Ligand compounds and their chelates targeting PSMA antigen and their applications for diagnosis and treatment of prostate cancer

Abstract

The present invention discloses a ligand compound and its chelate targeting PSMA antigen, and its application for diagnosing and treating prostate cancer, the ligand compound is a compound of formula (I) or its salt, ester or solvate. The present invention relates to the radiopharmaceutical technology field, and the chelate comprising the ligand compound of the present invention and a radioactive metal has a longer half-life in blood, better antigen affinity and tumor suppression effect, lower toxicity and higher safety as a radiopharmaceutical targeting PSMA, which can be used in nuclear medicine for the diagnosis and treatment of PSMA antigen-positive prostate cancer. TIFF2024544870000058.tif46170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS The present invention claims priority to an invention patent application filed in China on November 10, 2021, entitled "Ligand compound targeting PSMA antigen and its manufacturing method and application for diagnosis and treatment of prostate cancer", with application number 202111329108.1, the entire contents of which are incorporated herein by reference.

[0002] Technical Field The present invention belongs to the field of medicinal chemistry, specifically to ligand compounds and their chelates targeting PSMA antigen and their applications as diagnostic reagents for prostate cancer in nuclear medicine and for treating different stages of prostate cancer. [Background technology]

[0003] In 2020, there were 1,414,259 new cases of prostate cancer worldwide, accounting for 7.3% of all new cases, the third highest and the most common tumor type in men. In 2020, there were 375,304 new deaths from prostate cancer worldwide, accounting for 3.8% of all cancer deaths. This is because there are currently many treatment options for prostate cancer, including castration surgery, external beam radiation therapy, brachytherapy, endocrine therapy and chemotherapy, but a significant portion of patients progress to metastatic castration-resistant prostate cancer (mCRPC) after a series of treatments. For these patients, radiopharmaceuticals targeting prostate-specific membrane antigen (PSMA) have good therapeutic effects. In particular, 177 Lu-PSMA-617 was recently evaluated by the FDA as a breakthrough therapy.

[0004] 177Lu-PSMA-617 has a good therapeutic effect on metastatic castration-resistant prostate cancer, but its blood half-life is short and its retention time in tumors is short. For this reason, many researchers have significantly improved the half-life of drugs by increasing the albumin-binding side chain in the drug structure, thereby improving tumor radiation exposure. However, this method also significantly improves the radiation exposure of normal tissues, and there is a risk of toxic side effects, so there is a need to develop a compound that can significantly improve tumor radiation exposure but still has low radiation exposure of normal tissues, thereby improving the efficacy of diagnosis or treatment without increasing toxic side effects. There is a strong demand in the field for radiopharmaceuticals that target prostate-specific membrane antigen (PSMA) and have a longer blood half-life, better efficacy, and lower toxicity. Summary of the Invention [Problem to be solved by the invention]

[0005] In order to solve the technical problems existing in the prior art, the present invention discloses a novel ligand compound targeting PSMA and its chelate binding with radioactive metal, said ligand compound or chelate can be used as a reagent for treating or diagnosing prostate cancer in nuclear medicine, for treating or diagnosing different stages of prostate cancer, especially PSMA-positive prostate cancer. [Means for solving the problem]

[0006] The present invention uses the following technical solutions: The present invention discloses a ligand compound targeting PSMA antigen, or a pharma- ceutically acceptable salt, ester, or solvate thereof, wherein the chemical structure of the ligand compound targeting PSMA antigen is as follows: [ka] wherein a and b are each independently any one integer from 1 to 8, c and d are each independently any one integer from 1 to 4, preferably a and b are each independently any one integer from 2 to 6, c and d are each independently any one integer from 1 to 3, more preferably a and b are 4, c is 2, and d is 1; L1 is [ka] and preferably, L1 is linked to other fragments in the structural formula of the ligand compound via an amide bond; Here, R6, R7, and R8 are each independently any one of a hydrogen atom, an alkyl group, an alkoxy group, and a halogen atom; R1 is, [ka] It is one of the chemical structural formulas: wherein n is any one of an integer of 2 to 20, R3, R4, and R5 each independently represent any one of a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom, a cycloalkyl group, a heterocyclo group, and an aryl group, p is any one of an integer of 0 to 8, q is any one of an integer of 1 to 10, and L2 is an amino acid linker structure; R2 is an aryl or heteroaryl group, preferably an aryl group, and Y is a radiometal chelator group.

[0007] The present invention discloses a ligand compound targeting PSMA antigen, or a pharma- ceutically acceptable salt, ester, or solvate thereof, wherein the chemical structure of the ligand compound targeting PSMA antigen is as follows: [ka] Here, L1 is [ka] and preferably, L1 is linked to other fragments in the structural formula of the ligand compound via an amide bond; R1 is one of the following chemical structures: [ka] where n is an integer of 2 to 20; R3, R4, and R5 are each independently selected from the group consisting of hydrogen, an alkyl group, an alkoxy group, a halogen, a cycloalkyl group, a heterocyclo group, and an aryl group; p is an integer of 0 to 8; and q is an integer of 1 to 10; L2 is an amino acid linker structure, R2 is an aryl or heteroaryl group, preferably an aryl group, and Y is a radiometal chelator group.

[0008] In the above technical solution, Y is a radiometal chelator group, which can bind with radiometal, preferably the chelator is DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) or its derivatives, TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid) or its derivatives, SarAR (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexazabicyclo[6.6.6]-eicosane-1,8-diamine) or its derivatives, NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) or its derivatives, TRAP (1,4,7-triazacyclononane-1,4,7-trimethyl(2-carboxyethyl)phosphinic acid) or its derivatives, HBED ( N,N'-bis(2-hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid) or a derivative thereof, 2,3-HOPO (3-hydroxypyridin-2-one) or a derivative thereof, PCTA (3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-triene-3,6,9-triacetic acid) or a derivative thereof, DFO (desferrioxamine) or a derivative thereof, DTPA (diethylenetriaminepentaacetic acid) or a derivative thereof, OCTAPA (N,N'-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N'-diacetic acid) or a derivative thereof, H2-MACROPA (N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6) or a derivative thereof.

[0009] The present invention discloses a ligand compound for targeting PSMA antigen based on DOTA, or a pharma- ceutically acceptable salt, ester, or solvate thereof, wherein the chemical structure of the ligand compound for targeting PSMA antigen based on DOTA is as follows: [ka] Here, L1 is [ka] and preferably, L1 is linked to other fragments in the structural formula of the ligand compound via an amide bond; R1 is, [ka] It is one of the chemical structural formulas: wherein n is any one of an integer of 2 to 20, R3, R4, and R5 each independently represent any one of a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom, a cycloalkyl group, a heterocyclo group, and an aryl group, p is any one of an integer of 0 to 8, q is any one of an integer of 1 to 10, and L2 is an amino acid linker structure; R2 is an aryl group or a heteroaryl group, preferably an aryl group, and more preferably a naphthyl group.

[0010] Preferably, the chemical structure of the DOTA-based ligand compound targeting the PSMA antigen is as follows: [ka] Here, L1 and R1 are as defined in the chemical structural formula of the above DOTA-based ligand compound targeting the PSMA antigen.

[0011] In the above technical solution, the aryl group is a phenyl group, a naphthyl group or an anthryl group.

[0012] In the above technical solution, preferably, n is any one of integers of 4 to 18, the alkoxy group is an alkoxy group of 1 to 10 carbons, the alkyl group is an alkyl group of 1 to 10 carbons, q is any one of integers of 2 to 8, and p is any one of integers of 0 to 6; More preferably, n is an integer of 6 to 16, the alkoxy group is an alkoxy group having 1 to 6 carbon atoms, the alkyl group is an alkyl group having 1 to 6 carbon atoms, q is an integer of 2 to 5, and p is an integer of 0 to 4; More preferably, n is any one of integers from 8 to 14, the alkoxy group is an alkoxy group of 1 to 3 carbons, the alkyl group is an alkyl group of 1 to 3 carbons, q is 2 or 3, and p is 0 or 1.

[0013] In the present invention, the amino acid linker structure refers to a structure remaining after removing a hydroxyl group from the terminal carboxyl group of an amino acid and removing one hydrogen from the amino group linked to the methylene group adjacent to the terminal carboxyl group, in which the amino group and the phenylalkanoic acid group in the amino acid linker form an amide bond to constitute an R1 structure, and the amino acid is arginine, serine, histidine, lysine, glycine, or glutamine.

[0014] Preferably, R1 is the following chemical structure: [ka] Here, n is any one integer from 4 to 18, preferably any one integer from 6 to 16, and more preferably any one integer from 8 to 14.

[0015] Preferably, R1 is the following chemical structure: [ka] Here, R5 is hydrogen, an alkoxy group of 1 to 6 carbons or an alkyl group of 1 to 6 carbons, more preferably the alkoxy group is an alkoxy group of 1 to 3 carbons and the alkyl group is an alkyl group of 1 to 3 carbons.

[0016] Preferably, R1 is the following chemical structure: [ka] where R4 is hydrogen, an alkoxy group of 1 to 6 carbons, or an alkyl group of 1 to 6 carbons, q is an integer of 2 to 5, and L2 is an amino acid linker structure; More preferably, the alkoxy group is an alkoxy group of 1 to 3 carbons, the alkyl group is an alkyl group of 1 to 3 carbons, q is 2 or 3, and the amino acid in the amino acid linker is arginine, serine, histidine, lysine, glycine or glutamine.

[0017] Preferably, R1 is the following chemical structure: [ka] Here, R3 is hydrogen, an alkoxy group, or an alkyl group, and p is an integer of 0 to 7. Preferably, the alkoxy group is an alkoxy group having 1 to 10 carbons, the alkyl group is an alkyl group having 1 to 10 carbons, and p is an integer of 0 to 4; More preferably, the alkoxy group is an alkoxy group having 1 to 6 carbons, the alkyl group is an alkyl group having 1 to 6 carbons, and p is an integer of 0 to 2; Most preferably, the alkoxy group is an alkoxy group of 1 to 3 carbons, the alkyl group is an alkyl group of 1 to 3 carbons, and p is 0 or 1.

[0018] As a preferred example, the ligand compound targeting the PSMA antigen or the ligand compound targeting the PSMA antigen based on DOTA according to the present invention is one of PSMA-A, PSMA-B, PSMA-C, PSMA-D, PSMA-E, PSMA-F, PSMA-G, PSMA-H, PSMA-I, PSMA-J, PSMA-K, and PSMA-L.

[0019] As a specific preferred example, the present invention provides [ka] and pharma- ceutically acceptable salts, esters, or solvates thereof.

[0020] The present invention discloses a chelate, which comprises a ligand compound or a pharma- ceutically acceptable salt, ester or solvate thereof of the ligand compound and a radiometal, the ligand compound being the above-mentioned PSMA antigen targeting ligand compound or the DOTA-based PSMA antigen targeting ligand compound, or a specific preferred example of the ligand compound. The radiometal is bound to the above-mentioned ligand compound via a radiometal chelator group Y, the radiometal being: 64 Cu, 67 Cu, 90 Y, 111 In, 68 Ga, 117m Sn, 153 Sm, 149 Tb, 161 Tb, 177 Lu, 225 Ac, 213 Bi, 224 Ra, 212 Bi, 212 Pb, 225 Ac, 227 Th, 223 Ra, 47 Sc, 186 Re, 188 Re, 68 Ga, 64 Cu, 111 In, 89 Zr, 44 Sc, 99m Tc, 86 Y, 152 Tb or 155 Tb.

[0021] In some embodiments, the radiometal is a diagnostic radiometal ( 68 Ga,64 Cu, 111 In, 89 Zr, 44 Sc, 99m Tc, 86 Y, 152 Tb or 155 In some embodiments, the radiometal is a therapeutic radiometal (including but not limited to Tb), the chelates may be used to perform diagnostic imaging on PSMA-positive prostate cancer patients in the diagnosis of prostate cancer, and in some embodiments, the radiometal is a therapeutic radiometal ( 64 Cu, 67 Cu, 90 Y, 111 In, 117m Sn, 153 Sm, 149 Tb, 161 Tb, 177 Lu, 225 Ac, 213 Bi, 224 Ra, 212 Bi, 212 Pb, 225 Ac, 227 Th, 223 Ra, 47 Sc, 186 Re or 188 In the treatment of prostate cancer, when the compound is a vasopressin receptor agonist (including but not limited to Re), these compounds can be used to treat PSMA-positive prostate cancer patients.

[0022] As a preferred example, a radioactive metal is 177 This is Lu.

[0023] In a preferred embodiment, the chelate is 177 Lu, [ka] or a pharma- ceutically acceptable salt, ester or solvate thereof of the ligand compound.

[0024] A composition comprising the chelate described above and may further comprise a pharma- ceutically acceptable excipient.

[0025] A cancer diagnostic or therapeutic reagent may comprise the above chelate as an active ingredient and further comprise a pharma- ceutically acceptable excipient.

[0026] The present invention discloses the application of the above composition, the above chelate, the above ligand compound or its pharma- ceutical acceptable salt, ester or solvate in the manufacture of cancer diagnostic or therapeutic reagent. The ligand compound is the above PSMA antigen targeting ligand compound or the DOTA-based PSMA antigen targeting ligand compound, or a specific preferred example of the ligand compound. Preferably, the diagnosis is imaging diagnosis, the treatment is radiation therapy, the cancer is solid tumor or blood tumor, and further, the cancer is prostate cancer, more preferably prostate specific membrane antigen positive prostate cancer.

[0027] The present invention discloses a method for imaging a prostate cancer patient, comprising administering to the patient (preferably a diagnostically effective amount) of said chelate, or said composition, or said cancer diagnostic or therapeutic reagent, or a composition comprising said cancer diagnostic or therapeutic reagent and a pharma- ceutically acceptable excipient, and performing tissue imaging, preferably said prostate cancer is prostate specific membrane antigen positive prostate cancer, and said imaging is PET imaging or SPECT imaging.

[0028] The present invention discloses a method of treatment for a patient with prostate cancer, comprising administering to the patient (preferably a therapeutically effective amount) of said chelate, or said composition, or said cancer diagnostic or treatment reagent, or a composition comprising said cancer diagnostic reagent and a pharma- ceutically acceptable excipient, preferably, said prostate cancer is prostate-specific membrane antigen positive prostate cancer, and said treatment is radiation therapy.

[0029] The cancer diagnostic or therapeutic reagent, the chelate, the ligand compound or a pharma- ceutically acceptable salt, ester or solvate thereof disclosed by the present invention is used for the diagnosis or treatment of cancer, preferably, the diagnosis is imaging (e.g., PET imaging or SPECT imaging) diagnosis, the treatment is radiation therapy, the cancer is a solid tumor or a hematological tumor, and further, the cancer is prostate cancer, more preferably prostate-specific membrane antigen-positive prostate cancer. Effect of the Invention

[0030] The ligand compound targeted to PSMA antigen disclosed by the present invention has lower toxicity to normal tissues, higher exposure at tumor site, longer half-life in blood, better antigen affinity and tumor suppression effect, and good radiochemical purity stability and in vivo safety after chelation with metal, and can be used for diagnosis (e.g., performing PET or SPECT imaging) of prostate cancer patients positive for prostate specific membrane antigen (PSMA), and can also be used for treatment of prostate cancer patients positive for prostate specific membrane antigen. The radioactive metal and the ligand compound targeted to PSMA antigen disclosed by the present invention are very stable in coordination and will not fall off in vitro or in vivo, which is very advantageous for the subsequent production, transportation, storage and diagnosis and treatment of pharmaceuticals. [Brief description of the drawings]

[0031] [Figure 1] FIG. 1 shows SPECT / CT scans of 177Lu-PSMA-617 in LNCaP tumor-bearing mice and quantification of radioactivity distribution in the tumor and each tissue. [Diagram 2] FIG. 1 shows SPECT / CT scan images of 177Lu-PSMA-A in LNCaP tumor-bearing mice and quantification of radioactivity distribution in the tumor and each tissue. [Diagram 3] FIG. 1 shows SPECT / CT scan images of 177Lu-PSMA-B in LNCaP tumor-bearing mice and quantification of radioactivity distribution in the tumor and each tissue. [Figure 4] FIG. 1 shows SPECT / CT scan images of 177Lu-PSMA-C in LNCaP tumor-bearing mice and quantification of radioactivity distribution in the tumor and each tissue. [Diagram 5] FIG. 1 shows SPECT / CT scan images of 177Lu-PSMA-E in LNCaP tumor-bearing mice and quantification of radioactivity distribution in the tumor and each tissue. [Figure 6] FIG. 1 shows SPECT / CT scan images of 177Lu-PSMA-F in LNCaP tumor-bearing mice and quantification of radioactivity distribution in the tumor and each tissue. [Figure 7] FIG. 1 shows SPECT / CT scan images of 177Lu-PSMA-G in LNCaP tumor-bearing mice and quantification of radioactivity distribution in the tumor and each tissue. [Figure 8] FIG. 1 shows SPECT / CT scan images of 177Lu-PSMA-H in LNCaP tumor-bearing mice and quantification of radioactivity distribution in the tumor and each tissue. [Figure 9] FIG. 1 shows SPECT / CT scan images of 177Lu-PSMA-I in LNCaP tumor-bearing mice and quantification of radioactivity distribution in the tumor and each tissue. [Figure 10] FIG. 1 shows SPECT / CT scan images of 177Lu-PSMA-K in LNCaP tumor-bearing mice and quantification of radioactivity distribution in the tumor and each tissue. [Figure 11] FIG. 1 shows SPECT / CT scan images of 177Lu-PSMA-L in LNCaP tumor-bearing mice and quantification of radioactivity distribution in the tumor and each tissue. [Figure 12] FIG. 1 shows binding of 177Lu-PSMA-617 and 177Lu-PSMA-L to LNCaP cells. [Figure 13] FIG. 1 shows the pharmacokinetics of 177Lu-PSMA-617 and 177Lu-PSMA-L in mice and rats. [Figure 14]FIG. 1 shows the stability of radiochemical purity of 177Lu-PSMA-L in PBS buffer, 10% mouse serum. [Figure 15] FIG. 1 shows the effect of 177Lu-PSMA-L on white blood cells, hemoglobin, and platelets in mouse blood. [Figure 16] FIG. 1 shows the effect of 177Lu-PSMA-L on mouse body weight at different doses. [Figure 17] FIG. 1 shows the tumor-inhibitory effect of 177Lu-PSMA-617 and 177Lu-PSMA-L on LNCaP tumor-bearing mice and changes in animal body weight during treatment. [Figure 18] FIG. 1 shows radioactivity at tumor location and quantification of radioactivity at tumor location for 177Lu-PSMA-617 and 177Lu-PSMA-L during tumor regression in LNCaP tumor-bearing mice. [Figure 19] 1 is a liquid chromatogram of the compound PSMA-L. [Figure 20] 1 is a mass spectrum of the compound PSMA-L. [Figure 21] Nuclear magnetic resonance spectrum of compound PSMA-L, 1H NMR (600 MHz, dmso). [Figure 22] Nuclear magnetic resonance spectrum of compound PSMA-H, 1H NMR (600 MHz, dmso). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] The present invention discloses a compound of formula (I), or a salt, ester or solvate of said compound, or a pharma- ceutically acceptable salt or solvate thereof, wherein the compound of formula (I) is: [ka] The substituents are as defined above.

[0033] The chemical structure of PSMA-617 is as follows: [ka]

[0034] Some novel compounds that target PSMA disclosed in the present invention are exemplified as follows: PSMA-A: [ka] PSMA-B: [ka] PSMA-C: [ka] PSMA-D: [ka] PSMA-E: [ka] PSMA-F: [ka] PSMA-G: [ka] PSMA-H: [ka] PSMA-I: [ka] PSMA-J: [ka] PSMA-K: [ka] PSMA-L: [ka]

[0035] The raw materials of the present invention are all existing products, some of which are shown below: [Table 1]

[0036] The above reagents are all from conventional commercial purchasing routes and are chemically pure (>99.5%). Animal experiments were carried out using male BALB / c mice weighing 18-20g and male SD rats weighing 180-200g, randomly grouped to generally model tumor-bearing mice and meet the requirements of conventional animal experiments. In general terms, the crude was purified using reversed-phase high-performance liquid chromatography, the chemical structure information of the product was characterized by MALDI-TOF mass spectrometry, and the purity was given by analytical high-performance liquid chromatography (Agela C18 4.6x250mm, flow rate 1ml / min).

[0037] Example 1 Step (1): 1 g of Fmoc-Lys(Dde)-Wang resin (1 eq) was weighed and placed in a reactor as an insoluble solid support and swollen in 30 mL of DCM for 1 h. The liquid in the reactor was filtered by suction, and 30 mL of TEMP / DMF (30%, i.e., volume ratio 3:10) was added to the resin and reacted for 20 min to remove the Fmoc protecting group of the amino group. The liquid in the reactor was filtered by suction, and the resin was washed alternately with 30 mL of DMF and 30 mL of DCM six times, and then 8 eq of Urea(DSC) and 16 eq of DIEA were added and reacted for 120 min to form Urea(DSC)-Lys(Dde)-Wang resin. The liquid in the reactor was filtered by suction, washed alternately with 30 mL of DMF and 30 mL of DCM six times, then 8 eq of H-Glu(OtBu)2·HCl and 16 eq of DIEA were added and reacted with Urea(DSC)-Lys(Dde)-Wang resin for 24 h to form Glu(OtBu)2-Urea-Lys(Dde)-Wang resin. The liquid in the reactor was filtered by suction, washed alternately with 30 mL of DMF and 30 mL of DCM six times, then 30 mL of 3% hydrazine / DMF (volume ratio) solution was added and reacted for 20 min to remove the Dde protecting group of the Lys side chain amino group. The liquid in the reactor was filtered by suction, washed alternately with 30 mL of DMF and 30 mL of DCM six times, then 8 eq of Fmoc-2-Nal-OH, 8 eq of HOBT, and 8 eq of DIC were added and reacted for 2 h to obtain a peptide chain. The liquid in the reactor was filtered by suction, and the mixture was washed alternately with 30 mL of DMF and 30 mL of DCM six times, and then 30 mL of TEMP / DMF (30%) was added and reacted for 20 min to remove the Fmoc protecting group of Fmoc-2-Nal-OH. The liquid in the reactor was filtered by suction, and the mixture was washed alternately with 30 mL of DMF and 30 mL of DCM six times, and 8 eq of trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid (X6), 8 eq of HOBT, and 8 eq of DIC were added to the resin and reacted for 2 h to obtain the peptide chain Glu(OtBu)2-Urea-Lys[(2-Nal)-X6-Fmoc]-Wang resin.The liquid in the reactor was filtered by suction, and the mixture was washed alternately with 30 mL of DMF and 30 mL of DCM six times, and then 30 mL of TEMP / DMF (30%) was added and reacted for 20 min to remove the Fmoc protecting group of trans-4-(Fmoc-aminomethyl)cyclohexane carboxylic acid. The liquid in the reactor was filtered by suction, and the mixture was washed alternately with 30 mL of DMF and 30 mL of DCM six times, and then 8 eq of Dde-Lys(Fmoc)-OH, 8 eq of HOBT, and 8 eq of DIC were added and reacted for 4 h to obtain the peptide chain Glu(OtBu)2-Urea-Lys{(2-Nal)-X6-{Dde-Lys(Fmoc)]}-Wang resin.

[0038] Step (2): The peptide chain Glu(OtBu)2-Urea-Lys{(2-Nal)-X6-{Dde-Lys(Fmoc)]}-Wang resin was washed alternately with 30 mL of DMF and 30 mL of DCM six times, then 30 mL of 30% TEMP / DMF (volume ratio) was added and reacted for 20 min to remove the Fmoc protecting group. The liquid in the reactor was suction filtered, and the mixture was washed alternately with 30 mL of DMF and 30 mL of DCM six times, then 8 eq of DOTA, 8 eq of HOBT, and 8 eq of DIC were added and reacted for 4 h to obtain the peptide chain Glu(OtBu)2-Urea-Lys{(2-Nal)-X6-[Dde-Lys(DOTA)]}-Wang resin. The liquid in the reactor was filtered by suction, washed alternately with 30 mL of DMF and 30 mL of DCM six times, and then 30 mL of 3% hydrazine / DMF (volume ratio) solution was added and reacted for 20 min to remove the Dde protecting group. The liquid in the reactor was filtered by suction, washed alternately with 30 mL of DMF and 30 mL of DCM six times, and then 8 eq of amino acid raw material R, 8 eq of HOBT, and 8 eq of DIC were added and reacted for 2 h to obtain the peptide chain Glu(OtBu)2-Urea-Lys[(2-Nal)-X6-Lys(DOTA)-R]. The liquid in the reactor was filtered by suction, washed alternately with 30 mL of DMF and 30 mL of DCM six times, and then 30 mL of TEMP / DMF (30%) was added and reacted for 20 min to remove the Fmoc protecting group of R. The liquid in the reactor was filtered by suction, and the mixture was washed alternately with 30 mL of DMF and 30 mL of DCM six times, and then 8 eq of p-methoxybenzenebutyric acid (X8), 8 eq of HOBT, and 8 eq of DIC were added and reacted for 2 hours to obtain a peptide chain. The liquid in the reactor was filtered by suction, and the mixture was washed alternately with 30 mL of DMF and 30 mL of DCM six times, and the synthesis of the peptide chain was completed, that is, a crude peptide having a protecting group: Glu(OtBu)2- Urea-Lys[(2-Nal)-X6-Lys(DOTA)-R-X8]-Wang resin was obtained.Next, the resin was washed alternately with 30 mL of DMF and 30 mL of DCM six times, and the resin was dried as usual, then mixed with TFA and H2O in a volume ratio of 95:5 and reacted for 3 hours to cleave the polypeptide from the resin, thereby removing the side chain protecting groups, filtered, the filtrate was added to ice-cold anhydrous ether to precipitate and separate the polypeptide, centrifuged, the supernatant was poured off, then washed with ice-cold anhydrous ether, centrifuged, the solid at the bottom was dried, and the crude polypeptide was obtained. The crude was purified using reversed-phase high-performance liquid chromatography, and the solvent was freeze-dried to obtain a bulky polypeptide pure product, which is the ligand compound targeting the PSMA antigen of the product of the present invention.

[0039] In step (2) above, When the amino acid starting material R is Fmoc-Arg(Pbf)-OH, the product is the compound PSMA-A, which has a molecular weight of 1502.78; When the amino acid starting material R is Fmoc-His(Trt)-OH, the product is PSMA-B, with a molecular weight of 1483.73; When the amino acid starting material R is Fmoc-Lys(Boc)-OH, the product is PSMA-C, with a molecular weight of 1474.76; When the amino acid starting material R is Fmoc-Ser(tBu)-OH, the product is PSMA-D, with a molecular weight of 1433.65; When the amino acid starting material R is Fmoc-Gln(Trt)-OH, the product is PSMA-E, with a molecular weight of 1474.2.

[0040] Example 2 Step (1): 1 g of Fmoc-Lys(Dde)-Wang resin (1 eq) was weighed and placed in a reactor as an insoluble solid support and swollen in 30 mL of DCM for 1 h. The liquid in the reactor was filtered by suction, and 30 mL of TEMP / DMF (30%, i.e., volume ratio 3:10) was added to the resin and reacted for 20 min to remove the Fmoc protecting group of the amino group. The liquid in the reactor was filtered by suction, and the resin was washed alternately with 30 mL of DMF and 30 mL of DCM six times, and then 8 eq of Urea(DSC) and 16 eq of DIEA were added and reacted for 120 min to form Urea(DSC)-Lys(Dde)-Wang resin. The liquid in the reactor was filtered by suction, washed alternately with 30 mL of DMF and 30 mL of DCM six times, then 8 eq of H-Glu(OtBu)2·HCl and 16 eq of DIEA were added and reacted with Urea(DSC)-Lys(Dde)-Wang resin for 24 h to form Glu(OtBu)2-Urea-Lys(Dde)-Wang resin. The liquid in the reactor was filtered by suction, washed alternately with 30 mL of DMF and 30 mL of DCM six times, then 30 mL of 3% hydrazine / DMF (volume ratio) solution was added and reacted for 20 min to remove the Dde protecting group of the Lys side chain amino group. The liquid in the reactor was filtered by suction, washed alternately with 30 mL of DMF and 30 mL of DCM six times, then 8 eq of Fmoc-2-Nal-OH, 8 eq of HOBT, and 8 eq of DIC were added and reacted for 2 h to obtain a peptide chain. The liquid in the reactor was filtered by suction, and the mixture was washed alternately with 30 mL of DMF and 30 mL of DCM six times, and then 30 mL of TEMP / DMF (30%) was added and reacted for 20 min to remove the Fmoc protecting group of Fmoc-2-Nal-OH. The liquid in the reactor was filtered by suction, and the mixture was washed alternately with 30 mL of DMF and 30 mL of DCM six times, and 8 eq of trans-4-(Fmoc-aminomethyl)cyclohexanecarboxylic acid (X6), 8 eq of HOBT, and 8 eq of DIC were added to the resin and reacted for 2 h to obtain the peptide chain Glu(OtBu)2-Urea-Lys[(2-Nal)-X6-Fmoc]-Wang resin.The liquid in the reactor was filtered by suction, and the mixture was washed alternately with 30 mL of DMF and 30 mL of DCM six times, and then 30 mL of TEMP / DMF (30%) was added and reacted for 20 min to remove the Fmoc protecting group of trans-4-(Fmoc-aminomethyl)cyclohexane carboxylic acid. The liquid in the reactor was filtered by suction, and the mixture was washed alternately with 30 mL of DMF and 30 mL of DCM six times, and then 8 eq of Dde-Lys(Fmoc)-OH, 8 eq of HOBT, and 8 eq of DIC were added and reacted for 4 h to obtain the peptide chain Glu(OtBu)2-Urea-Lys{(2-Nal)-X6-{Dde-Lys(Fmoc)]}-Wang resin.

[0041] Step (2): The peptide chain Glu(OtBu)2-Urea-Lys{(2-Nal)-X6- {Dde-Lys(Fmoc)]}-Wang resin was washed alternately six times with 30 mL of DMF and 30 mL of DCM, then 30 mL of 30% TEMP / DMF (volume ratio) was added and reacted for 20 min to remove the Fmoc protecting group of Dde-Lys(Fmoc). The liquid in the reactor was suction filtered, and the mixture was washed alternately six times with 30 mL of DMF and 30 mL of DCM, then 8 eq of DOTA, 8 eq of HOBT, and 8 eq of DIC were added and reacted for 4 h to obtain the peptide chain Glu(OtBu)2-Urea-Lys{(2-Nal)-X6-[Dde-Lys(DOTA)]}-Wang resin. The liquid in the reactor was filtered by suction, washed alternately with 30 mL of DMF and 30 mL of DCM six times, added with 30 mL of 3% hydrazine / DMF (volume ratio) solution, reacted for 20 min, and the Dde protecting group was removed. The liquid in the reactor was filtered by suction, washed alternately with 30 mL of DMF and 30 mL of DCM six times, then added with 8 eq of R1 precursor compound, 8 eq of HOBT, and 8 eq of DIC, reacted for 2 h, and the peptide chain Glu(OtBu)2-Urea-Lys[(2-Nal)-X6-Lys(DOTA)-R1] was obtained. The liquid in the reactor was filtered by suction, washed alternately with 30 mL of DMF and 30 mL of DCM six times, and the resin was dried as usual, then mixed with TFA and H2O in a volume ratio of 95:5 and reacted for 3 hours to cleave the polypeptide from the resin, thereby removing the side chain protecting group, filtered, the filtrate was added to ice-cold anhydrous ether to precipitate and separate the polypeptide, centrifuged, the supernatant was poured out, then washed with ice-cold anhydrous ether and centrifuged, the solid at the bottom was dried, and the crude polypeptide was obtained. The crude was purified using reversed-phase high-performance liquid chromatography, and the solvent was freeze-dried to obtain a bulky polypeptide pure product, which is the ligand compound targeting the PSMA antigen of the product of the present invention.

[0042] In step (2) above, When the R1 precursor compound is hexadecanedioic acid, the product is PSMA-F, with a molecular weight of 1439.51 and a purity of 93.65%; When the R1 precursor compound is tetradecanedioic acid, the product is PSMA-G, with a molecular weight of 1411.88 and a purity of 95.85%; When the R1 precursor compound is dodecanedioic acid, the product is PSMA-H, with a molecular weight of 1383.22 and a purity of 97.32%; When the R1 precursor compound is p-methoxybenzoic acid, the product is PSMA-I, with a molecular weight of 1304.56 and a purity of 96.83%; When the R1 precursor compound is X56, the product is PSMA-K, with a molecular weight of 1516.53 and a purity of 95.42%; X56 is [ka] This is the structure.

[0043] Example 3 Step (1): 1 g of Fmoc-Lys(Dde)-Wang resin (1 eq) was weighed and placed in a reactor as an insoluble solid support and swollen in 30 mL of DCM for 1 h. The liquid in the reactor was filtered by suction, and 30 mL of TEMP / DMF (30%, i.e., volume ratio 3:10) was added to the resin and reacted for 20 min to remove the Fmoc protecting group of the amino group. The liquid in the reactor was filtered by suction, and the resin was washed alternately with 30 mL of DMF and 30 mL of DCM six times, and then 8 eq of Urea(DSC) and 16 eq of DIEA were added and reacted for 120 min to form Urea(DSC)-Lys(Dde)-Wang resin. The liquid in the reactor was filtered by suction, washed alternately with 30 mL of DMF and 30 mL of DCM six times, then 8 eq of H-Glu(OtBu)2·HCl and 16 eq of DIEA were added and reacted with Urea(DSC)-Lys(Dde)-Wang resin for 24 h to form Glu(OtBu)2-Urea-Lys(Dde)-Wang resin. The liquid in the reactor was filtered by suction, washed alternately with 30 mL of DMF and 30 mL of DCM six times, then 30 mL of 3% hydrazine / DMF (volume ratio) solution was added and reacted for 20 min to remove the Dde protecting group of the Lys side chain amino group. The liquid in the reactor was filtered by suction, and the mixture was washed alternately with 30 mL of DMF and 30 mL of DCM six times, and then 8 eq of Fmoc-2-Nal-OH, 8 eq of HOBT, and 8 eq of DIC were added and reacted for 2 h to obtain the peptide chain Glu(OtBu)2-Urea-Lys(2-Nal)-Wang resin. The liquid in the reactor was filtered by suction, and the mixture was washed alternately with 30 mL of DMF and 30 mL of DCM six times, and then 30 mL of TEMP / DMF (30%, i.e., volume ratio 3:10) was added and reacted for 20 min to remove the Fmoc protecting group of Fmoc-2-Nal-OH. The liquid in the reactor was filtered by suction, and the resin was washed alternately with 30 mL of DMF and 30 mL of DCM six times, and 8 eq of X9, 8 eq of HOBT, and 8 eq of DIC were added to the resin and reacted for 2 h to obtain the peptide chain Glu(OtBu)2-Urea-Lys[(2-Nal)-X9-Fmoc]-Wang resin. The liquid in the reactor was filtered by suction, and the resin was washed alternately with 30 mL of DMF and 30 mL of DCM six times, and then 30 mL of TEMP / DMF (30%) was added and reacted for 20 min to remove the Fmoc protecting group of X9.The liquid in the reactor was filtered by suction and washed alternately six times with 30 mL of DMF and 30 mL of DCM. Then, 8 eq of Dde-Lys(Fmoc)-OH, 8 eq of HOBT, and 8 eq of DIC were added and reacted for 4 hours to obtain the peptide chain Glu(OtBu)2-Urea-Lys{(2-Nal)-X9-{Dde-Lys(Fmoc)]}-Wang resin.

[0044] Step (2): The peptide chain Glu(OtBu)2-Urea-Lys{(2-Nal)-X9- {Dde-Lys(Fmoc)]}-Wang resin was washed alternately with 30 mL of DMF and 30 mL of DCM six times, then 30 mL of 30% TEMP / DMF (volume ratio) was added and reacted for 20 min to remove the Fmoc protecting group. The liquid in the reactor was suction filtered, and the mixture was washed alternately with 30 mL of DMF and 30 mL of DCM six times, then 8 eq of DOTA, 8 eq of HOBT, and 8 eq of DIC were added and reacted for 4 h to obtain the peptide chain Glu(OtBu)2-Urea-Lys{(2-Nal)-X9-[Dde-Lys(DOTA)]}-Wang resin. The liquid in the reactor was filtered by suction, washed alternately with 30 mL of DMF and 30 mL of DCM six times, added with 30 mL of 3% hydrazine / DMF (volume ratio) solution, reacted for 20 min, and the Dde protecting group was removed. The liquid in the reactor was filtered by suction, washed alternately with 30 mL of DMF and 30 mL of DCM six times, then added with 8 eq of R1 precursor compound, 8 eq of HOBT, and 8 eq of DIC, reacted for 2 h, and the peptide chain Glu(OtBu)2-Urea-Lys[(2-Nal)-X9-Lys(DOTA)-R1] was obtained. The liquid in the reactor was filtered by suction, washed alternately with 30 mL of DMF and 30 mL of DCM six times, and the resin was dried as usual, then mixed with TFA and H2O in a volume ratio of 95:5 and reacted for 3 hours to cleave the polypeptide from the resin, thereby removing the side chain protecting group, filtered, the filtrate was added to ice-cold anhydrous ether to precipitate and separate the polypeptide, centrifuged, the supernatant was poured out, then washed with ice-cold anhydrous ether and centrifuged, the solid at the bottom was dried, and the crude polypeptide was obtained. The crude was purified using reversed-phase high-performance liquid chromatography, and the solvent was freeze-dried to obtain a bulky polypeptide pure product, which is the ligand compound targeting the PSMA antigen of the product of the present invention.

[0045] In step (2) above, When the R1 precursor compound is p-methoxybenzoic acid, the product is PSMA-J, with a molecular weight of 1309.29 and a purity of 96.00%; When the R1 precursor compound is X56, the product is PSMA-L with a molecular weight of 1536.37 and a purity of 96.13%.

[0046] X56 has the following structure: [ka]

[0047] It can be prepared according to the following reaction: [ka]

[0048] Compound 1 (1g) was dissolved in 15mL of dichloromethane, CDI (1.05eq) was added, and the mixture was stirred at room temperature for 1h. Compound 2 (1eq) was added, and the mixture was reacted for 2h. The reaction was completed, and the mixture was separated by column chromatography to obtain 2.2g of compound 3. Compound 3 (2.2g) was dissolved in 10mL of dichloromethane, 5mL of TFA was added, and the mixture was stirred at room temperature for 1h. The solvent was removed to obtain the crude product of compound 4, which was directly used in the next step. Compound 5 (1.05g) was dissolved in 15mL of dichloromethane, CDI (1.05eq) was added, and the mixture was stirred at room temperature for 1h. Compound 4 (1eq) and TEA (1.1eq) were added, and the mixture was reacted for 2h. The reaction was completed, and the mixture was separated by column chromatography to obtain 1.4g of compound 6. Compound 6 (1.4 g) was dissolved in 8 mL of dichloromethane, 4 mL of TFA was added, and the mixture was stirred at room temperature for 1 h. The solvent was then removed to obtain a crude product of compound 7, which was then separated to obtain 520 mg of pure compound X56.

[0049] The structural formula of X9 is as follows: [ka]

[0050] It can be prepared according to the following reaction: [ka]

[0051] Compound 1 (1g, 5.64 mmol) and Na2CO3 (1.2 g, 11.29 mmol) were added to 1,4-dioxane / H2O, stirred at room temperature for 30 min, and then compound 2 (1.9 g, 5.64 mmol) in 1,4-dioxane was added dropwise to the system and reacted at room temperature for 2 h, and the reaction was detected to be complete by LCMS. The reaction solution was concentrated to a small volume, back-extracted with ethyl acetate three times, the aqueous phase was kept, and the pH of the aqueous phase was adjusted to weak acidity with HCl (4N), extracted with ethyl acetate, concentrated, and then purified by pre-HPLC and lyophilized to obtain 1.1 g of a white solid as compound X9.

[0052] Example 4 177 Lu-labeled precursor compound (chelate) The metal bath reactor was turned on and preheated to 95°C. The precursor (ligand compound targeting PSMA antigen) was diluted to 100ng / μL with 0.5M sodium acetate buffer at pH 4.5 to form a precursor solution. 37MBq (1mCi) 177 Take LuCl3 solution (about 50 pmol), then add 15 times the equivalent of the precursor solution, supplement with sodium acetate buffer to 50 μL, and react at 95 °C, 800 rpm for 30 min. 177 The Lu-labeled precursor compound was obtained and existed in the form of a solution. The purity was detected by TLC using 1% EDTA as the developing solvent. If the purity was greater than 95%, no further treatment was required. If the purity was less than 95%, further purification was required: desalted using a C18 column and uncoordinated. 177 Lu was removed.

[0053] 177 The radiochemical purity of the Lu-labeled compounds PSMA-617, PSMA-A, PSMA-B, PSMA-C, PSMA-D, PSMA-E, PSMA-F, PSMA-G, PSMA-H, PSMA-I, PSMA-J, PSMA-K and PSMA-L can all reach 95% or more.

[0054] Example 5 SPECT / CT scan and data processing 177 Lu-labeled precursor compounds were diluted with saline to 7.4MBq (200μCi) / 200μL, and each tumor-bearing mouse was administered approximately 7.4MBq (200μCi) of drug via tail vein injection. After administration, the mice were continuously anesthetized with isoflurane at 1, 4, 8, 24, 48, and 72h, respectively, and placed in a prone position on an examination bed to perform SPECT / CT scans. The acquisition method was static 12min SPECT, medium-resolution whole-body CT. During this process, the animal's weight, injection amount, injection time, and residual amount were recorded according to the record table, and the measurement time of the injection amount and the measurement time of the residual amount were recorded, respectively. After scanning, the data was reconstructed, and each organ tissue was analyzed and drawn with PMOD software, the drug distribution was quantified, the images and data were saved, and the data were further statistically analyzed.

[0055] FIG. 1 to FIG. 11 are 177 SPECT / CT scans of Lu-labeled compounds PSMA-617, PSMA-A, PSMA-B, PSMA-C, PSMA-E, PSMA-F, PSMA-G, PSMA-H, PSMA-I, PSMA-K and PSMA-L and quantitative values ​​of drug distribution in each tissue are shown. Drug exposure in each tissue (Table 1, where PSMA-D is the predicted value) was calculated, and it was found that compared with PSMA-617, the ligand compound of the present invention can improve the exposure of LNCaP tumors and tissues, especially the exposure of PSMA-L in normal tissues is maintained at a low level, so PSMA-L can significantly improve the drug exposure of LNCaP tumors while maintaining low drug exposure in normal tissues, and is a more potent compound than PSMA-617.

[0056] [Table 2]

[0057] Example 6 Cell binding ability PSMA-positive LNCaP cells were expanded and cultured, and 10 5The cells were seeded in a 24-well plate at a density of 1000 cells / well. After the cells attached to the wall, the medium was removed by aspiration and radioactivity gradient counting was performed. 177 Lu-labeled compounds and the positive control PSMA-617 were added, with the highest concentration being 5 × 10 6 cpm / 0.5mL, and gradient dilution was performed at a dilution factor of 1 / 3. After adding the labeled compounds, the mixture was incubated at 37°C for 1h, the medium was aspirated and removed, the cells were washed three times with PBS, and 0.2mL of 1M NaOH solution was added to lyse the cells. The lysate was aspirated into a radioimmunotube, and the radioactivity count of each sample tube was detected by a gamma counter. The data was analyzed to compare the binding ability of the candidate compounds and the positive control compound PSMA-617 to PSMA-positive cells.

[0058] Figure 12 shows 177 Lu-PSMA-617 and 177 Shows binding of Lu-PSMA-L to LNCaP cells. 177 than Lu-PSMA-617 177 It was found that Lu-PSMA-L had a higher binding ability to LNCaP cells. 177 Lu-PSMA-L 177 It was shown to have higher antigen affinity than Lu-PSMA-617.

[0059] Example 7 Pharmacokinetics Male BALB / c mice, weighing 18-20g. Male SD rats, weighing 180-200g. Randomly divided into groups of 3. After isoflurane anesthesia, 177 Compounds labeled with Lu (1.85MBq (50μCi)) were injected into the tail vein. After administration, 20μL of blood was collected from the orbit at 1min, 5min, 10min, 15min, 0.5h, 1h, 2h, 4h, 8h, 24h and 72h, respectively, and placed in a pre-weighed centrifuge tube. The radioactivity count of the blood in the centrifuge tube and the weight of the centrifuge tube containing the blood were measured, and the percentage of radioactivity count per unit weight of blood relative to the administered dose was calculated. Blood concentration-time curves were generated to calculate the blood exposure of the compounds of the present invention and the positive control compound PSMA-617.

[0060] Figure 13 shows177 Lu-PSMA-617 and 177 The pharmacokinetics of Lu-PSMA-L in mice and rats are shown. 177 Lu-PSMA-L has a high metabolic rate in both mice and rats. 177 It was found to be slower than Lu-PSMA-617, resulting in a longer half-life in the blood and higher drug exposure, and this higher blood concentration was only maintained for 1 h after administration, after which 177 Lu-PSMA-L was also largely removed from the blood, thus increasing the drug-tumor action concentration and time without increasing toxic side effects on normal tissues.

[0061] Example 8 Stability of Radiochemical Purity 177 200 μCi of the Lu-labeled compound was mixed with 0.5 mL of PBS and 10% mouse serum, respectively. After mixing, samples were taken at 12 h, 24 h, 48 h, 72 h, and 96 h, and the radiochemical purity was detected by TLC to examine the stability of the radiochemical purity of the compound.

[0062] Figure 14 shows 177 The stability of the radiochemical purity of Lu-PSMA-L in PBS buffer and 10% mouse serum was demonstrated. 177 Lu-PSMA-L was found to be very stable in both PBS buffer and 10% mouse serum, with its radiochemical purity maintained at 100% within 96 hours. 177 The coordination of Lu and PSMA-L was found to be very stable and was not shed either in vitro or in vivo, which is highly advantageous for subsequent pharmaceutical production, transportation, storage, and diagnostic therapy.

[0063] Example 9 Hematological Toxicity Mice were randomly assigned to groups of 5 mice per group based on body weight. 177Lu-labeled compound (7.4MBq (200μCi) or 14.8MBq (400μCi)) was administered to each animal via tail vein injection, and PBS was administered to the control group. After 7 days, the animals were anesthetized, and 1mL or more of blood was collected and placed in an anticoagulant tube, and the white blood cell, hemoglobin, and platelet contents in the blood were detected using a blood biochemistry device designed for mice. The control group and the treatment group were compared to learn the degree of bone marrow suppression caused by the drug.

[0064] FIG. 15 shows the effect of the IgG on leukocytes, hemoglobin and platelets in mouse blood. 177 The effect of Lu-PSMA-L was shown. At doses of 7.4MBq (200μCi) and 14.8MBq (400μCi), the contents of white blood cells, hemoglobin, and platelets in the mouse blood were not significantly different from the control PBS group. 177 This suggests that Lu-PSMA-L has low hematotoxicity and weak inhibition of bone marrow. 177 Regarding the pharmacokinetic properties of Lu-PSMA-L, 177 Lu-PSMA-L maintained high blood concentrations for only 1 h after administration and was rapidly cleared from the blood, thereby reducing damage to normal cells in the blood.

[0065] Example 10 Dose Tolerance Mice were randomly assigned to groups of 5 mice per group based on body weight. 177 Lu-labeled compound (14.8MBq (400μCi) or 29.6MBq (800μCi)) was administered to each mouse via tail vein injection, and the control group was administered the solvent. After administration, the mice were weighed every 3 days and the death rate of the mice was recorded. The control group and the administration group were compared to determine the maximum tolerated dose of the drug in mice.

[0066] FIG. 16 shows the effect of different doses on mouse body weight. 177 The effect of Lu-PSMA-L was shown. It was found that the mice's body weight did not decrease significantly at doses of 14.8MBq (400μCi) or 29.6MBq (800μCi). 177 High dose tolerance to Lu-PSMA-L 177This suggests that Lu-PSMA-L is highly safe.

[0067] Example 11 Tumor suppression PSMA-positive LNCaP cells were expanded and then harvested at 1 × 10 7 The mice were subcutaneously inoculated with 1000 mg / mouse. 3 Once the tumors had grown to a size large enough to be viable, they were randomly assigned to groups of 3-4 mice each based on tumor size. 177 400 μCi of a compound of the invention labeled with Lu or 177 The positive control compound PSMA-617 labeled with Lu was administered via tail vein injection. After administration, the tumor size and body weight of the mice were measured every 3 days, and the death status of the mice was recorded. The control group and each treatment group were compared to know the inhibition of LNCaP tumor by different drugs. On the 6th day after administration, the treatment groups were subjected to SPECT / CT scan to know the exposure of the tumor location to different drugs during treatment.

[0068] FIG. 17 shows the effect of LNCaP tumor-bearing mice 177 Lu-PSMA-617 and 177 The tumor-inhibitory effect of Lu-PSMA-L and changes in animal body weight during treatment are shown. 177 Lu-PSMA-L showed tumor-suppressing activity in LNCaP tumor-bearing mice. 177 During treatment, there was no significant difference in the animal weights of each group, and the mice received 14.8 MBq (400 μCi) of 177 Lu-PSMA-617 and 14.8MBq (400μCi) 177 These results suggest that the patient is resistant to both Lu and PSMA-L.

[0069] FIG. 18 shows the effect of IFN-γ on tumor suppression in LNCaP tumor-bearing mice. 177 Lu-PSMA-617 and 177 The radioactivity and quantification value of Lu-PSMA-L at the tumor site were shown. 177 Exposure of Lu-PSMA-L at tumor location 177Lu-PSMA-617, which was consistent with the results of tumor inhibition by the drug.

[0070] FIG. 19 is a liquid chromatogram of the compound PSMA-L. FIG. 20 is a mass spectrum of the compound PSMA-L; FIG. 21 shows the nuclear magnetic resonance spectrum of the compound PSMA-L. 1 H NMR (600 MHz, dmso) FIG. 22 shows the nuclear magnetic resonance spectrum of the compound PSMA-H. 1 H NMR (600 MHz, dmso).

[0071] Prostate cancer is cancer that begins in the prostate, a small, walnut-shaped gland in the male pelvis. In castration-resistant prostate cancer (CRPC), tumors show signs of growth despite hormonal therapy to reduce testosterone. Radioligand therapy combines targeted compounds and radioisotopes that can bind to tumor-expressing markers, causing DNA damage and inhibiting tumor growth and replication. Such treatment methods can deliver radiation to tumor targets while limiting damage to surrounding normal tissue. 177 Lu-PSMA-617 is a PSMA-targeted radioligand therapy, which is used to treat metastatic castration-resistant prostate cancer (mCRPC) and has already entered clinical research.Compared to this, the chelate of the ligand compound of the present invention and radioactive metal has lower toxicity to normal tissues, higher exposure at tumor site, longer half-life in blood, better antigen affinity and tumor inhibition effect, as well as good radiochemical purity stability and in vivo safety, and has high application value in the diagnosis and treatment of prostate cancer.

Claims

1. A ligand compound targeting the PSMA antigen, or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein the chemical structural formula of the ligand compound is: 【Chemistry 1】 and wherein a and b are each independently an integer of 1 to 8, c and d are each independently an integer of 1 to 4, preferably a and b are each independently an integer of 2 to 6, c and d are each independently an integer of 1 to 3, more preferably a and b are 4, c is 2, and d is 1; L １ teeth, 【Chemistry 2】 and preferably, L １ is linked to other fragments in the structural formula of the ligand compound via an amide bond, Here, R ６ , R ７ , R ８ are each independently one of hydrogen, an alkyl group, an alkoxy group, and a halogen; R １ teeth, 【Transformation 3】 It is one of the following chemical structural formulas: where n is an integer from 2 to 20, and R ３ , R ４ , R ５ are each independently any one of hydrogen, an alkyl group, an alkoxy group, a halogen atom, a cycloalkyl group, a heterocyclo group, and an aryl group; p is any one integer of 0 to 8; q is any one integer of 1 to 10; L ２ is an amino acid linker structure, R ２ is an aryl group or a heteroaryl group, preferably an aryl group; and Y is a radioactive metal chelator group, or a pharmaceutically acceptable salt, ester, or solvate thereof.

2. The chemical structural formula of the ligand compound is as follows: 【Chemistry 4】 Here, L １ teeth, 【Transformation 5】 and preferably, L １ is linked to other fragments in the structural formula of the ligand compound via an amide bond, R １ , R ２ and Y are as defined in claim 1, or a pharmaceutically acceptable salt, ester or solvate thereof.

3. The radioactive metal chelator may be DOTA or a derivative thereof, TETA or a derivative thereof, SarAR or a derivative thereof, NOTA or a derivative thereof, TRAP or a derivative thereof, HBED or a derivative thereof, 2,3-HOPO or a derivative thereof, PCTA or a derivative thereof, DFO or a derivative thereof, DTPA or a derivative thereof, OCTAPA or a derivative thereof, H ２ 2. The ligand compound according to claim 1, or a pharmaceutically acceptable salt, ester or solvate thereof, which is any one of MACROPA and its derivatives.

4. A ligand compound that targets the PSMA antigen based on DOTA, or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein the chemical structure of the ligand compound is: 【Transformation 6】 and Here, L １ teeth, 【Transformation 7】 and preferably, L １ is linked to other fragments in the structural formula of the ligand compound via an amide bond, R １ teeth, 【Transformation 8】 It is one of the following chemical structural formulas: where n is an integer from 2 to 20, and R ３ , R ４ , R ５ are each independently any one of hydrogen, an alkyl group, an alkoxy group, a halogen atom, a cycloalkyl group, a heterocyclo group, and an aryl group; p is any one integer of 0 to 8; q is any one integer of 1 to 10; L ２ is an amino acid linker structure, R ２ is an aryl group or a heteroaryl group, preferably an aryl group, more preferably a naphthyl group, or a pharmaceutically acceptable salt, ester or solvate thereof.

5. The chemical structural formula of the ligand compound is as follows: 【Chemistry 9】 Here, R １ , L １ The ligand compound according to claim 4, or a pharmaceutically acceptable salt, ester or solvate thereof, wherein:

6. wherein n is an integer of 6 to 16, the alkoxy group is an alkoxy group having 1 to 6 carbon atoms, the alkyl group is an alkyl group having 1 to 6 carbon atoms, q is an integer of 2 to 5, and p is an integer of 0 to 4; The ligand compound or its pharmaceutically acceptable salt, ester, or solvate thereof according to claim 1 or 4, characterized in that n is preferably any one integer of 8 to 14, the alkoxy group is an alkoxy group of 1 to 3 carbons, the alkyl group is an alkyl group of 1 to 3 carbons, p is 0 or 1, and q is 2 or 3.

7. 5. The ligand compound or its pharmaceutically acceptable salt, ester or solvate thereof according to claim 1 or 4, wherein the aryl group is a phenyl group, a naphthyl group or an anthryl group.

8. The ligand compound or its pharmaceutically acceptable salt, ester or solvate thereof according to claim 1 or 4, characterized in that the amino acid in the amino acid linker structure is arginine, serine, histidine, lysine, glycine or glutamine.

9. The R １ is the following chemical structure: 【Chemistry 10】 where n is an integer between 6 and 16, The ligand compound or its pharmaceutically acceptable salt, ester or solvate thereof according to claim 1 or 4, characterized in that n is preferably any one integer of 8 to 14.

10. The R １ is the following chemical structure: 【Chemistry 11】 Here, R ５ is hydrogen, an alkoxy group of 1 to 6 carbons, or an alkyl group of 1 to 6 carbons; The ligand compound or its pharmaceutically acceptable salt, ester or solvate thereof according to claim 1 or 4, characterized in that the alkoxy group is preferably an alkoxy group of 1 to 3 carbon atoms, and the alkyl group is preferably an alkyl group of 1 to 3 carbon atoms.

11. The R １ is the following chemical structure: 【Chemistry 12】 Here, R ４ is hydrogen, an alkoxy group of 1 to 6 carbon atoms, or an alkyl group of 1 to 6 carbon atoms; q is an integer of 2 to 5; L ２ is an amino acid linker structure, The ligand compound, or a pharmaceutically acceptable salt, ester, or solvate thereof according to claim 1 or 4, characterized in that the alkoxy group is an alkoxy group of 1 to 3 carbon atoms, the alkyl group is an alkyl group of 1 to 3 carbon atoms, the amino acid in the amino acid linker structure is arginine, serine, histidine, lysine, glycine, or glutamine, and q is 2 or 3.

12. The R １ is the following chemical structure: 【Chemistry 13】 Here, R ３ is hydrogen, an alkoxy group of 1 to 6 carbon atoms, or an alkyl group of 1 to 6 carbon atoms, and p is an integer of 0 to 2; The ligand compound or its pharmaceutically acceptable salt, ester or solvate thereof according to claim 1 or 4, characterized in that the alkoxy group is an alkoxy group of 1 to 3 carbons, the alkyl group is an alkyl group of 1 to 3 carbons, and p is 0 or 1.

13. The ligand compound is 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 The ligand compound according to claim 1 or 4, or a pharmaceutically acceptable salt, ester or solvate thereof, selected from the compounds: 【Request Item 14】 【Chemistry 18】 or a pharmaceutically acceptable salt, ester or solvate thereof.

15. A chelate comprising the ligand compound of claim 1, 4 or 14, or a pharmaceutically acceptable salt, ester or solvate thereof, and a radiometal, wherein the radiometal is complexed to the radiometal chelator group; Preferably, the radiometal is ６４ Cu, ６７ Cu, ９０ Y. １１１ In, ６８ Ga, １１７ｍ Sn, １５３ Sm, １４９ Tb, １６１ Tb, １７７ Lu, ２２５ Ac, ２１３ Bi, ２２４ Ra, ２１２ Bi, ２１２ Pb, ２２５ Ac, ２２７ Th, ２２３ Ra, ４７ Sc, １８６ Re, １８８ Re, ６８ Ga, ６４ Cu, １１１ In, ８９ Zr, ４４ Sc, ９９ｍ Tc, ８６ Y. １５２ Tb or １５５ Tb, More preferably, the radioactive metal is １７７ Lu, chelate.

16. １７７ Lu and 【Chemistry 19】 or a pharmaceutically acceptable salt, ester, or solvate thereof.

17. 16. A composition comprising the chelate of claim 15, preferably said composition further comprising a pharmaceutically acceptable excipient.

18. A cancer diagnostic or therapeutic reagent comprising the chelate of claim 15, preferably said cancer diagnostic or therapeutic reagent further comprising a pharmaceutically acceptable excipient.

19. Use of the ligand compound according to claim 1, 4 or 14, or a pharmaceutically acceptable salt, ester or solvate thereof, in the manufacture of a cancer diagnostic or therapeutic reagent, comprising: Preferably, the cancer is a solid tumor or a hematological tumor; More preferably, the cancer is prostate cancer; More preferably, the cancer is prostate-specific membrane antigen-positive prostate cancer.

20. 16. A method for imaging a patient with prostate cancer, comprising administering to the patient a chelate according to claim 15 and performing tissue imaging, Preferably, the prostate cancer is prostate-specific membrane antigen-positive prostate cancer; Preferably, the imaging is PET imaging or SPECT imaging.

21. 16. A method of treatment for a patient with prostate cancer, comprising administering to the patient a chelate according to claim 15, Preferably, the prostate cancer is prostate-specific membrane antigen-positive prostate cancer; Preferably, the treatment is radiation therapy.

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