Pharmaceutical composition and preparation method therefor

Abstract

Provided are a pharmaceutical composition and a preparation method therefor. Specifically, provided are an aqueous pharmaceutical composition of a radionuclide-labeled fibroblast activation protein-targeting ligand, and a preparation method therefor. The aqueous pharmaceutical composition has high radiochemical purity.

Description

A pharmaceutical composition and its preparation method Technical Field

[0001] This disclosure relates to an aqueous pharmaceutical composition of a radionuclide-labeled ligand targeting a fibroblast activation protein and a method for preparing the same, belonging to the pharmaceutical field. Background Technology

[0002] Fibroblast activation protein (FAP) is a type II transmembrane serine protease that plays a crucial role in the metabolism of various endogenous peptides and peptide drugs. FAP-2286, described in WO2021005125A1, contains a peptide that effectively and selectively binds to FAP and is linked to DOTA via a linker; this compound is currently in the clinical trial stage. There is an urgent need to find FAP inhibitors and their pharmaceutical compositions suitable for clinical use.

[0003] PCT / CN2024 / 104918 provides a fibroblast activation protein ligand and its radionuclide label, and it is necessary to develop a pharmaceutical composition suitable for clinical use. Summary of the Invention

[0004] This disclosure provides an aqueous pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof. C is a chelating agent, and the chelating agent is selected from DOTA or NOTA;

[0005] R is a radionuclide, which is complexed with chelating agent C. The radionuclide includes diagnostically active or therapeutically active radionuclides, and the diagnostically active radionuclide is selected from... 43 Sc、 44 Sc、 51 Mn, 52 Mn, 64 Cu、 67 Ga、 68 Ga、 86 Y、 89 Zr、 94m Tc, 99m Tc, 111 In、 152 Tb, 155 Tb, 201 Tl、 203 Pb, 18 F, 76 Br、 77 Br、 123 I, 124 I, 125 I;

[0006] The therapeutically active nuclide is selected from 47 Sc、 67 Cu、 89 Sr、 90 Y、 153 Sm、 149 Tb, 161 Tb, 177 Lu、 186 Re、 188 Re、 212 Pb, 213 Bi、 223 Ra、 225 Ac、 226 Th、 227 Th、 131 I, 211 At;

[0007] The pharmaceutical composition contains at least one anti-radiation degradation agent.

[0008] In an optional implementation, the chelating agent is selected from DOTA.

[0009] In an optional embodiment, the diagnostically active radionuclide is selected from... 43 Sc、 44 Sc、 64 Cu、 67 Ga、 68 Ga、 86 Y、 89 Zr、 99m Tc, 111 In、 152 Tb, 155 Tb, 203 Pb, 18 F, 76 Br、 77 Br、 123 I, 124 I, 125 I.

[0010] In an optional embodiment, the diagnostically active radionuclide is selected from... 64 Cu、 68 Ga、 89 Zr、 99m Tc, 111 In、 18 F, 123 I and 124 I.

[0011] In an optional embodiment, the therapeutically active radionuclide is selected from... 47 Sc、 67 Cu、 90 Y、 177 Lu、188 Re、 212 Pb, 213 Bi、 225 Ac、 227 Th、 131 I, 211 At.

[0012] In an optional embodiment, the therapeutically active radionuclide is selected from... 90 Y、 177 Lu、 225 Ac、 227 Th、 131 I and 211 At.

[0013] In an optional embodiment, the radionuclide R is selected from... 177 Lu、 161 Tb, 212 Pb, 18 F, 225 Ac、 68 Ga、 64 Cu.

[0014] In an optional embodiment, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from,

[0015] In some embodiments, the radionuclide is present at a concentration that provides radioactivity from 100 to 1000 MBq / mL.

[0016] In an optional embodiment, the radionuclide is present at a concentration that provides radioactivity from 300 to 800 MBq / mL.

[0017] In an optional embodiment, the radionuclide is present at a concentration that provides radioactivity from 350 to 450 MBq / mL.

[0018] In some embodiments, the anti-radiation degrading agent is selected from one or more of gentian acid or its salts, ascorbic acid or its salts, cysteine ​​or its salts, acetylcysteine ​​or its salts, methionine, methionine, histidine, melatonin, ethanol, and Se-methionine.

[0019] In an optional embodiment, the anti-radiation degrading agent is selected from one or more of gentian acid or its salt, ascorbic acid or its salt, and cysteine ​​or its salt.

[0020] In an optional embodiment, the anti-radiation degrading agent is selected from a combination of gentianic acid or its salt, ascorbic acid or its salt, and cysteine ​​or its salt.

[0021] In some embodiments, the concentration of gentianic acid or its salt is selected from 0.10 mg / mL to 3 mg / mL.

[0022] In an optional embodiment, the concentration of gentianic acid or its salt is selected from 0.20 mg / mL to 1 mg / mL.

[0023] In an optional embodiment, the concentration of gentianic acid or its salt is selected from 0.20 mg / mL to 0.60 mg / mL.

[0024] In an optional embodiment, the concentration of gentianic acid or its salt is selected from 0.40 mg / mL to 0.60 mg / mL, for example 0.41 mg / mL, 0.42 mg / mL, 0.43 mg / mL, 0.44 mg / mL, 0.45 mg / mL, 0.46 mg / mL, 0.47 mg / mL, 0.48 mg / mL, 0.49 mg / mL, 0.50 mg / mL, 0.51 mg / mL, 0.52 mg / mL, 0.53 mg / mL, 0.54 mg / mL, 0.55 mg / mL, 0.56 mg / mL, 0.57 mg / mL, 0.58 mg / mL, 0.59 mg / mL, 0.60 mg / mL, or any value between any two points.

[0025] In some embodiments, the concentration of the ascorbic acid or its salt is selected from 1 mg / mL to 100 mg / mL.

[0026] In an optional embodiment, the concentration of the ascorbic acid or its salt is selected from 10 mg / mL to 80 mg / mL.

[0027] In an optional embodiment, the concentration of the ascorbic acid or its salt is selected from 30 mg / mL to 70 mg / mL.

[0028] In an optional embodiment, the concentration of the ascorbic acid or its salt is selected from 30 mg / mL to 40 mg / mL, for example 30 mg / mL, 31 mg / mL, 32 mg / mL, 33 mg / mL, 34 mg / mL, 35 mg / mL, 36 mg / mL, 37 mg / mL, 38 mg / mL, 39 mg / mL, 40 mg / mL, or any value between any two points.

[0029] In some embodiments, the concentration of the cysteine ​​or its salt is selected from 0.50 mg / mL to 10 mg / mL.

[0030] In an optional embodiment, the concentration of the cysteine ​​or its salt is selected from 2 mg / mL to 10 mg / mL.

[0031] In an optional embodiment, the concentration of the cysteine ​​or its salt is selected from 2 mg / mL to 6 mg / mL.

[0032] In an optional embodiment, the concentration of the cysteine ​​or its salt is selected from 2 mg / mL to 3 mg / mL, for example, 2.1 mg / mL, 2.2 mg / mL, 2.3 mg / mL, 2.4 mg / mL, 2.5 mg / mL, 2.6 mg / mL, 2.7 mg / mL, 2.8 mg / mL, 2.9 mg / mL, 3.0 mg / mL, or any value between any two points.

[0033] In some embodiments, the pharmaceutical composition contains a buffer with a pH selected from 4.0-6.5.

[0034] In an optional embodiment, the pH of the pharmaceutical composition is selected from 4.5-6.0.

[0035] In an optional embodiment, the pH of the pharmaceutical composition is selected from 5.0-5.5, for example, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, or any value between any two points.

[0036] In some embodiments, the pharmaceutical composition contains a buffer selected from acetate buffers, citrate buffers, formate buffers, and phosphate buffers.

[0037] In an optional embodiment, the buffer is sodium acetate, or a combination of acetate and sodium acetate.

[0038] In an optional embodiment, the buffer is sodium acetate.

[0039] In some embodiments, the concentration of sodium acetate in the pharmaceutical composition is selected from 0.10 mg / mL to 5 mg / mL.

[0040] In an optional embodiment, the concentration of sodium acetate is selected from 0.1 mg / mL to 2 mg / mL.

[0041] In an optional embodiment, the concentration of sodium acetate is selected from 1 mg / mL to 2 mg / mL, for example, 1.0 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, 2.0 mg / mL, or any value between any two points.

[0042] In some embodiments, the pharmaceutical composition contains a pH adjuster.

[0043] In an optional embodiment, the pH adjuster is sodium hydroxide.

[0044] In some embodiments, the pharmaceutical composition contains a metal masking agent.

[0045] In an optional embodiment, the metal masking agent is selected from DTPA (diethylenetriaminepentaacetic acid) or its salt, DMSA (dimercaptosuccinic acid) or its salt, TTHA (triethylenetetraminehexaacetic acid) or its salt.

[0046] In some embodiments, the concentration of DTPA or a salt thereof in the pharmaceutical composition is selected from 0.01 mg / mL to 0.2 mg / mL.

[0047] In an optional embodiment, the concentration of the DTPA or its salt is selected from 0.02 mg / mL to 0.1 mg / mL, for example, 0.02 mg / mL, 0.03 mg / mL, 0.04 mg / mL, 0.05 mg / mL, 0.06 mg / mL, 0.07 mg / mL, 0.08 mg / mL, 0.09 mg / mL, 0.10 mg / mL, or any value between any two points.

[0048] In some embodiments, the pharmaceutical composition has a radiochemical purity of ≥90.0%.

[0049] In an optional embodiment, the composition has a radiochemical purity of ≥95.0%.

[0050] In some embodiments, the pharmaceutical composition has a radiochemical purity of ≥90.0% after being stored at or below room temperature for 72 hours.

[0051] In an optional embodiment, the composition has a radiochemical purity of ≥95.0% after being stored at or below room temperature for 72 hours.

[0052] This disclosure provides, in one aspect, a compound represented by formula (IA),

[0053] The mass fraction of trifluoroacetic acid is selected from 1-30%.

[0054] In some embodiments, the compound represented by formula (IA) provided in this disclosure has a trifluoroacetic acid mass fraction selected from 5-15%.

[0055] In specific embodiments, the compound represented by formula (IA) provided in this disclosure, wherein the mass fraction of trifluoroacetic acid is selected from 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, ... 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6.0%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7%, 6.8%, 6.9%, 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7% 7.8%, 7.9%, 8.0%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%, 9.0%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%, 10.0%, 10.1%, 10 0.2%, 10.3%, 10.4%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9%, 11.0%, 11.1%, 11.2%, 11.3%, 11.4%, 11.5%, 11.6%, 11.7%, 11.8%, 11.9%, 12.0%, 12.1%, 12.2%, 12.3%, 12.4%, 12.5%, 12.6%, 12.7%, 12.8%, 12.9%, 13.0%, 13.1%, 13.2%, 13.3%, 13.4%, 13.5%, 13.6%, 13.7%, 13.8%, 13.9%, 14.0%, 14.1%, 14.2%, 14.3% 14.4%, 14.5%, 14.6%, 14.7%, 14.8%, 14.9%, 15.0%, 15.1%, 15.2%, 15.3%, 15.4%, 15.5%, 15.6%, 15.7%, 15.8%, 15.9%, 16.0%, 16.1%, 16.2%, 16.3%, 16.4% %, 16.5%, 16.6%, 16.7%, 16.8%, 16.9%, 17.0%, 17.1%, 17.2%, 17.3%, 17.4%, 17.5%, 17.6%, 17.7%, 17.8%, 17.9%, 18.0%, 18.1%, 18.2%, 18.3%, 18.4%, 18.5%, 18.6%, 18.7%, 18.8%, 18.9%, 19.0%, 19.1%, 19.2%, 19.3%, 19.4%, 19.5%, 19.6%, 19.7%, 19.8%, 19.9%, 20.0%, 20.1%, 20.2%, 20.3%, 20.4%, 20.5%, 20.6%, 20.7%, 20.8%, 20.9%, 21.0%, 21.1%, 21.2%, 21.3%, 21.4% 21.5%, 21.6%, 21.7%, 21.8%, 21.9%, 22.0%, 22.1%, 22.2%, 22.3%, 22.4%, 22.5%, 22.6%, 22.7%, 22.8%, 22.9%, 23.0%, 23.1%, 23.2%, 23.3%, 23.4%, 23.5%, 23.6%, 23.7%, 23.8%, 23.9%, 24.0%, 24.1%, 24.2%, 24.3%, 2 4.4%, 24.5%, 24.6%, 24.7%, 24.8%, 24.9%, 25.0%, 25.1%, 25.2%, 25.3%, 25.4%, 25.5%, 25.6%, 25.7%, 25.8%, 25.9%, 26.0%, 26.1%, 26.2%, 26.3%, 26.4%, 26.5%, 26.6%, 26.7%, 26.8%, 26.9%, 27.0%, 27.1%, 27.2%, 27. 3%, 27.4%, 27.5%, 27.6%, 27.7%, 27.8%, 27.9%, 28.0%, 28.1%, 28.2%, 28.3%, 28.4%, 28.5%, 28.6%, 28.7%, 28.8%, 28.9%, 29.0%, 29.1%, 29.2%, 29.3%, 29.4%, 29.5%, 29.6%, 29.7%, 29.8%, 29.9%, 30.0%, or any value between two points.

[0056] In some embodiments, the compound represented by formula (IA) provided in this disclosure is a solid.

[0057] In some embodiments, the compound represented by formula (IA) provided in this disclosure is an amorphous compound.

[0058] In some embodiments, the compound represented by formula (IA) provided in this disclosure is a lyophilized powder.

[0059] This disclosure further provides a method for preparing the compound represented by formula (IA) above, comprising the step of reacting compound DOTA-09 with 1.0-2.0 equivalents (molar ratio) of trifluoroacetic acid.

[0060] The method for preparing the compound shown in formula (IA) provided in this disclosure, wherein the multiple of trifluoroacetic acid can be selected from 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0 equivalents (molar ratio), or any value between any two points.

[0061] In some embodiments, the method for preparing the compound represented by formula (IA) provided in this disclosure uses a reaction solvent that is a mixture of a nitrile solvent and water.

[0062] In an optional embodiment, the method for preparing the compound represented by formula (IA) provided in this disclosure uses acetonitrile as the nitrile solvent.

[0063] In an optional embodiment, the method for preparing the compound represented by formula (IA) provided in this disclosure further includes a freeze-drying step.

[0064] This disclosure further provides the use of the aforementioned pharmaceutical composition, or the compound represented by the aforementioned formula (IA), in the preparation of a medicament for imaging diseases or conditions associated with fibroblast activation protein, or for treating diseases or conditions associated with fibroblast activation protein.

[0065] In some embodiments, the diseases or conditions associated with fibroblast activation proteins described in this disclosure are selected from proliferative diseases, chronic inflammation, fibrosis (liver, kidney, lung), tissue remodeling, scarring, tissue infection, or inflammatory lesions. The proliferative diseases are selected from the group consisting of breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, thyroid cancer, lung adenocarcinoma, kidney cancer, liver cancer, lung cancer, esophageal cancer, hepatobiliary cancer, gastric cancer, nasopharyngeal carcinoma, head and neck cancer, bladder cancer, glioblastoma, peritoneal metastatic cancer, melanoma, fibrosarcoma, bone and connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, and adenocarcinoma, as well as benign tumors. The chronic inflammation is selected from rheumatoid arthritis, osteoarthritis, Crohn's disease, or atherosclerotic plaques. The tissue remodeling occurs after myocardial infarction. The scarring is selected from scar formation, scar tumors, or keloid scars.

[0066] This disclosure further provides the use of the aforementioned pharmaceutical composition, or the compound represented by the aforementioned formula (IA), in the preparation of a medicament for the prevention, diagnosis, and treatment of proliferative diseases, chronic inflammation, fibrosis (liver, kidney, lung), tissue remodeling, scarring, tissue infection, or inflammatory lesions, wherein the proliferative disease is selected from the group consisting of breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, thyroid cancer, lung adenocarcinoma, kidney cancer, liver cancer, lung cancer, esophageal cancer, hepatobiliary cancer, gastric cancer, nasopharyngeal carcinoma, head and neck cancer, bladder cancer, glioblastoma, peritoneal metastatic cancer, melanoma, fibrosarcoma, bone and connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, and adenocarcinoma, and benign tumors; the chronic inflammation is selected from rheumatoid arthritis, osteoarthritis, Crohn's disease, or atherosclerotic plaques; the tissue remodeling occurs after myocardial infarction; and the scarring is selected from scar formation, scar tumors, or scar tissue.

[0067] On the other hand, this disclosure provides a method for preparing the aforementioned aqueous pharmaceutical composition, comprising the following steps:

[0068] (1) Prepare an aqueous solution containing a radioactive nuclide 1;

[0069] (2) Prepare an aqueous solution containing the precursor compound 2;

[0070] (3) Prepare an aqueous solution containing a buffer and at least one anti-radiation degradation agent;

[0071] (4) Mix the solutions obtained in steps (1), (2), and (3) and heat the resulting mixture;

[0072] The precursor compound is the compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, wherein the chelating agent C is DOTA, and the radionuclide is 177 Lu.

[0074] In some embodiments, the preparation method provided in this disclosure uses a precursor compound represented by formula (IA).

[0075] In some embodiments, the radiation-degrading agent in the aqueous solution 3 provided in this disclosure is selected from one or more of gentian acid or its salt, cysteine ​​or its salt, ascorbic acid or its salt, acetylcysteine ​​or its salt, methionine, histidine, melatonin, ethanol and Se-methionine.

[0076] In an optional embodiment, the anti-radiation degrading agent is selected from one or more of gentianic acid or its salts, cysteine ​​or its salts.

[0077] In an optional embodiment, the anti-radiation degrading agent is selected from a combination of gentianic acid and cysteine ​​hydrochloride.

[0078] In some embodiments, the concentration of gentianic acid or its salt in the aqueous solution 3 is selected from 5.0 mg / mL to 50.0 mg / mL in the preparation method provided in this disclosure.

[0079] In an optional embodiment, the concentration of gentianic acid or its salt is selected from 5.0 mg / mL to 30.0 mg / mL.

[0080] In an optional embodiment, the concentration of gentianic acid or its salt is selected from 20.0 mg / mL to 30.0 mg / mL, for example, 21.0 mg / mL, 22.0 mg / mL, 23.0 mg / mL, 24.0 mg / mL, 25.0 mg / mL, 26.0 mg / mL, 27.0 mg / mL, 28.0 mg / mL, 29.0 mg / mL, 30.0 mg / mL, or any value between any two points.

[0081] In some embodiments, the preparation method provided in this disclosure uses an aqueous solution 3 with a concentration of cysteine ​​or its salt selected from 10.0 mg / mL to 50.0 mg / mL.

[0082] In an optional embodiment, the concentration of the cysteine ​​or its salt is selected from 25.0 mg / mL to 35.0 mg / mL, for example, 25.0 mg / mL, 26.0 mg / mL, 27.0 mg / mL, 28.0 mg / mL, 29.0 mg / mL, 30.0 mg / mL, 31.0 mg / mL, 32.0 mg / mL, 33.0 mg / mL, 34.0 mg / mL, 35.0 mg / mL, or any value between any two points.

[0083] In some embodiments, the preparation method provided in this disclosure uses an aqueous solution 3 containing a buffer selected from acetate buffers, citrate buffers, formate buffers, and phosphate buffers.

[0084] In an optional embodiment, the buffer is selected from sodium acetate, or a combination of acetate and sodium acetate.

[0085] In an optional embodiment, the buffer is sodium acetate.

[0086] In some embodiments, the concentration of sodium acetate in the aqueous solution 3 in the preparation method provided in this disclosure is selected from 30.0 mg / mL to 80.0 mg / mL.

[0087] In an optional embodiment, the concentration of sodium acetate is selected from 60.0 mg / mL to 80.0 mg / mL, for example, 60.0 mg / mL, 61.0 mg / mL, 62.0 mg / mL, 63.0 mg / mL, 64.0 mg / mL, 65.0 mg / mL, 66.0 mg / mL, 67.0 mg / mL, 68.0 mg / mL, 69.0 mg / mL, 70.0 mg / mL, 71.0 mg / mL, 72.0 mg / mL, 73.0 mg / mL, 74.0 mg / mL, 75.0 mg / mL, 76.0 mg / mL, 77.0 mg / mL, 78.0 mg / mL, 79.0 mg / mL, 80.0 mg / mL, or any value between any two points.

[0088] In some embodiments, the pH of the aqueous solution 3 provided in this disclosure is selected from 4.0-6.0.

[0089] In an optional embodiment, the pH of the aqueous solution 3 is selected from 4.5-5.5, for example, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, or any value between any two points.

[0090] In some embodiments, the concentration of the precursor compound in the aqueous solution 2 is selected from 0.5 mg / mL to 5.0 mg / mL in the preparation method provided in this disclosure.

[0091] In some embodiments, the concentration of the precursor compound in the aqueous solution 2 is selected from 1.0 mg / mL to 5.0 mg / mL in the preparation method provided in this disclosure.

[0092] In an optional embodiment, the concentration of the precursor compound is selected from 1.0 mg / mL to 2.0 mg / mL, for example, 1.0 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, 2.0 mg / mL, or any value between any two points.

[0093] In some embodiments, the preparation method provided in this disclosure uses a radionuclide as... 177 Lu, in aqueous solution 1 177 The amount of Lu is selected from 0.01 Ci to 5.0 Ci.

[0094] In an optional implementation, aqueous solution 1 177 The amount of Lu is selected from 0.1 Ci to 1.0 Ci.

[0095] In some embodiments, the preparation method provided in this disclosure includes, in the aqueous solution 1, the aqueous solution 1 contains 177 LuCl3 and HCl.

[0096] In some embodiments, the preparation method provided in this disclosure uses a heating reaction temperature selected from 70°C to 200°C.

[0097] In an optional implementation, the temperature of the heating reaction is selected from 80°C to 100°C.

[0098] In an optional implementation, the temperature of the heating reaction is selected from 85°C to 95°C.

[0099] In some embodiments, the preparation method provided in this disclosure uses a heating reaction time selected from 5 to 30 minutes.

[0100] In an optional implementation, the heating reaction time is selected from 10-20 minutes.

[0101] In some embodiments, the preparation method provided in this disclosure further includes:

[0102] (5) Prepare an aqueous solution containing at least one anti-radiation degradation agent 4;

[0103] (6) Dilute the solution obtained in step (4) with aqueous solution 4.

[0104] In some embodiments, the radiation-resistant degrading agent in the aqueous solution 4 of the preparation method provided in this disclosure is selected from one or more of cysteine ​​or its salts, ascorbic acid or its salts.

[0105] In an optional embodiment, the radiation-resistant degrading agent is selected from a combination of ascorbic acid and cysteine ​​hydrochloride.

[0106] In some embodiments, the concentration of ascorbic acid or its salt in the aqueous solution 4 provided in this disclosure is selected from 20.0 mg / mL to 50.0 mg / mL.

[0107] In an optional embodiment, the concentration of the ascorbic acid or its salt is selected from 30.0 mg / mL to 40.0 mg / mL, for example, 30.0 mg / mL, 31.0 mg / mL, 32.0 mg / mL, 33.0 mg / mL, 34.0 mg / mL, 35.0 mg / mL, 36.0 mg / mL, 37.0 mg / mL, 38.0 mg / mL, 39.0 mg / mL, 40.0 mg / mL, or any value between any two points.

[0108] In some embodiments, the preparation method provided in this disclosure uses an aqueous solution 4 in which the concentration of cysteine ​​or its salt is selected from 1.0 mg / mL to 5.0 mg / mL.

[0109] In an optional embodiment, the concentration of cysteine ​​or its salt is selected from 1.0 mg / mL to 3.0 mg / mL, for example, 1.0 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, 2.0 mg / mL, 2.1 mg / mL, 2.2 mg / mL, 2.3 mg / mL, 2.4 mg / mL, 2.5 mg / mL, 2.6 mg / mL, 2.7 mg / mL, 2.8 mg / mL, 2.9 mg / mL, 3.0 mg / mL, or any value between any two points.

[0110] In some embodiments, the preparation method provided in this disclosure further includes a metal masking agent in the aqueous solution 4.

[0111] In an optional embodiment, the metal masking agent is selected from DTPA (diethylenetriaminepentaacetic acid) or its salt, DMSA (dimercaptosuccinic acid) or its salt, TTHA (triethylenetetraminehexaacetic acid) or its salt.

[0112] In an optional embodiment, the metal masking agent is selected from DTPA (diethylenetriaminepentaacetic acid) or its salt.

[0113] In some embodiments, the preparation method provided in this disclosure uses DTPA or its salts at a concentration selected from 0.01 mg / mL to 0.1 mg / mL.

[0114] In an optional embodiment, the concentration of DTPA or its salt is selected from 0.03 mg / mL to 0.06 mg / mL, for example, 0.03 mg / mL, 0.04 mg / mL, 0.05 mg / mL, 0.06 mg / mL, or any value between any two points.

[0115] In some embodiments, the preparation method provided in this disclosure further includes a pH adjuster in the aqueous solution 4.

[0116] In an optional embodiment, the pH adjuster is sodium hydroxide.

[0117] In some embodiments, the preparation method provided in this disclosure uses sodium hydroxide with a concentration selected from 1.0 mg / mL to 10.0 mg / mL.

[0118] In an optional embodiment, the concentration of sodium hydroxide is selected from 5.0 mg / mL to 10.0 mg / mL, for example, 5.1 mg / mL, 5.2 mg / mL, 5.3 mg / mL, 5.4 mg / mL, 5.5 mg / mL, 5.6 mg / mL, 5.7 mg / mL, 5.8 mg / mL, 5.9 mg / mL, 6.0 mg / mL, 6.1 mg / mL, 6.2 mg / mL, 6.3 mg / mL, 6.4 mg / mL, 6.5 mg / mL, 6.6 mg / mL, 6.7 mg / mL, 6.8 mg / mL, 6.9 mg / mL, 7.0 mg / mL, 7.1 mg / mL, 7.2 mg / mL, 7.3 mg / mL, 7.4 mg / mL. g / mL, 7.5 mg / mL, 7.6 mg / mL, 7.7 mg / mL, 7.8 mg / mL, 7.9 mg / mL, 8.0 mg / mL, 8.1 mg / mL, 8.2 mg / mL, 8.3 mg / mL, 8.4 mg / mL, 8.5 mg / mL, 8.6 mg / mL, 8.7 mg / mL, 8.8 mg / mL, 8.9 mg / mL, 9.0 mg / mL, 9.1 mg / mL, 9.2 mg / mL, 9.3 mg / mL, 9.4 mg / mL, 9.5 mg / mL, 9.6 mg / mL, 9.7 mg / mL, 9.8 mg / mL, 9.9 mg / mL, 10.0 mg / mL, or any value between two points.

[0119] Radiation-resistant degradative agents: Stabilizers that protect organic molecules from radioactive degradation. For example, when gamma rays emitted from a radioactive nuclide break the bonds formed between the atoms of an organic molecule and free radicals, those free radicals are then removed by the stabilizer. This prevents the free radicals from undergoing any other chemical reactions that could lead to unwanted, potentially ineffective, or even toxic molecules.

[0120] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0121] In this disclosure, "mixing" means that the order in which the components are added is not limited. For example, mixing A and B can mean either A is added to B or B is added to A.

[0122] "Buffer" refers to a buffer that is resistant to pH changes through the action of its acid-base conjugate components. Examples of buffers that maintain pH within an appropriate range include acetates, formates, citrates, succinates, gluconates, histidines, oxalates, lactates, phosphates, citrates, tartrates, fumarates, glycylglycine, and other organic acid buffers.

[0123] "Acetate buffer" is a buffer containing acetate ions. Examples of acetate buffers include sodium acetate, histidine acetate, potassium acetate, calcium acetate, magnesium acetate, etc. A preferred acetate buffer is sodium acetate buffer.

[0124] A "phosphate buffer" is a buffer that contains phosphate ions. Examples of phosphate buffers include disodium hydrogen phosphate-sodium dihydrogen phosphate and disodium hydrogen phosphate-potassium dihydrogen phosphate. A preferred phosphate buffer is a disodium hydrogen phosphate-sodium dihydrogen phosphate buffer.

[0125] "Citrate buffer" is a buffer that includes citrate ions. A preferred citrate buffer is a citrate-sodium citrate buffer.

[0126] "Formate buffer" is a buffer that includes formate ions. The preferred formate buffer is sodium formate-formate buffer.

[0127] The term "metal masking agent" as used in this disclosure refers to a chelating agent suitable for complexing radioactive nuclide metal ions, such as DTPA: diethylenetriaminepentaacetic acid. This definition can be found in the definition of "Sequestering agent" in WO2020021322A.

[0128] The values ​​described in this disclosure, such as concentration and pH, are instrument measurements or calculated values ​​after instrument measurement, and there is a certain degree of error. Generally speaking, plus or minus 10% is within the reasonable error range.

[0129] Unless otherwise specified, the room temperature mentioned in this disclosure is 20℃-30℃.

[0130] The term "radiochemical purity" as used in this disclosure refers to the percentage of a specified radionuclide present in a specified chemical or biological form. Radiochromatography, such as HPLC or instantaneous thin-layer chromatography (iTLC), is the most widely accepted method for determining radiochemical purity in the field of radiopharmaceuticals.

[0131] The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

[0132] The compounds disclosed herein can exist in specific geometric or stereoisomeric forms. This disclosure envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this disclosure. The compounds containing asymmetric carbon atoms of this disclosure can be isolated in optically active pure form or in racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0133] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound disclosed herein, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0134] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. In the chemical structure of the compounds described in this disclosure, the bonds... No configuration was specified, i.e., key The configuration can be E-type or Z-type, or both E-type and Z-type. In the chemical structure of the compounds described in this disclosure, the bonds... It represents the interaction formed or potentially formed between a nuclide and neighboring atoms, and can include coordinate bonds, ionic bonds, van der Waals forces, etc.

[0135] The compounds and intermediates disclosed herein may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. Attached Figure Description

[0136] Figure 1 shows the compounds disclosed herein and... 68 Uptake values ​​of Ga-FAP-2286 in tumors at different time points.

[0137] Figure 2 shows the compounds disclosed herein and... 68 Tumor / kidney uptake ratio of Ga-FAP-2286 at different time points.

[0138] Figure 3 shows the compounds disclosed herein and 177 Uptake values ​​of Lu-FAP-2286 in tumors at different time points.

[0139] Figure 4 shows the compounds disclosed herein and 177 Tumor / kidney uptake ratio of Lu-FAP-2286 at different time points.

[0140] Figure 5 shows the compound disclosed herein and 68 Uptake values ​​of Ga-FAP-2286 in tumors at different time points.

[0141] Figure 6 shows the compounds disclosed herein and... 68 The ratio of Ga-FAP-2286 uptake by tumor / kidney at different time points.

[0142] Figure 7 shows the relationship between the compound disclosed in this paper and Al. 18 F-NOTA-2286 uptake values ​​in tumors at different time points.

[0143] Figure 8 shows the relationship between the compound disclosed in this paper and Al. 18 F-NOTA-2286 uptake values ​​in tumors / kidneys at different time points.

[0144] Figure 9 shows different radiation doses. 177 Tumor growth curves of U-87MG model mice after Lu-DOTA-09 administration (n=8, mean ± standard deviation).

[0145] Figure 10 shows different radiation doses. 177 Changes in body weight in mice during Lu-DOTA-09 administration (n=8, mean ± standard deviation).

[0146] Figure 11 shows different radiation doses. 177 Survival period of U-87MG model mice after Lu-DOTA-09 administration. Detailed Implementation

[0147] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0148] Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available conventional reagents.

[0149] The HPLC / MS analytical chromatographic conditions are as follows:

[0150] 10 μl of sample was automatically injected per sample. Mobile phase: A: 0.1% formic acid aqueous solution, B: 0.1% formic acid acetonitrile solution. Flow rate: 1.5 mL / min. Gradient: B increased from 10% to 95% within 0-6 min, from 95% to 100% within 6-8 min, from 100% to 10% within 8-8.10 min, and maintained at 10% within 8.10-11.0 min.

[0151] Equipment model: Thermo Fisher ULTIMATE3000 ISQEM.

[0152] Column: Eclipse Plus C18, 3.5nm, 4.6×100mm.

[0153] UV detection wavelength: 220 nm.

[0154] Compound purity data were obtained through manual integration, and molecular weight [M+1] was collected. + Or [M-1] - .

[0155] The chromatographic conditions for preparative liquid chromatography are as follows:

[0156] Mobile phase: A: 0.1% aqueous trifluoroacetic acid solution, B: 0.1% trifluoroacetic acid acetonitrile solution. Flow rate: 60 mL / min. Gradient: B increases from 25% to 45% within 0-20.0 min, B increases from 45% to 70% within 20.0-30.0 min, and B remains at 70% within 30.0-40.0 min.

[0157] Equipment model: Agilent AGILENT1260Ⅱ.

[0158] Chromatographic column: HPLCONE, 5.0μm, 30×250mm.

[0159] UV detection wavelength: 220 nm.

[0160] The chromatographic conditions for radio-HPLC analysis are as follows:

[0161] 5-20 μl of sample was automatically injected per sample. Mobile phase: A: 0.1% formic acid aqueous solution, B: 0.1% formic acid acetonitrile solution. Flow rate: 0.8 mL / min. Gradient: B increased from 10% to 50% within 0-24 min, B increased from 50% to 10% within 24-25 min, and B was maintained at 10% within 25-35 min.

[0162] Equipment model: Thermo Fisher ULTIMATE3000 ISQEM.

[0163] Chromatographic column: XBridge C18 3.5μm, 4.6*150mm.

[0164] UV detection wavelength: 225nM.

[0165] Radioactive detector: 30,000 cps / V.

[0166] Radiochemical purity is obtained through manual integration.

[0167] In the examples, the abbreviations correspond to the full Chinese names:

[0168] Example 1. Preparation of DOTA-09

[0169] a. Loading the first amino acid onto a solid support

[0170] CTC resin (degree of substitution = 1.09 mmol / g) was selected as the solid-phase support. The resin was swollen with DMF for 1 h. Then, an amino acid solution was prepared: 3.00 eq Fmoc-Cys(Trt)-OH and 6.00 eq DIPEA were dissolved in 8 times the weight of the resin in DMF. After stirring evenly, the solution was reacted with the resin for 3 h. The resin was washed, and the ends were capped with methanol and DIPEA. The resin was washed 4 to 6 times with 8 times the weight of the resin in DMF. The resin was then washed successively with 8 times the weight of the resin in isopropyl ether, DCM, and isopropyl ether. After shrinking the resin, it was dried and the degree of substitution was measured for later use.

[0171] b. Amino acid coupling

[0172] During synthesis, each amino acid is coupled using the general coupling method described below.

[0173] The Fmoc-Cys(Trt)-CTC resin obtained in the previous step was swollen with 8 times its weight of DMF for 1 hour. The Fmoc protecting group was removed twice with 8 times its weight of 20% piperidine / DMF solution (5 min for the first time, 20 min for the second time). After deprotection, the resin was washed 4–6 times with 8 times its weight of DMF. An amino acid activation solution was prepared: 3.0 eq amino acids and 3.0 eq HBTU were dissolved in 8 vol DMF. 3.0 eq DIPEA was added for activation for 2–5 min, followed by reaction. After the reaction, deprotection was performed, and the resin was washed 4–6 times with 8 times its weight of DMF. After coupling the linear peptide resin using the above method, the resin was washed, shrunken, and dried for later use.

[0174] c. Pyrolysis

[0175] The obtained peptide resin was lysed using a lysis buffer with a ratio of TFA / DTT / H2O / Tips = 94 / 2.5 / 2.5 / 1. The amount of lysis buffer added was 8 to 10 times the mass of the peptide resin. After lysis for 2 hours, the filtrate was obtained by filtration. The filtrate was then poured into isopropyl ether at a mass of 80 to 100 times the mass of the peptide resin to crystallize. After filtration, the filtrate was rinsed with isopropyl ether and dried to obtain linear crude peptides.

[0176] d. Cycloning

[0177] The obtained linear crude peptide was dissolved in a 1:1 mixture of acetonitrile and purified water (400 times the mass of the crude peptide). First, 7.2 eq of DIPEA was added, followed by 1.2 eq of 1,3,5-tris(bromomethyl)benzene. After the reaction was complete, 3.6 eq of mercaptoethylamine was added directly to the system. The reaction was then desolvated under reduced pressure, and the residue was purified by preparative liquid chromatography and lyophilized to obtain the cyclic peptide intermediate.

[0178] e. Connect to DOTA

[0179] The obtained cyclic peptide lyophilized powder was dissolved in 10 times its mass of DMF, and 4.0 eq DIPEA and 2.0 eq DOTA-NHS were added. The reaction was monitored by LCMS until the end of the reaction. After purification by preparative liquid chromatography, the target compound was obtained by lyophilization.

[0180] Purity: 98.9%;

[0181] MS m / z (ESI): 1637.78 [MH] - .

[0182] Example 2. Preparation of the compound shown in formula (IA)

[0183] Instrument Information

[0184] (1) The DOTA-09 prepared in Example 1 was dissolved in a mixed solvent of acetonitrile and water, and purified using a CS-Prep200 industrial preparative chromatography system. The mobile phase information is as follows:

[0185] Mobile phase A: 0.1% trifluoroacetic acid aqueous solution

[0186] Mobile phase B: 0.1% trifluoroacetic acid acetonitrile solution

[0187] (2) The fraction obtained in step 1 was concentrated to a certain volume using a CS-Prep200 industrial preparative chromatography system. The mobile phase information is as follows:

[0188] Mobile phase A: purified water

[0189] Mobile phase B: Preparation of acetonitrile

[0190] (3) Add a calculated amount (1.0-1.5N) of trifluoroacetic acid, then concentrate and freeze dry to obtain the product.

[0191] Example 3. Preparation of Nota-09

[0192] a. Loading the first amino acid onto a solid support

[0193] CTC resin (degree of substitution = 1.09 mmol / g) was selected as the solid-phase support. The resin was swollen with DMF for 1 h. Then, an amino acid solution was prepared: 3.00 eq Fmoc-Cys(Trt)-OH and 6.00 eq DIPEA were dissolved in 8 times the weight of the resin in DMF. After stirring evenly, the solution was reacted with the resin for 3 h. The resin was washed, end-capped with methanol and DIPEA, and washed 4-6 times with 8 times the weight of the resin in DMF. The resin was then washed successively with 8 times the weight of the resin in isopropyl ether, DCM, and isopropyl ether. After shrinking the resin, it was dried and the degree of substitution was measured for later use.

[0194] b. Amino acid coupling

[0195] During synthesis, each amino acid is coupled using the general coupling method described below.

[0196] The Fmoc-Cys(Trt)-CTC resin obtained in the previous step was swollen with 8 times its weight of DMF for 1 hour. The Fmoc protecting group was removed twice with 8 times its weight of 20% piperidine / DMF solution (5 min for the first time, 20 min for the second time). After deprotection, the resin was washed 4-6 times with 8 times its weight of DMF. An amino acid activation solution was prepared: 3.0 eq amino acids and 3.0 eq HBTU were dissolved in 8 vol DMF. 3.0 eq DEPEA was added for activation for 2-5 min, followed by reaction. After the reaction, deprotection was performed, and the resin was washed 4-6 times with 8 times its weight of DMF. After coupling the linear peptide resin using the above method, the resin was washed, shrunken, and dried for later use.

[0197] c. Pyrolysis

[0198] The obtained peptide resin was lysed using a lysis buffer with a ratio of TFA / DTT / H2O / Tips = 94 / 2.5 / 2.5 / 1. The amount of lysis buffer added was 8 to 10 times the mass of the peptide resin. After lysis for 2 hours, the filtrate was obtained by filtration. The filtrate was then poured into isopropyl ether at a mass of 80 to 100 times the mass of the peptide resin to crystallize. After filtration, the filtrate was rinsed with isopropyl ether and dried to obtain linear crude peptides.

[0199] d. Cycloning

[0200] The obtained linear crude peptide was dissolved in a 1:1 mixture of acetonitrile and purified water (400 times the mass of the crude peptide). First, 7.2 eq of DIPEA was added, followed by 1.2 eq of 1,3,5-tris(bromomethyl)benzene. After the reaction was complete, 3.6 eq of mercaptoethylamine was added directly to the system. The reaction was then desolvated under reduced pressure, and the residue was purified by preparative liquid chromatography and lyophilized to obtain the cyclic peptide intermediate.

[0201] e. Connect to NOTA

[0202] The obtained lyophilized cyclic peptide powder was dissolved in 10 times its mass of DMF, and 4.0 eq DIPEA and 2.0 eq NOTA-NHS were added. The reaction was monitored by LC-MS until completion. After purification by preparative liquid chromatography, the target compound was obtained by lyophilization. Purity: 99.7%, MS m / z (ESI): 1536.65 [MH] - .

[0203] Example 4. 68 Preparation of Ga-DOTA-09

[0204] Rinse with 0.1N hydrochloric acid 68 GaCl3 solution was added to a reaction vessel along with 0.1 mL of 1 mM sodium acetate aqueous solution; then 0.9 mL of the above solution was added. 68GaCl3 solution. Add 5 μl of DOTA-09 (1 mg / mL) solution and 67 μl of gentian acid solution (15 mg / mL), mix well, adjust the pH of the reaction solution to 3.5-5.0, and heat at 95℃ for 15 min. Radiochemical purity was determined by radio-HPLC to be 93.38%.

[0205] Example 5. 177 Preparation of Lu-DOTA-09

[0206] In a reaction vessel, 75 μl of 0.4 M acetate / sodium acetate buffer, 7.5 μl of DOTA-09 solution (1 mg / mL), 31.5 μl of gentian acid solution (15 mg / mL), and 7-15 mCi Lu-177 nuclide were added sequentially. The mixture was thoroughly mixed, and the pH of the reaction solution was adjusted to 4.0-4.5. The mixture was heated at 90-95 °C for 15 min. After cooling to room temperature, 1.4 mL of diluent (10 mg / mL vitamin C saline solution) was added. The radiochemical purity was determined by radio-HPLC to be 94.20%.

[0207] Example 6. 68 Preparation of Ga-NOTA-09

[0208] Elute with 0.1N hydrochloric acid 68 GaCl3 solution was added to a reaction vessel along with 0.1 mL of 1 mM sodium acetate aqueous solution; then 0.9 mL of the above solution was added. 68 GaCl3 solution. Add 5 μl of NOTA-09 aqueous solution (1 mg / mL) and 67 μl of gentianic acid aqueous solution (15 mg / mL), mix well, and react at room temperature for 15 min with the pH of the reaction solution set to 3.5-5.0. Analyze using radio-HPLC to determine radiochemical purity; the purity is 92.36%.

[0209] Example 7. A1 18 Preparation of F-NOTA-09

[0210] Dissolve 1 μl of 10 mM NOTA-09 aqueous solution in 50-100 μl of 0.5 M acetate / sodium acetate buffer at pH 4.0-4.4. Then add 2 mM AlCl3 aqueous solution at a molar ratio of 2:1, followed by 1850 MBq of 18F purified by QMA. -50 μL of ions were reacted at 100 °C for 10–15 min. Purification was performed using an HLB cartridge column, followed by elution with ethanol / water (1:1) and dilution with physiological saline to below 10% ethanol concentration. Radiochemical purity (91.57%) was determined using radio-HPLC.

[0211] Example 8. 64 Preparation of Cu-DOTA-09

[0212] Dissolve 5 μl of 10 mM DOTA-09 aqueous solution in 100 μl of sodium acetate solution with pH = 3.5-6.5, then add 1850 MBq of solution dissolved in 0.1 M hydrochloric acid. 64 50 μl of CuCl2 solution was reacted at 80 °C for 15 min, purified using a C18 column, and diluted with physiological saline to a concentration of less than 10% ethanol. Radiochemical purity (98.59%) was determined using radio-HPLC.

[0213] Example 9. 64 Preparation of Cu-NOTA-09

[0214] Dissolve 5 μl of 10 mM NOTA-09 aqueous solution in 100 μl of sodium acetate solution with pH = 3.5-6.5, then add 1850 MBq of solution dissolved in 0.1 M hydrochloric acid. 64 50 μl of CuCl2 solution was reacted at 80 °C for 15 min, purified using a C18 column, and diluted with physiological saline to a concentration of less than 10% ethanol. Radiochemical purity (97.37%) was determined using radio-HPLC.

[0215] Example 10. 225 Preparation of Ac-DOTA-09

[0216] Add 318 μl of tris(hydroxymethyl)aminomethane buffer (pH 8, 0.25 M), 5 μl of DOTA-09 solution (1 μmol / mL), and 20-50 μCi to the reaction vessel in sequence. 225 Ac nuclides were thoroughly mixed. An appropriate amount of 0.1N hydrochloric acid was added to adjust the pH of the reaction system to 6.0-8.0, and the mixture was heated at 90-95℃ for 10-20 minutes. After heating, the mixture was cooled to room temperature, and 0.65 mL of a 10 mg / mL sodium ascorbate saline solution was added. The radiochemical purity was determined using radio-HPLC, and was greater than 90%.

[0217] Comparative Example 1. Preparation of Nota-2286

[0218] Using a method similar to that in Example 3, the target compound NOTA-2286 was obtained with a purity of 97.35% and an MS m / z (ESI) of 1367.78 [MH]. - .

[0219] Comparative Example 2.A1 18 Preparation of F-NOTA-2286

[0220] The target compound Al was obtained using a method similar to that used in Example 7. 18 F-NOTA-2286, radiochemical purity 95.37%.

[0221] Comparative Example 3. 68 Preparation of Ga-NOTA-2286

[0222] The target compound was obtained using a method similar to that used in Example 6. 68 Ga-NOTA-2286, radiochemical purity 96.29%.

[0223] Comparative Example 4. 68 Preparation of Ga-FAP-2286

[0224] The target compound was obtained using a method similar to that used in Example 4. 68 Ga-FAP-2286, radiochemical purity 94.98%.

[0225] Comparative Example 5. 177 Preparation of Lu-FAP-2286

[0226] The target compound was obtained using a method similar to that used in Example 5. 177 Lu-FAP-2286, radiochemical purity 97.76%.

[0227] Biological evaluation

[0228] The following test examples further describe and explain this disclosure, but these test examples are not intended to limit the scope of this disclosure.

[0229] Test Example 1: FAPα Enzyme Activity Assay

[0230] 1.1 Experimental Materials and Instruments

[0231] Table 1. Information on the source of experimental materials and instruments

[0232] 1.2 Experimental Procedure

[0233] Dilute the substrate (Z-Gly-Pro-AMC) to a 0.5 mM stock solution using DMSO. Dilute the 0.5 mM stock solution to 50 μM with PBS before each experiment. Dilute the FAPα protein to 0.5 ng / μl with PBS. Dilute the test compound and positive control to 100 nM or 200 nM with PBS to determine the single-point inhibition rate. For compounds with single-point inhibition rates comparable to the positive control, further IC50 measurements are performed. 50 Values. The test compound and positive control were diluted with PBS to a maximum concentration of 10 μM and a minimum concentration of 0 nM, using a 5-fold serial dilution, for a total of 8 gradients. Test method: Add 85 μl of FAPα dilution and 10 μl of compound dilution to the ELISA plate, mix well, and incubate at 37°C for 10 min. Add 5 μl of 50 μM substrate, mix well, and incubate at 37°C for 10 min. Read the values ​​using the ELISA reader: excitation light 380 nm, emission light 465 nm.

[0234] 1.3 Experimental Results

[0235] Table 2. IC50 of the compounds disclosed herein for FAPα 50 value

[0236] Note: The structure of FAP-2286 is shown below:

[0237] Reference: European Journal of Nuclear Medicine and Molecular Imaging(2022)49:3651–3667

[0238] Test Example 2. PET / SPECT Imaging Test of Labeled Compounds

[0239] 2.1 Experimental Materials

[0240] Cell information: U-87MG cells (Wuhan Pronosai Life Science Technology Co., Ltd.); Culture conditions: U-87MG cell-specific culture medium (MEM + 10% FBS + 1% P / S); Passages: 6-9 generations.

[0241] Experimental animals: strain: B-NDG (Biocytok Jiangsu Gene Biotechnology Co., Ltd.); age: 5-8 weeks; weight: 20-24g.

[0242] Reagents: PBS (Solepro, P1020); Matrigel (ABW, 0827045); Trypsin-EDTA (Gibco, 25200-072); U-87MG special medium (Pronosai, CM-0238).

[0243] Instruments: Small animal PET / CT (ediso, nanoScan PET / CT 4heads); activity meter (Capintec); electronic balance (Changzhou Shuangjie, DT100).

[0244] 2.2 Experimental Procedure

[0245] Model building

[0246] Prepare a sufficient quantity of U-87MG cells and inoculate them into the posterior part of the right forelimb of B-NDG mice. The inoculation volume is 100 μl, containing 50% Matrigel and 5 × 10⁻⁶ cells. 6 Each cell was inoculated. Tumor volume and animal weight were monitored twice weekly after inoculation, and tumors with a volume of 200-500 mg / m³ were selected. 3 Mice from the model group were enrolled in this experiment, and each group was randomly assigned according to tumor volume.

[0247] Operating steps

[0248] 1) Wipe the work surface with 75% medical alcohol and cover it with a disposable sterile tablecloth;

[0249] 2) Prepare a 0.5mL insulin syringe, alcohol swabs, cotton swabs, and a marker in the injection room. Place the syringe in the mouse restraint and disinfect the mouse's tail with alcohol swabs;

[0250] 3) Each mouse was injected with the prepared test sample via the tail vein, and the time of each injection, the activity of the syringe, and the activity of the empty syringe were recorded.

[0251] 4) After anesthetizing the tumor-bearing mice with isoflurane, place them prone on the small animal PET / SPECT bed and fix them in place;

[0252] 5) PET / SPECT static images were acquired at different time points after drug administration; a whole-body CT scan was performed before each static scan to obtain images of the distribution of the labeled compound throughout the tumor-bearing mice, and PET / SPECT images of each experimental animal at different time points after drug administration were obtained. Major organs were selected and delineated, including: tumor, muscle, bone, lung, brain, liver, and kidney.

[0253] 6) Observe the radioactive concentration and clearance of the labeled compound in tumors and non-target tissues in tumor-bearing mice.

[0254] 2.3 Experimental Results

[0255] Table 3. Compounds disclosed herein and 68 Uptake of Ga-FAP-2286 in tumors and tumor / kidney ratio

[0256] In mouse models68 Ga-DOTA-09 uptake in tumors (Figure 1) and the tumor / kidney ratio (Figure 2) were significantly higher than those in the control group. 68 Ga-FAP-2286.

[0257] Table 4. Compounds disclosed herein and 177 Uptake of Lu-FAP-2286 in tumors and tumor / kidney ratio

[0258] In mouse models, 177 Lu-DOTA-09 decreases slowly in tumors, maintaining a relatively stable intratumoral retention. 177 Lu-FAP-2286 retention within the tumor decreased rapidly after 4 hours (Figure 3). 177 The tumor / kidney ratio of Lu-DOTA-09 (Figure 4) was higher than that of the control. 177 Lu-FAP-2286.

[0259] Table 5. Compounds disclosed herein and 68 Uptake of Ga-NOTA-2286 in tumors and tumor / kidney ratio

[0260] In mouse models, 68 Ga-DOTA-09 uptake in tumors (Figure 5) and the tumor / kidney ratio (Figure 6) were significantly higher than those in the control group. 68 Ga-NOTA-2286.

[0261] Table 6. Compounds disclosed herein and Al 18 Uptake of F-NOTA-2286 in tumors and tumor / kidney ratio.

[0262] In mouse models, Al 18 F-NOTA-09 uptake in tumors (Figure 7) and the tumor / kidney ratio (Figure 8) were significantly higher than those of the control Al. 18 F-NOTA-2286.

[0263] Test Example 3. 177 Blood drug concentration assay of Lu-labeled compounds

[0264] 3.1 Experimental Materials

[0265] Laboratory animals: strain: SD rats (Beijing Vital River Laboratory Animal Technology Co., Ltd.); age: 5-6 weeks; weight: 100-150g.

[0266] Reagent: Sodium chloride injection (Shandong Qidu Pharmaceutical Co., Ltd.)

[0267] Instruments: Activity meter (Capintec); 0.0001 g balance (Sartorius Scientific Instruments Co., Ltd.); Low-energy gamma counter (PerkinElmer Instruments, Inc.).

[0268] 3.2 Experimental Procedure

[0269] 1) Weigh and mark the empty tubes in advance by performing γ-counting.

[0270] 2) After the rats were injected with the test sample via the tail vein, blood was collected from the animals via the orbital blood collection method at 2 min, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 24 h, 48 h and 72 h, and the sample tubes containing blood were weighed.

[0271] 3) Calculate the net weight of the blood and use a gamma counter to count the radioactivity of the blood sample.

[0272] 4) Determine the distribution of the labeled compound in the blood of rats at different time points. Accurately dilute the test sample 100 times, take 0.5 mL in a counting tube as the standard 1%ID (i.e., one percent of the injection dose), and simultaneously measure the radioactivity count of the 1%ID standard and the biological sample on a gamma counter.

[0273] 5) Use DAS software to calculate pharmacokinetic parameters.

[0274] Data in rat blood are expressed as the percentage of radioactivity count per gram of blood relative to the total dose (radioactivity count) (%ID / g). The specific calculation formula is as follows:

[0275] %ID / g = CPM organ or tissue / (total CPM dose × W organ or tissue) × 100%

[0276] The data for each sampling point is expressed as mean ± standard deviation (mean ± SD).

[0277] Simultaneously, the drug concentration in the blood is estimated based on the radioactivity count in the blood. The specific calculation formula is as follows:

[0278] 2.3 Experimental Results

[0279] Table 7. Compounds disclosed herein and 177 Pharmacokinetic parameters of Lu-FAP-2286

[0280] In vivo pharmacokinetic studies showed that 177 Lu-DOTA-09 half-life in rats (t 1 / 2 Both the mean time to stay (MRTlast) and the mean time to stay (MTLlast) were significantly longer than 177Lu-FAP-2286 exhibits a long intratumoral residence time consistent with mouse imaging studies.

[0281] Test Example 4. In vivo efficacy study of the disclosed compound in U-87MG model mice.

[0282] 4.1 Cell Information

[0283] Name: U-87MG cells

[0284] Source: Wuhan Pronosai Life Science Technology Co., Ltd.

[0285] Product Number: CL-0238

[0286] Batch number: YBMIL8BQH0

[0287] Culture conditions: U-87MG cell culture medium (90% MEM + 10% FBS + 1% P / S)

[0288] Number of generations: 23-36

[0289] 4.2 Laboratory Animals

[0290] Strains: B-NDG

[0291] Rating: SPF

[0292] Age in months: 5 weeks

[0293] Weight: 21-24g

[0294] Sex and number: Male, 90 were introduced for U-87MG model construction, and 40 were selected for inclusion in the group.

[0295] Source: Biocytogen Jiangsu Gene Biotechnology Co., Ltd.

[0296] Production License: SCXK(Su)2021-0005.

[0297] Certificate Number: B202311200038

[0298] 4.3 Experimental Drugs

[0299] name: 177 Lu-DOTA-09 (Preparation details are in Example 35)

[0300] Specifications and composition: 31 mCi / 2.5 mL / 37.5 nmol

[0301] 177 Lu-FAP-2286 (Reference Comparative Example 5)

[0302] Specifications and composition: 15.87 mCi / 1.25 mL / 18.75 nmol

[0303] 4.4 Instrument and Equipment Information

[0304] Table 8. Instrument and Equipment Information

[0305] 4.5 Reagent Information

[0306] Table 9. Reagent Information

[0307] 4.6 Experimental Design

[0308] Prepare approximately 4.5 × 10 8 A suspension of U-87MG cells was inoculated into the posterior part of the right forelimb of B-NDG mice in a volume of 100 μL, containing 50% Matrigel and 5 × 10⁶ cells. 6 Cells. A total of 90 mice were inoculated, and the tumors were allowed to grow to 150 cm. 3 Around 40 mice with uniformly sized tumors were selected for inclusion in the group.

[0309] The dosing regimen is as follows:

[0310] Route of administration: Tail vein injection;

[0311] Dosage volume: 0.03-0.07 mL / animal;

[0312] Dosage frequency and dosage: The control group received PBS. 177 Lu-FAP-2286 group: 0.8 mCi / animal per dose. 177 In the Lu-DOTA-09 0.4mCi group, a single dose of 0.4mCi per animal was administered. 177 In the Lu-DOTA-09 0.8mCi group, a single dose of 0.8mCi per animal was administered. 177 Lu-DOTA-09 0.8mCi × 2 fractions were administered twice, with 0.8mCi per mouse, 35 days apart. Eight mice were in each group, and the administration time and drug activity were recorded in detail for each mouse.

[0313] 4.7 Operating Procedures

[0314] After tumor modeling, tumor size was observed. Tumor volume and animal weight were measured using a digital caliper the day before or on the day of drug administration. Animals were then evenly divided into 5 groups based on tumor volume: control group, ... 177 Lu-FAP-2286 0.8mCi group 177 Lu-DOTA-09 0.4mCi group, 177 Lu-DOTA-09 0.8mCi group,177 Lu-DOTA-09 0.8mCi*2 sets, 8 animals per set.

[0315] On the day of administration, prepare the test sample after receiving it (use the stock solution directly) and measure its activity. Wipe the work surface with 75% medical alcohol and lay a disposable sterile tablecloth. Prepare a 0.5mL insulin syringe, alcohol wipes, cotton swabs, and a marker in the injection room. Place the mice in a restraint and disinfect their tails with alcohol wipes. Administer the prepared test sample via the tail vein to each mouse and record the time of each injection.

[0316] Tumor and body weight measurements began the day after drug administration. Tumor measurements and weight were performed at least twice a week, recording the long and short diameters of the tumor each time, ideally from the same location. Any abnormalities or deaths were promptly recorded. Animals were euthanized if the average tumor diameter exceeded 20 mm, or if ulceration or necrosis occurred. Tumor volume was calculated as follows: Tumor volume (mm²) 3 = Major diameter × Minor diameter × Minor diameter × 0.52.

[0317] 4.8 Experimental Results and Discussion

[0318] Tumor growth curve

[0319] Experimental results show that different doses 177 Lu-DOTA-09 showed a certain inhibitory effect on tumor growth in U-87MG model mice (Figure 9).

[0320] U-87MG tumors grow rapidly; in the control group, the tumor size reached 3057.58±715.73 mm on day 20 after medication. 3 , 177 The tumor size in the Lu-FAP-2286 0.8mCi group was 1833.89±338.00mm. 3 , 177 The tumor size in the Lu-DOTA-09 0.4mCi group was 790.09±618.40mm. 3 , 177 Lu-DOTA-09 0.8mCi group and 177 The tumor size in the Lu-DOTA-09 0.8mCi*2 group was 314.25±65.57mm. 3 and 326.04±82.5mm 3 The tumor inhibition rates of the four treatment groups were 40.02%, 74.16%, 89.72%, and 89.34% respectively 20 days after administration.

[0321] 35 days after the first dose,177 The second administration of Lu-DOTA-09 0.8mCi*2 group continued to inhibit tumor growth.

[0322] On the 46th day after taking the medicine, 177 The tumor size in the Lu-DOTA-09 0.8mCi group was 3605.05±803.40mm. 3 , 177 The tumor size in the Lu-DOTA-09 0.8mCi*2 group was 1735±482.69mm. 3 .

[0323] mouse weight

[0324] 177 During Lu-DOTA-09 administration, mouse body weight was simultaneously monitored, and no significant changes in body weight were observed in any of the four dosage groups, indicating that... 177 Lu-DOTA-09 did not produce any toxic side effects that caused weight loss in tumor-bearing animals (Figure 10).

[0325] mouse lifespan

[0326] Statistics show that 177 Lu-DOTA-09 significantly improved the survival rate of U-87MG model mice (Figure 11). In the control group, tumor overload occurred 20 days after administration, and all mice died from tumor bearing by day 42, with a median survival of 35 days. 177 In the Lu-DOTA-09 0.8mCi*2 group of mice, about half of the mice were still alive 59 days after drug administration, indicating that... 177 Lu-DOTA-09 significantly improved the survival of tumor-bearing mice. Statistical analysis showed that the control group, 177 Lu-FAP-2286 0.8mCi group 177 Lu-DOTA-09 0.4mCi group, 177 Lu-DOTA-09 0.8mCi group and 177 The median survival times for the Lu-DOTA-09 0.8mCi*2 group were 35 days, 39 days, 42 days, 49 days, and 57.5 days, respectively.

[0327] Experimental conclusions

[0328] 177 Lu-DOTA-09 as 177 Lu-labeled radioactive targeted drugs significantly inhibited the growth of FAP-positive tumors and prolonged the survival of mice in U-87MG model mice.

[0329] Example 10. Injection formulations 1 to 4 and their preparation methods

[0330] Table 10. Prescriptions 1 to 4 of the injection solution disclosed herein Note: N / A means not added or not measured.

[0331] The specific preparation steps of the radioactive injection solution disclosed herein are as follows (taking Formula 1 as an example):

[0332] 1. Solution preparation

[0333] Preparation of intermediate 1 solution:

[0334] Take a 100mL beaker and a rotor, add 20.00g of water for injection, add 19.63mg of the compound shown in formula (IA), add 4.94g of water for injection to bring the weight to 24.98g, stir and mix well to obtain intermediate 1 solution.

[0335] or

[0336] Take a 100mL beaker and a rotor, add 20.00g of water for injection, add 34.17mg of the compound shown in formula (IA), add 4.94g of water for injection to bring the weight to 24.98g, stir and mix well to obtain intermediate 1 solution.

[0337] Preparation of intermediate 2 solution:

[0338] Take a 250mL beaker and a rotor, add 70.00g of water for injection, then add 12027.37mg of sodium acetate, 3331.58mg of cysteine ​​hydrochloride and 2300.00mg of gentianic acid in sequence, stir to dissolve, add 17.34g of water for injection to bring the weight to 105.00g, stir to mix well, and obtain intermediate 2 solution.

[0339] Preparation of intermediate 3 solution:

[0340] Take a 1000mL beaker and a rotor, weigh 500.00g of water for injection, add 5468.34mg of sodium hydroxide, 31.61mg of penteacin, 178.00mg of cysteine ​​hydrochloride and 3083.00mg of vitamin C in sequence, add 82.18g of water for injection to bring the weight to 612.60g, stir for 20min until it is visually completely dissolved to obtain intermediate 3 solution.

[0341] 2. Mark

[0342] Take without carrier 177 Add 37 GBq of LuCl3 hydrochloric acid solution to a COP vial, add 1.5 mL of intermediate 1 solution and 2 mL of intermediate 2 solution, react at 90 °C for 15 min, dilute and mix with 88.25 mL of intermediate 3 solution to obtain the final product with a radiochemical purity ≥95%.

[0343] Fill according to usage requirements, with each vial containing 8.3mL-22.8mL. The headspace is filled with nitrogen, and the oxygen content is ≤3%.

[0344] 3. Stability data

[0345] The stability data of prescriptions 1 to 4 after being placed at room temperature for 72 hours are shown in Table 11 below.

[0346] Table 11. HPLC Radiochemical Purity

[0347] As shown in Table 11, the HPLC radiochemical purity of the injection formulations 1-4 disclosed in this publication did not change significantly 72 hours after labeling, demonstrating excellent stability.

[0348] Example 11. Screening of anti-radiation degradation agents in the injection solution of this disclosure

[0349] Table 12. Prescriptions for the injection solutions disclosed herein, 5 to 9. Note: N / A represents no addition or no measurement.

[0350] According to prescriptions 5-9 in Table 12, and referring to the preparation method of prescription 1 described in Example 10, the injection solutions were prepared respectively.

[0351] 1. Stability data for prescriptions 5 to 9

[0352] The stability data of prescriptions 5 to 9 after being placed at room temperature for 72 hours are shown in Table 13 below.

[0353] Table 13. HPLC Radiochemical Purity

[0354] As shown in Table 13, the HPLC radiochemical purity of the injection formulation 5-9 disclosed in this paper did not change significantly after 72 hours of labeling, demonstrating excellent stability.

[0355] Example 12. Screening of pH value for the injection solution disclosed in this invention

[0356] Table 14. Prescriptions for the injectable solutions disclosed herein, 10 to 13. Note: N / A represents no addition or no measurement.

[0357] According to prescriptions 10-13 in Table 14, and referring to the preparation method of prescription 1 described in Example 10, injection solutions were prepared respectively.

[0358] 1. Stability data of prescriptions from 10 to 13

[0359] The stability data of prescriptions 10 to 13 after being placed at room temperature for 72 hours are shown in Table 15 below.

[0360] Table 15. HPLC Radiochemical Purity

[0361] As shown in Table 15, the HPLC radiochemical purity of the injection formulation 10-13 disclosed in this publication did not change significantly 72 hours after labeling, demonstrating good stability.

[0362] Example 13. pH screening of the labeling system

[0363] Table 16. Prescriptions for the injection solutions disclosed herein: 1, 14-15 Note: N / A means not added or not measured.

[0364] The specific preparation steps of the radioactive injection solution disclosed herein are as follows (taking Formula 1 as an example):

[0365] 1. Solution preparation

[0366] Preparation of intermediate 1 solution:

[0367] Weigh 16.16 mg of the compound shown in formula (IA) and add 10 mL of ultrapure water to obtain intermediate 1 solution.

[0368] Preparation of intermediate 2 solution:

[0369] Weigh 29 mL of ultrapure water, and add 4810.95 mg of sodium acetate, 1311.48 mg of cysteine ​​hydrochloride and 920.00 mg of gentianic acid in sequence. Stir to dissolve, and measure the pH to be 5.0 to obtain intermediate 2 solution.

[0370] Preparation of intermediate 3 solution:

[0371] Weigh 4560.06 mg sodium hydroxide, 26.21 mg DTPA, 1251.85 mg cysteine ​​hydrochloride and 19513.32 mg vitamin C, and dilute to 500 mL with water for injection to obtain intermediate 3 solution.

[0372] 2. Mark

[0373] Take 15 μL of intermediate 1 solution, add 20 μL of intermediate 2 solution (pH 5.0), and add 10 mL of Ci 177 The LuCl3 hydrochloric acid solution was then placed in a metal bath heated to 90°C and reacted for 15 minutes.

[0374] The final formulation solution was obtained by diluting with 790 μL of intermediate 3.

[0375] The filling steps can be referred to the preparation method described in Example 10.

[0376] The stability data of prescriptions 1 and 14-15 after being placed at room temperature for 72 hours are shown in Table 17 below.

[0377] Table 17. HPLC Radiochemical Purity

[0378] As shown in Table 17, the initial radiochemical purity of the injection formulations 1, 14, and 15 disclosed in this publication is greater than 95%, which meets the quality requirements.

[0379] Example 14. Screening based on labeled reaction temperature and time

[0380] The injection solution was prepared according to the prescription 1 and preparation method described in Example 10.

[0381] The labeling process is designed as follows: labeling processes 1-5. The temperature and time of the labeling reaction in each process, as well as the initial radiochemical purity of the resulting injection solution, are shown in Table 18.

[0382] Table 18. Marking Processes 1-5

[0383] As shown in Table 18, the initial radiochemical purity of the injection solutions prepared by labeling processes 1-5 is greater than 95%, which meets the quality requirements.

Claims

1. An aqueous pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, C is a chelating agent, and the chelating agent is selected from DOTA or NOTA; DOTA is the preferred choice; R is a radionuclide, which is complexed with chelating agent C. The radionuclide includes diagnostically active or therapeutically active radionuclides, and the diagnostically active radionuclide is selected from... 43 Sc、 44 Sc、 51 Mn, 52 Mn, 64 Cu、 67 Ga、 68 Ga、 86 Y、 89 Zr、 94m Tc, 99m Tc, 111 In、 152 Tb, 155 Tb, 201 Tl、 203 Pb, 18 F, 76 Br、 77 Br、 123 I, 124 I, 125 I; Preferably 43 Sc、 44 Sc、 64 Cu、 67 Ga、 68 Ga、 86 Y、 89 Zr、 99m Tc、 111 In、 152 Tb、 155 Tb、 203 Pb、 18 F、 76 Br、 77 Br、 123 I、 124 I、 125 I; More 64 Cu、 68 Ga、 89 Zr、 99m Tc, 111 In、 18 F, 123 I and 124 I; The therapeutically active nuclide is selected from 47 Sc、 67 Cu、 89 Sr、 90 Y、 153 Sm、 149 Tb, 161 Tb, 177 Lu、 186 Re、 188 Re、 212 Pb, 213 Bi、 223 Ra、 225 Ac、 226 Th、 227 Th、 131 I, 211 At; Preferably 47 Sc 67 Cu 90 Y 177 Lu 188 Re 212 Pb 213 Bi 225 Ac 227 Th 131 I 211 At More 90 Y、 177 Lu、 225 Ac、 227 Th、 131 I and 211 At; The pharmaceutical composition contains at least one anti-radiation degradation agent.

2. The pharmaceutical composition of claim 1, wherein the radionuclide R is selected from... 177 Lu、 161 Tb, 212 Pb, 18 F, 225 Ac、 68 Ga、 64 Cu.

3. The pharmaceutical composition of claim 1 or 2, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from, 4. The pharmaceutical composition according to any one of claims 1-3, wherein the radionuclide is present at a concentration providing radioactivity from 100 to 1000 MBq / mL; Preferably, the radionuclide is present at a concentration that provides radioactivity from 300 to 800 MBq / mL; More preferably, the radionuclide is present at a concentration that provides radioactivity from 350 to 450 MBq / mL.

5. The pharmaceutical composition according to any one of claims 1-4, wherein the anti-radiation degrading agent is selected from one or more of gentianic acid or its salt, ascorbic acid or its salt, cysteine ​​or its salt, acetylcysteine ​​or its salt, methionine, methionine, histidine, melatonin, ethanol and Se-methionine; Preferably, the anti-radiation degrading agent is selected from one or more of gentianic acid or its salt, ascorbic acid or its salt, and cysteine ​​or its salt; More preferably, the anti-radiation degrading agent is selected from a combination of gentianic acid or its salt, ascorbic acid or its salt, and cysteine ​​or its salt.

6. The pharmaceutical composition of claim 5, wherein the concentration of gentianic acid or its salt is selected from 0.10 mg / mL to 3 mg / mL, the concentration of ascorbic acid or its salt is selected from 1 mg / mL to 100 mg / mL, and the concentration of cysteine ​​or its salt is selected from 0.50 mg / mL to 10 mg / mL; Preferably, the concentration of gentianic acid or its salt is selected from 0.20 mg / mL to 1 mg / mL, the concentration of ascorbic acid or its salt is selected from 10 mg / mL to 80 mg / mL, and the concentration of cysteine ​​or its salt is selected from 2 mg / mL to 10 mg / mL; More preferably, the concentration of gentic acid or its salt is selected from 0.20 mg / mL to 0.60 mg / mL, the concentration of ascorbic acid or its salt is selected from 30 mg / mL to 70 mg / mL, and the concentration of cysteine ​​or its salt is selected from 2 mg / mL to 6 mg / mL; Most preferably, the concentration of gentic acid or its salt is selected from 0.40 mg / mL to 0.60 mg / mL, the concentration of ascorbic acid or its salt is selected from 30 mg / mL to 40 mg / mL, and the concentration of cysteine ​​or its salt is selected from 2 mg / mL to 3 mg / mL.

7. The pharmaceutical composition according to any one of claims 1 to 6, comprising a buffer, wherein the pH is selected from 4.0-6.5, preferably 4.5-6.0, more preferably 5.0-5.

5.

8. The pharmaceutical composition of claim 7, wherein the buffer is selected from acetate buffers, citrate buffers, formate buffers, and phosphate buffers; Preferably, the buffer is sodium acetate, or a combination of acetic acid and sodium acetate; More preferably, the buffer is sodium acetate.

9. The pharmaceutical composition of claim 8, wherein the concentration of sodium acetate is selected from 0.10 mg / mL to 5 mg / mL; Preferably, the concentration of the sodium acetate is selected from 0.1 mg / mL to 2 mg / mL; More preferably, the concentration of the sodium acetate is selected from 1 mg / mL to 2 mg / mL.

10. The pharmaceutical composition according to any one of claims 1 to 9, comprising a pH adjuster; Preferably, the pH adjuster is sodium hydroxide.

11. The pharmaceutical composition according to any one of claims 1 to 10, comprising a metal masking agent; Preferably, the metal masking agent is selected from DTPA or its salt, DMSA or its salt, TTHA or its salt; More preferably, the metal masking agent is selected from DTPA or its salts.

12. The pharmaceutical composition of claim 11, wherein the concentration of the DTPA or a salt thereof is selected from 0.01 mg / mL to 0.2 mg / mL; Preferably, the concentration of the DTPA or its salt is selected from 0.02 mg / mL to 0.1 mg / mL.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the composition has a radiochemical purity ≥ 90.0%; Preferably, the composition has a radiochemical purity of ≥95.0%.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the composition has a radiochemical purity of ≥90.0% after being stored at or below room temperature for 72 hours; Preferably, the composition has a radiochemical purity of ≥95.0% after being stored at or below room temperature for 72 hours.

15. A compound represented by formula (IA), in, The mass fraction of trifluoroacetic acid is selected from 1-30%, preferably from 5-15%.

16. The compound of claim 15, wherein it is a solid; preferably, it is a lyophilized powder.

17. A method for preparing the compound of formula (IA) as described in claim 15 or 16, comprising the step of reacting compound DOTA-09 with 1.0-2.0 equivalents of trifluoroacetic acid. Preferably, the step includes reacting compound 2 with 1.0-1.5 equivalents of trifluoroacetic acid.

18. The preparation method according to claim 17, wherein the reaction solvent is a mixed solvent of a nitrile solvent and water, preferably, the nitrile solvent is acetonitrile.

19. The preparation method according to claim 18, further comprising a freeze-drying step.

20. Use of the pharmaceutical composition of any one of claims 1 to 14, or the compound of formula (IA) as described in claim 15 or 16, in the preparation of a medicament for imaging diseases or conditions associated with fibroblast activation protein, or for treating diseases or conditions associated with fibroblast activation protein.

21. The use as described in claim 20, wherein, The diseases or conditions associated with fibroblast activation proteins are selected from proliferative diseases, chronic inflammation, fibrosis (liver, kidney, lung), tissue remodeling, scarring, tissue infection, or inflammatory lesions; The proliferative diseases mentioned are selected from the group consisting of breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, thyroid cancer, lung adenocarcinoma, kidney cancer, liver cancer, lung cancer, esophageal cancer, hepatobiliary tract cancer, gastric cancer, nasopharyngeal carcinoma, head and neck cancer, bladder cancer, glioblastoma, peritoneal metastatic cancer, melanoma, fibrosarcoma, bone and connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma and adenocarcinoma, as well as benign tumors; The chronic inflammation is selected from rheumatoid arthritis, osteoarthritis, Crohn's disease, or atherosclerotic plaques; The tissue remodeling occurred after myocardial infarction; The term "scar disease" is selected from scar formation, scar tumors, or scar scars.

22. The use of the pharmaceutical composition of any one of claims 1 to 14, or the compound of formula (IA) as described in claim 15 or 16, in the preparation of a medicament for the prevention, diagnosis, or treatment of proliferative diseases, chronic inflammation, fibrosis (liver, kidney, lung), tissue remodeling, scarring, tissue infection, or inflammatory lesions, wherein, The proliferative diseases mentioned are selected from the group consisting of breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, thyroid cancer, lung adenocarcinoma, kidney cancer, liver cancer, lung cancer, esophageal cancer, hepatobiliary tract cancer, gastric cancer, nasopharyngeal carcinoma, head and neck cancer, bladder cancer, glioblastoma, peritoneal metastatic cancer, melanoma, fibrosarcoma, bone and connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma and adenocarcinoma, as well as benign tumors; The chronic inflammation is selected from rheumatoid arthritis, osteoarthritis, Crohn's disease, or atherosclerotic plaques; The tissue remodeling occurred after myocardial infarction; The term "scar disease" is selected from scar formation, scar tumors, or scar scars.

23. A method for preparing an aqueous pharmaceutical composition according to any one of claims 1 to 14, comprising the following steps: (1) Prepare an aqueous solution containing a radioactive nuclide 1; (2) Prepare an aqueous solution containing the precursor compound 2; (3) Prepare an aqueous solution containing a buffer and at least one anti-radiation degradation agent; (4) Mix the solutions obtained in steps (1), (2), and (3) and heat the resulting mixture; The precursor compound is the compound of formula (II) or a pharmaceutically acceptable salt thereof. Preferably, the chelating agent C is DOTA, and the radionuclide is... 177 Lu.

24. The preparation method according to claim 23, wherein the precursor compound is a compound of formula (IA).

25. The preparation method according to claim 23 or 24, wherein the anti-radiation degrading agent in aqueous solution 3 is selected from one or more of gentian acid or its salt, cysteine ​​or its salt, ascorbic acid or its salt, acetylcysteine ​​or its salt, methionine, histidine, melatonin, ethanol and Se-methionine; Preferably, the anti-radiation degrading agent is selected from one or more of gentianic acid or its salt, cysteine ​​or its salt; More preferably, the anti-radiation degrading agent is selected from a combination of gentianic acid and cysteine ​​hydrochloride.

26. The preparation method according to claim 25, wherein the concentration of gentianic acid or its salt in aqueous solution 3 is selected from 5.0 mg / mL to 50.0 mg / mL; Preferably, the concentration of gentianic acid or its salt is selected from 5.0 mg / mL to 30.0 mg / mL; More preferably, the concentration of gentianic acid or its salt is selected from 20.0 mg / mL to 30.0 mg / mL.

27. The preparation method according to claim 25, wherein the concentration of cysteine ​​or its salt in aqueous solution 3 is selected from 10.0 mg / mL to 50.0 mg / mL; Preferably, the concentration of the cysteine ​​or its salt is selected from 25.0 mg / mL to 35.0 mg / mL.

28. The preparation method according to claim 23, wherein the buffer in the aqueous solution 3 is selected from acetate buffer, citrate buffer, formate buffer, and phosphate buffer; Preferably, the buffer is selected from sodium acetate, or a combination of acetic acid and sodium acetate; More preferably, the buffer is sodium acetate.

29. The preparation method according to claim 28, wherein the concentration of sodium acetate in aqueous solution 3 is selected from 30.0 mg / mL to 80.0 mg / mL; Preferably, the concentration of the sodium acetate is selected from 60.0 mg / mL to 80.0 mg / mL.

30. The preparation method according to any one of claims 23 to 29, wherein the pH of the aqueous solution 3 is selected from 4.0-6.0; Preferably, the pH of the aqueous solution 3 is selected from 4.5-5.

5.

31. The preparation method according to any one of claims 23 to 30, wherein the concentration of the precursor compound in aqueous solution 2 is selected from 0.5 mg / mL to 5.0 mg / mL; Preferably, the concentration of the precursor compound is selected from 1.0 mg / mL to 5.0 mg / mL; More preferably, the concentration of the precursor compound is selected from 1.0 mg / mL to 2.0 mg / mL.

32. The preparation method according to any one of claims 23 to 31, wherein the radionuclide is 177 Lu, in aqueous solution 1 177 The amount of Lu is selected from 0.01 Ci to 5.0 Ci; Preferably, in aqueous solution 1 177 The amount of Lu is selected from 0.1 Ci to 1.0 Ci.

33. The preparation method according to claim 32, wherein the aqueous solution 1 contains 177 LuCl3 and HCl.

34. The preparation method according to any one of claims 23 to 33, wherein the temperature of the heating reaction is selected from 70℃ to 200℃; Preferably, the temperature of the heating reaction is selected from 80℃-100℃; More preferably, the temperature of the heating reaction is selected from 85°C to 95°C.

35. The preparation method according to any one of claims 23 to 34, wherein the heating reaction time is selected from 5 to 30 minutes; Preferably, the heating reaction time is selected from 10-20 minutes.

36. A method for preparing an aqueous pharmaceutical composition according to any one of claims 1 to 14, comprising the steps of any one of claims 23 to 35, further comprising: (5) Prepare an aqueous solution containing at least one anti-radiation degradation agent 4; (6) Dilute the solution obtained in step (4) with aqueous solution 4.

37. The preparation method according to claim 36, wherein the anti-radiation degrading agent in aqueous solution 4 is selected from one or more of cysteine ​​or its salt, ascorbic acid or its salt; Preferably, the anti-radiation degrading agent is selected from a combination of ascorbic acid and cysteine ​​hydrochloride.

38. The preparation method according to claim 37, wherein the concentration of ascorbic acid or its salt in aqueous solution 4 is selected from 20.0 mg / mL to 50.0 mg / mL; Preferably, the concentration of the ascorbic acid or its salt is selected from 30.0 mg / mL to 40.0 mg / mL.

39. The preparation method according to claim 38, wherein the concentration of cysteine ​​or its salt in aqueous solution 4 is selected from 1.0 mg / mL to 5.0 mg / mL; Preferably, the concentration of the cysteine ​​or its salt is selected from 1.0 mg / mL to 3.0 mg / mL.

40. The preparation method according to claim 36, wherein the aqueous solution 4 further contains a metal masking agent; Preferably, the metal masking agent is selected from DTPA or its salt, DMSA or its salt, TTHA or its salt; More preferably, the metal masking agent is selected from DTPA or its salts.

41. The preparation method according to claim 40, wherein the concentration of DTPA or its salt is selected from 0.01 mg / mL to 0.1 mg / mL; Preferably, the concentration of DTPA or its salt is selected from 0.03 mg / mL to 0.06 mg / mL.

42. The preparation method according to claim 36, wherein the aqueous solution 4 further contains a pH adjuster; Preferably, the pH adjuster is sodium hydroxide.

43. The preparation method according to claim 42, wherein the concentration of sodium hydroxide is selected from 1.0 mg / mL to 10.0 mg / mL; Preferably, the concentration of the sodium hydroxide is selected from 5.0 mg / mL to 10.0 mg / mL.

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