groups:

[0052] M is

[0053] n is an integer of 1.

[0054] In some embodiments,

[0055] G is a group of

[0056] L is a group of

[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 application provides a radionuclide label comprising a compound described herein or a salt thereof, and a radionuclide.

[0061] In some embodiments, the radionuclide is selected from the group consisting of a radio-diagnostic nuclide and a radio-therapeutic nuclide, but not limited thereto. The radio-diagnostic nuclide label can be used for tumor imaging, which is beneficial for the diagnosis of tumors, while the radio-therapeutic nuclide label can be used for the diagnosis and treatment of tumors.

[0062] In some embodiments, the radio-diagnostic nuclide is any one or more selected from the group consisting of 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 Pb; preferably 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; preferably 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; preferably 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; preferably 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 preferably 177 Lu, 225 Ac or 212 Pb; more preferably 177 Lu or 212 Pb; more preferably 177 Lu; more preferably 212 Pb.

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

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

[0067] Another aspect of the present application provides use of the above-mentioned compound or its salt or radionuclide label thereof in the preparation of a tumor imaging agent or an anti-tumor drug.

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

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

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

[0071] wherein M, L, n are defined as described herein.

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

[0073] Another aspect of the present application relates to a compound of the following formula or a salt thereof:

[0074] The compounds according to the present application can be prepared by a person skilled in the art with reference to the synthesis methods in the examples in combination with the prior art. 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] MALDI-TOF mass spectrometer is a matrix-assisted laser desorption ionization time-of-flight mass spectrometer;

[0088] Sep-Pak C18 column is WAT023501 SEP-PAK LIGHT C18;

[0089] Biomolecular interaction instrument model is Biacore T200;

[0090] Protein is Recombinant Human FAP Protein of Sino Biological;

[0091] Reagents related to chip coupling and regeneration are purchased from cytivo company;

[0092] The instrument model of the counter for measuring the radioactivity of the tissue biodistribution is WIZARD2 2-Detector Gamma Counter, and the part number is 2470-0020;

[0093] The remaining reagents are purchased from China Pharmaceutical.

[0094] English abbreviation interpretation: DCM: dichloromethane; DMF: N,N-dimethylformamide; HBTU: benzotriazole-N,N,N,N-tetramethyluronium hexafluorophosphate; DIEA: N,N-diisopropyl ethylamine TFA: trifluoroacetic acid EDT: 1,2-ethanedithiol ddH2O: deuterium water TIS: triisopropylsilane tBu-DOTA: tri-tert-butyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

[0095] Synthesis of compound a of example 1

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

[0097] S2: Resin swelling: add about 10 mL of DMF into the reaction bottle, and shake for 30 min;

[0098] S3: Deprotection twice, each time add a solution containing 20% volume of piperidine in DMF (10 mL) and react for 15 min, then wash the resin with DMF for 3 times, and wash the resin with DCM for 3 times;

[0099] S4: Add the first amino acid Fmoc-L-Phe-OH: add 4 times molar amount of Fmoc-L-Phe-OH based on the resin, 4 times molar amount of HBTU, and 8 times molar amount of DIEA, condensation reaction for 3 h, DMF flush the resin for 3 times, DCM flush the resin for 3 times;

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

[0101] S6: Deprotection twice, each time add 20% volume of piperidine in DMF solution (10 mL) and react for 15 min, then DMF flush the resin for 3 times, DCM flush the resin for 3 times;

[0102] S7: Remove the solvent, put into 5 mL DMF solution of 4 times molar amount of hexanoic acid prepared in advance for condensation;

[0103] S8: Cut the resin: remove the solvent, add 20 mL of cleavage solution with volume ratio of TFA: TIS: EDT: ddH2O = 95%: 2.5%: 1.25%: 1.25%, react for 2.5 h;

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

[0105] S10: Precipitation of the polypeptide: transfer the crude peptide dissolved in TFA to a centrifuge tube, add 10 times volume of ice ethyl ether to it, then centrifuge at 8000 g at 4°C to remove the solvent to obtain the precipitated crude peptide;

[0106] S11: Take 10 mg of the crude polypeptide, dissolve in a mixed solution with volume ratio of 1:3 = acetonitrile: dd water (ddH2O), take 0.5 mg of the sample to collect the target peak solution in a C18 reverse phase chromatography preparation system, set the HPLC parameters: Wavelength: 210 nm and 254 nm; Flow Rate: 3 mL / min; Inj. Vol: 1 mL; Column Temp: 25°C; A phase: 0.1% TFA in water; B phase: acetonitrile. Freeze-dry the target peak solution to obtain compound a, which is a FAP-2286 precursor, and store at -20°C.

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

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

[0109] S2: Resin swelling: add DMF about 10 mL into the reaction bottle, and shake for 30 min;

[0110] S3: Deprotection twice, each time add 20% piperidine in DMF solution (10 mL) and react for 15 min, then wash the resin with DMF for 3 times, and wash the resin with DCM for 3 times;

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

[0112] S5: Repeat S3-S4, sequentially connect Fmoc-L-Val-OH and Fmoc-L-Met-OH;

[0113] S6: Deprotection twice, each time add 20% piperidine in DMF solution (10 mL) and react for 15 min, wash the resin with DMF for 3 times, and wash the resin with DCM for 3 times;

[0114] S7: Remove the solvent, and add 4 times molar amount of tBu-DOTA in DMF solution prepared in advance for condensation;

[0115] S7: Cut the resin: remove the solvent, and add TFA: TIS: EDT: ddH2O = 95%: 2.5%: 1.25%: 1.25% cleavage solution by volume ratio, and react for 3 h;

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

[0117] S7: Precipitation of the polypeptide: transfer the crude peptide dissolved in TFA to a centrifuge tube, add 10 times of ice ethyl ether to it, and then remove the solvent by a centrifuge at 4°C 8000 g to obtain the precipitated crude peptide;

[0118] S8: Take 10 mg of the crude polypeptide, dissolve in a mixture of acetonitrile: dd water with a volume ratio of 1:3, take 0.5 mg of the sample to collect the target peak solution in the C18 reverse phase chromatography preparation system, set the HPLC parameters: Wavelength: 210 nm and 254 nm; Flow Rate: 3 mL / min; Inj. Vol: 1 mL; Column Temp: 25°C; A phase: 0.1% TFA aqueous solution, B phase: acetonitrile. The target peak solution is freeze-dried to obtain compound b, which is stored at -20°C.

[0119] In addition to replacing the amino acid to be connected in step S5 with the amino acid in Table 1 below, compounds b1 to b4 are obtained in the same manner.

[0120] Table 1

[0121] Synthesis of compound b5 of Example 3

[0122] S1: Put 1.55 g of resin H-L-Cys(Trt)-2-Chlorotrityl Resin with a substitution degree of 0.322 mmol / g into a polypeptide sand core reaction column;

[0123] S2: Resin swelling: add DMF about 10 mL in the reaction bottle, and aerate for 30 min;

[0124] S3: Deprotection 2 times, each time add 20% piperidine in DMF solution (10 mL) and react for 15 min, then wash the resin with DMF 3 times, and wash the resin with DCM 3 times;

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

[0126] S5: Repeat S3-S4, sequentially connect Fmoc-L-Phe-OH, Boc-Gly-OH;

[0127] S6: Remove Dde 2 times, each time add 5% volume hydrazine in DMF solution (10 mL) and react for 15 min, wash the resin with DMF 3 times, and wash the resin with DCM 3 times;

[0128] S7: 4-phenyl-Α-D-mannoside isothiocyanate synthesis: remove the solvent, add 4-phenyl-Α-D-mannoside isothiocyanate and 2 times the molar amount of DIEA, and condense for 3 h;

[0129] S8: Cleavage: remove solvent, add cleavage solution of TFA: TIS: ddH2O: benzyl thioether = 90%: 2.5%: 2.5%: 5% in volume ratio, react for 3.5h;

[0130] S9: Cleavage complete, remove solvent by rotary evaporator to get crude peptide dissolved in TFA;

[0131] S10: Precipitation of polypeptide: transfer crude peptide dissolved in TFA to centrifuge tube, add 10 times ice ethyl ether, then remove solvent by centrifuge to get precipitated crude peptide;

[0132] S11: take 200mg crude polypeptide, dissolve in mixed solution of acetonitrile: dd water = 1:3 in volume ratio, take 20mg sample to collect target peak solution in C18 reverse phase chromatography preparation system, set HPLC parameters: Wavelength: 214nm and 254nm; Flow Rate: 25mL / min; Inj. Vol: 5mL; Column Temp: 25℃; Phase A: 0.05% TFA in water; Phase B: 0.05% TFA in acetonitrile. Freeze dry target peak solution to get compound b5, store at -20℃.

[0133] Synthesis of compound d in Example 4

[0134] Dissolve compound a (3mg, 3.363μmol) and compound c (1mg, 4.036μmol) in mixed solution of acetonitrile and dd water = 1:1, add saturated sodium bicarbonate to adjust pH to about 8, react for 3h at room temperature, quench with formic acid, concentrate by nitrogen blowing to remove excess solvent, collect target peak solution in C18 reverse phase chromatography preparation system, set HPLC parameters: Wavelength: 210nm and 254nm; Flow Rate: 3mL / min; Inj. Vol: 1mL; Column Temp: 25℃; Mobile phase A: 0.1% TFA in water; Mobile phase B: acetonitrile, to get compound d.

[0135] Synthesis of compound e and e1 to e4 in Example 5

[0136] Compound d (1 mg, 0.876 μmol) was dissolved with compound b (0.8 mg, 0.876 μmol) in 500 μL acetonitrile and 500 μL dd water, saturated sodium bicarbonate was added to adjust pH to about 8, reaction at room temperature overnight, formic acid was added to quench, concentrated to remove solvent, the solution of target peak was collected in C18 reverse phase chromatography preparation system, 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 in water, 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 instead of compound b, respectively.

[0138] Synthesis of compound e5 in Example 6

[0139] Compound d (80 mg, 0.07 mmol) was dissolved with compound b5 (53 mg, 0.07 mmol) in 2 mL acetonitrile and 8 mL dd water, saturated sodium bicarbonate was added to adjust pH to about 8, reaction at room temperature overnight, formic acid was added to quench, concentrated to remove solvent, the solution of target peak was collected in C18 reverse phase chromatography preparation system, 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; A phase: 0.05% TFA in water; B phase: 0.05% TFA in acetonitrile, to obtain compound e5.

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

[0141] Compound e (0.5 mg, 0.249 μmol) was dissolved with compound f (0.234 mg, 0.747 μmol) in DMF, DIEA (0.161 mg, 1.245 mmol) was added, reaction at room temperature overnight, diluted with dd water, the solution of target peak was collected in C18 reverse phase chromatography preparation system, 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 in water, mobile phase B: acetonitrile, to obtain compound g.

[0142] The compounds g1-g10 were obtained in the same way by replacing compound e with compounds e1-e4 and replacing compound f with f1, f2 or f3 in Table 2 below.

[0143] Table 2

[0144] Synthesis of compound g11 in Example 8

[0145] Compound e5 (67 mg, 0.035 mmol, 1 eq) was dissolved in DMF with compound p-NCS-Bn-TCMC (102 mg, 0.175 mmol, 3-5 eq), DIEA (45 mg, 0.35 mmol, 10 eq) was added and the reaction was left to proceed overnight at room temperature, diluted 10 times with ddH20 (or the DMF was evaporated) and the target peak solution was collected in a C18 reverse phase chromatography preparation system with the following HPLC parameters: Wavelength: 214 nm and 254 nm; Flow Rate: 25 mL / min; Inj. Vol: 5 mL; Column Temp: 25 °C; Phase A: 0.05% acetic acid in water; Phase B: 0.05% acetic acid in acetonitrile to obtain compound g11.

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

[0147] Table 3

[0148] Comparative Example 1 FAP-2286

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

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

[0151] The compounds of the application were prepared by the following methods 68 Ga-labelled compounds, for example radiolabelled compounds were 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 uL precursor compound dissolved in dd water (concentration of 10 ug / uL) in an ep tube, add 180 uL of 3M sodium acetate to adjust the pH to 4-5;

[0153] S2: Add 400 uL of 0.6M radioactive 68 Ga in an ep tube, react at 95℃ for 10 min;

[0154] S3: After the reaction, perform paper chromatography to test the purity, the developing agent is methanol: 1M ammonium formate = 1:1, if the purity does not reach more than 90%, use a Sep-Pak C18 small column for purification, the specific operation is: first activate with 20 mL of anhydrous ethanol, then rinse once with 20 mL of dd water, load the radioactive sample, wash off the free Ga with 20 mL of dd water, then elute with 75% ethanol, discard the first 500 uL of product, every 100 uL is a tube, measure the radioactive dose, take the tube with the highest radioactive dose as the 68 Ga-labeled product.

[0155] The radioactive labeled compounds 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 177 Lu-labeled compounds of the present application, for example, the radioactive labeled compound 177 Lu-g4.

[0158] Dissolve 1 ug of precursor compound g4 in 100 uL of ultrapure water, vortex to fully dissolve; add 10 uL of sodium acetate solution (pH 5.0-5.5) to the above solution; inject 1 uL of eluent containing 177 LuCl3(radioactive activity 1-5 mCi), immediately vortex to mix; incubate the mixture at 80-95℃ for 10-15 min; labeling result: 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-labelled compounds

[0165] Preparation of compounds of the application by the following method 203 Preparation of Pb-labelled compounds, for example radio-labelled compounds prepared using compound g11 as a precursor compound 203 Pb-g11.

[0166] Take compound g11 dissolved in labelling buffer (1-4M sodium acetate etc., containing 5-15% vol ethanol, pH 5-6), add 50-200 MBq of 203 PbCl2solution, maintain pH 4-6; allow mixture to react at 37-80°C for 15-40 min. After reaction is complete, add formulation buffer (ascorbic acid, ethanol etc.), adjust pH to 6.0-7.5 with PBS (pH 7.2) buffer and NaOH, take sample for analysis of properties, pH, radiochemical purity (radio-HPLC), radioactivity concentration etc. Radiochemical yield (RCY) is 90-99%, radiochemical purity (RCP) is >99% by radio-HPLC.

[0167] Radio-labelled compounds can be prepared in the same way using compounds g, g1, g2, g3, g4, g5, g6, g7, g8, g9 and g10 as precursor compounds respectively 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-labelled compounds

[0169] Preparation of compounds of the application by the following method 225 Preparation of Ac-labelled compounds, for example radio-labelled compounds prepared using compound g4 as a precursor compound 225 Ac-g4.

[0170] Dissolve 10 μg of compound g4 in sodium acetate buffer (pH 4-6) with225 Ac hydrochloric solution (activity > 50 MBq / μL) was heated in a pH 7-8 buffer system at 90-100 degrees Celsius for 15-20 min; after the reaction was completed, the sample was analyzed by thin layer chromatography (iTLC) using sodium citrate buffer.

[0171] The radiolabeled compounds can be prepared in the same way using compounds g, g1, g2, g3, g5, g6, g7, g8, g9, g10 and g11 as precursor compounds, respectively. 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 method of Ga labeled compounds in glioblastoma model U87

[0173] Ga-g4 and 68 Ga-FAP-2286 prepared in Example 9 were used as radiolabeled compounds for imaging experiments. 68 Ga-FAP-2286 prepared in Example 9 were used as radiolabeled compounds for imaging experiments.

[0174] About 150 μCi of the radiolabeled compound was injected into the tail vein of a mouse with a glioblastoma model (U87 cells), and after 10 min, the mouse was anesthetized with isoflurane, and the anesthetized mouse was placed in a Siemens mouse Pet / CT instrument for a 10 min CT scan and a 15 min PET scan.

[0175] The results are shown in Figures 1 and 2, respectively. Figure 1 shows the imaging images at 30 min, 1 h and 2 h after injection of 68 Ga-FAP-2286, and Figure 2 shows the imaging images at 30 min, 1 h and 2 h after injection of 68 Ga-g4. By comparing the results of Figures 1-2, it can be seen that, compared with 68 Ga-FAP-2286, 68 Ga-g4 showed higher tumor uptake and lower liver uptake at 30 min; secondly, because 68 Ga-g4 is metabolized faster than 68 Ga-FAP-2286, it can better reduce damage in the body by radioactivity.

[0176] The uptake of radiolabeled compounds was obtained by direct quantification of the imaging results using software, and the results are shown in Table 4.

[0177] Table 4 Uptake of tumors, liver and kidney

[0178] As can be seen from Table 4, the compound of the present application has a higher uptake in tumors than 68 Ga-g4 has a higher uptake in tumors than 68 Ga-FAP-2286, and also has lower liver and kidney uptake, has better imaging results, and can better reduce damage of radioactivity in the body.

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

[0180] The 177 Lu-g4 was mixed with an equal volume of fetal bovine serum and phosphate buffer solution (PBS, pH 7.4) respectively, and incubated in a constant temperature incubator at 25±1℃ for 0h (baseline), 24h, 48h and 72h respectively. Immediately at each time node, the labeling reaction was terminated by quenching with a buffer containing 50% (v / v) PBS or 50% (v / v) FBS. Instant thin layer chromatography (iTLC) analysis was performed on the samples.

[0181] As shown in Figure 3, 177 Lu-g4 was stable in the two incubation systems respectively under room temperature conditions for 24h, 48h and 72h.

[0182] Example 16 177 SPECT imaging of Lu-labeled compounds in tumor-bearing mice

[0183] HEK293-hFAP cells were resuspended in PBS and mixed with an equal volume of Matrigel, and subcutaneously inoculated into BALB / c female nude mice. When the tumor volume was 200-300mm 3 When the tumor volume was 200-300mm 177 Lu-FAP-2286 or 177 Lu-g4 diluted in normal saline was injected into the tail vein, and the uptake of the reconstructed mouse tumors (SUVmax) was delineated at 1h, 4h and 24h after injection respectively.

[0184] As shown in Table 5, 177 Lu-g4 had significant tumor uptake in HEK293-hFAP tumor-bearing mice, and retained more in the tumor over time.

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

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

[0187] HEK293-hFAP cells were resuspended with complete culture medium DMEM + 10% FBS, plated in Poly-D-Lysine pre-treated 6-well culture plates, and incubated in a 5% CO2, 37°C cell culture incubator overnight. Then the culture supernatant was discarded, and 2 mL of culture medium containing 0.2 nM of 177 Lu-g4, 177 Lu-FAP-2286 was added to each well, and incubated in the incubator for 1 hr and 4 hr respectively. After incubation, the supernatant was removed, and the cells were washed twice with PBS. 0.4 mL of 1 M NaOH solution was added to each well, and the cells were lysed at room temperature for 10 min. The culture wells were washed twice with PBS, and the PBS wash was collected. The total radioactivity counts of the NaOH lysate and PBS wash were measured by a γ-Counter.

[0188] As shown in Figure 4, 177 The cellular uptake of Lu-g4 in HEK293-hFAP cells increased by 20% from 1 hr to 4 hr. 177 The cellular uptake of Lu-FAP-2286 in HEK293-hFAP cells was essentially unchanged from 1 hr to 4 hr.

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

[0190] HT1080-hFAP cells were resuspended in PBS, mixed with an equal volume of Matrigel, and subcutaneously inoculated into BALB / c nude mice. After grouping the tumor-bearing mice (N = 4), each mouse was injected with a single dose of saline, 40 MBq of 177 Lu-g4, or 177 Lu-FAP-2286 via the tail vein. The mice were allowed to freely eat sterilized water and mouse chow. Tumor volume was measured every two days after administration, and the tumor volume was calculated using the formula: Tumor volume (mm 3 ) = 0.5 x tumor long diameter x tumor short diameter 2 . At 21 days after administration, the kidneys and livers of the mice in the 177 Lu-g4 administration group were collected for HE staining.

[0191] As shown in Figure 5, both 40 MBq of 177 Lu-g4 or 177 Lu-FAP-2286 can significantly inhibit tumor growth, 177 the tumor growth inhibition effect of Lu-g4 is better than that of 177Lu-FAP-2286.

[0192] As shown in Figure 6, 177 The liver and kidney tissue structure remained normal after Lu-g4 administration for 21 days.

[0193] Example 19 225 Tissue distribution of Ac-labeled compounds in tumor-bearing mice

[0194] HT080-hFAP cells were resuspended in PBS and mixed with an equal volume of Matrigel and subcutaneously inoculated into BALB / c female nude mice. When the tumor volume was 200-300 mm 3 Ac-g4 diluted in normal saline was injected into the tail vein of the mice. 225 At 4 hr after injection, the kidney and tumor tissues of the mice were taken, washed with normal saline, dried with absorbent paper and weighed. The radioactivity count of each tissue was determined by a γ-Counter, and the percentage injected dose rate per gram of tissue, %ID / g, was calculated.

[0195] As shown in the tissue biodistribution data in Table 6, 225 The uptake of Ac-g4 in the tumor tissue was greater than that in the kidney at 4 hr.

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

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

[0198] HEK293-hFAP cells were resuspended in PBS and mixed with an equal volume of Matrigel and subcutaneously inoculated into BALB / c female nude mice. When the tumor volume was 200-300 mm 3 Pb-g11 (N = 4) diluted in normal saline was injected into the tail vein of the mice. 212 At 1 hr, 4 hr and 24 hr after injection, the mice were sacrificed by cervical dislocation, and the liver, kidney, bone, muscle and tumor tissues of the mice were taken, washed with normal saline, dried with absorbent paper and weighed. The radioactivity count of each tissue was determined by a γ-Counter, and the percentage injected dose rate per gram of tissue, %ID / g, was calculated.

[0199] As shown in Table 7, 212Pb-g11 has obvious uptake in tumor, 1 hr, 4 hr, 24 hr average is 8.81% ID / g, 8.57% ID / g and 4.73% ID / g. It is quickly cleared in blood, 1 hr, 4 hr, 24 hr average is 1.81% ID / g, 0.73% ID / g and 0.04% ID / g; in the kidney distribution 1 hr, 4 hr, 24 hr average is 33.80% ID / g, 27.17% ID / g, 15.05% ID / g; in other tissues uptake is low.

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

[0201] Example 21 SPR surface plasmon resonance assay affinity Kd

[0202] The affinity Kd of FAP protein to FAP-2286, compound g, g1 was determined by SPR surface plasmon resonance.

[0203] The experiment was carried out in Biacore T200 equipment (General Electric) according to the operation manual. The chip uses CM5 series chip with carboxyl surface, and the coupling conditions are selected by experiment, pH = 5.5, and the regeneration conditions are Glycine-HCl pH 2.0. The affinity data obtained are shown in Table 8.

[0204] Table 8

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

[0206] Example 22 SA sensor chip assay affinity Kd

[0207] The biotinylated FAP protein of 10-50 ug / ml was immobilized on the surface of the SA sensor chip, and then different concentrations of the test molecules or the corresponding control samples were injected into the chip surface. The mobile phase was composed of Running buffer (HEPES pH 7.4, NaCl, P20, DMSO, etc.), 90s binding and 1800s dissociation. The Biacore 8K analysis software was used to analyze the binding kinetics data of different test molecules. The original data was fitted by the Langmuir binding model of 1:1 binding, and the kinetic parameters of binding rate (kon) and dissociation rate (koff) were calculated, 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 the affinity of compounds g4, g11 is significantly better than FAP-2286, proving that the compounds of the application have better affinity for the FAP protein of human origin.

[0211] Example 23 68 Imaging of Ga-labeled molecules in humans

[0212] The imaging agent was injected intravenously at 0.03-0.05 mCi / kg 68 Ga-g4-labeled molecules, after the drug was administered to humans, the whole body PET / CT examination (uEXPLORER, United Imaging) was performed after 60 min of rest, the scanning range was from the top of the skull to the sole, 1 bed, time 5 min. The image was obtained by using the Ordered Subset Expectation Maximization (OSEM) method for reconstruction. The results of the scan are shown in Figures 7A-7H, in which 7A esophageal cancer, 7B cervical cancer, 7C lung cancer, 7D gastric cancer, 7E renal cancer, 7F liver cancer, 7G colon cancer, 7H prostate cancer, the results show that the radionuclide label of the application is distributed in various tumors.

Claims

1. A compound represented by the following formula (I) or a salt thereof: ###00001### (I) G each independently represents a monosaccharide, disaccharide, 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 which can bind to a radionuclide; n is an integer from 1 to 3.

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

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

4. The compound of any one of claims 1 to 3, or a salt thereof, wherein, M is a group selected from the following structures: Preferably, M is Preferably, M is Preferably, M is 5. The compound of any one of claims 1-4 or a salt thereof, 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 are each independently selected from the following groups: L is selected from the group consisting of: M and L are linked by an amide bond and are a group selected from the following structures:

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

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

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

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

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

13. The compound according to claim 1, wherein the compound is preferably selected from the group consisting of: ###00011### or a salt thereof.

14. A radionuclide label comprising the compound of any one of claims 1 to 13, or a salt thereof, and a radionuclide; Preferably, wherein, the radionuclide is selected from the group consisting of a radio-diagnostic nuclide and a radio-therapeutic nuclide; preferably, The radiodiagnostic nuclide is any one or more selected from the group consisting of 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 Pb; preferably 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; preferably 86 Y, Al[ 18 F], 64 Cu, 68 Ga, 89 Zr, 99 mTc, 124 I, 203 Pb; preferably 86 Y, Al[ 18 F], 64 Cu, 68 Ga, 89 Zr, 99 mTc, 124 I; more preferably 68 Ga, 203 Pb or 64 Cu; more preferably 68 Ga or 64 Cu; more preferably 68 Ga; more preferably 203 Pb; more preferably 64 Cu; preferably, The radiotherapeutic radionuclide is any one or more of 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 Tb; preferably 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 Th; preferably 67 Cu, 90 Y, 125 I, 131 I, 177 Lu, 227 Th, 223 Ra, 225 Ac, 211 At, 161 Tb, 149 Tb; preferably 67 Cu, 90 Y, 125 I, 131 I, 177 Lu, 227 Th, 223 Ra, 225 Ac, 211 At; more preferably 227 Th, 177 Lu, 225 Ac, or 212 Pb; more preferably 177 Lu, 225 Ac or 212 Pb; more preferably 177 Lu or 212 Pb; more preferably 177 Lu; more preferably 212 Pb.

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

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

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

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

19. Use of the compound of any one of claims 1 to 13, or a salt thereof, or the radionuclide label of any one of claims 14 to 18, for the manufacture of a tumor imaging agent or an anti-tumor drug.

20. The use of claim 19, wherein, the tumor is a FAP high-expressing tumor, such as a solid tumor (in particular a FAP high-expressing solid tumor); in particular, the tumor is an epithelial tumor, a sarcoma or a mesothelioma; in particular, the tumor is selected from the group consisting of a sarcoma, a mesothelioma, an esophageal tumor, a glioblastoma, a melanoma, a colorectal cancer, a pancreatic cancer, a lung cancer, a breast cancer, a gastric cancer, a renal cancer, a cervical cancer, a liver cancer, a prostate cancer or a glottic cancer.

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

22. A compound represented by formula (II): ###00015### (II) or a salt thereof. wherein M, L, n are each defined as in any one of claims 1 to 13, respectively; In particular, the compound of formula (II) is selected from:

23. A compound of formula d: ###00019### d or a salt thereof.

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