Dansylamide-modified compounds targeting PSMA, preparation method therefor, and use thereof

Abstract

Provided are dansylamide-modified compounds targeting PSMA, of which the structure is represented by formula A or formula I, wherein R1 is an amino acid analogue structure, R2 is a compound structure targeting the prostate-specific membrane antigen, R3 is a nuclide chelating group, and L is -(X)n-(CH2)m-(Y)q-, X and Y being independently selected from lysine, glutamic acid or derivative structures containing lysine or glutamic acid, n being an integer from 0 to 10, m being an integer from 0 to 20, q being an integer from 0 to 6, and each CH2 being independently replaceable with -OCH2-, -NH(CO)-, or -(CO)-NH-. Also provided is a radionuclide marker based on the compound structure. The compounds and the radionuclide marker have high tumor uptake and retention times and therefore are suitable for radionuclide therapy and imaging of tumors highly-expressing PSMA.

Description

Dansylamide-modified PSMA-targeting compound and its preparation method and application Technical Field

[0001] The present invention belongs to the field of, but is not limited to, prostate cancer diagnosis and treatment technology, and specifically relates to a prostate-specific membrane antigen (PSMA) targeting compound with high tumor uptake and long retention, and a radionuclide-labeled disease diagnosis and treatment probe thereof. Background Art

[0002] Prostate-specific membrane antigen (PSMA) is only expressed in low amounts in normal tissues but is overexpressed in approximately 90% of prostate cancer lesions (100-1000 times higher than the reference value). The level of PSMA expression in lesions is closely correlated with tumor aggressiveness and malignancy. Therefore, accurate assessment of PSMA expression in lesions is crucial for the diagnosis, staging, efficacy evaluation, progression, and prognosis of prostate cancer. Currently, PSMA imaging has become an indispensable imaging modality for prostate cancer patients. Furthermore, PSMA is also highly expressed in other tumors, such as lung cancer, liver cancer, gastric cancer, breast cancer, colorectal cancer, renal cell carcinoma, bladder cancer, brain tumors, thyroid cancer, and adenoid cystic carcinoma, showing great potential for application in the diagnosis and treatment of tumors beyond prostate cancer.

[0003] Radioligand therapy (RLT) targeting PSMA is one of the important treatments for metastatic castration-resistant prostate cancer (mCRPC). 177 Lu-PSMA-617 is the most commonly used radionuclide therapy for RLT. In September 2021, Novartis announced 177 Results of the Phase III VISION clinical trial of Lu-PSMA-617 in the treatment of PSMA-positive mCRPC patients showed that compared with the best standard of care (SOC), 177 Lu-PSMA-617 combined with SOC significantly improved the median radiographic progression-free survival (8.7 months vs. 3.4 months) and median overall survival (15.3 months vs. 11.3 months) in patients with mCRPC. 177Lu-PSMA-617) was approved by the FDA for the treatment of adult patients with PSMA-positive mCRPC who had previously received androgen receptor inhibitors and taxane chemotherapy. 177 Lu-PSMA-617 has made some progress in the treatment of mCRPC patients, but a considerable number of prostate cancer patients still do not respond well to treatment. In terms of treatment, due to the rapid metabolism and elution of small molecule peptides such as PSMA-617, the effective dose at the tumor site is low and the retention time is too short. High doses or more frequent administration methods are required to meet treatment needs, which increases the possibility of adverse reactions and imposes a heavy economic and social burden. Therefore, optimizing the pharmacokinetics of molecular probes, improving the utilization rate of radionuclides such as Lu-177, and reducing the dose of radionuclides are one of the important directions for the development of integrated radionuclide diagnosis and treatment. To this end, this study proposed a method based on dansylamide compounds to greatly improve the uptake and retention of PSMA probes at the tumor site, which is of great significance to the clinical application of integrated diagnosis and treatment based on PSMA.

[0004] Summary of the Invention

[0005] Against this backdrop, the primary objective of the present invention is to develop novel prostate-specific membrane antigen-targeted compounds based on dansylamide to enhance tumor uptake and prolong tumor retention. This invention overcomes the limitations of small-molecule PSMA-targeted probes, such as rapid metabolism and short target organ retention, improving the efficacy of PSMA-targeted radionuclide therapy and imaging, and has the potential for widespread clinical application.

[0006] Another object of the present invention is to provide a series of radiolabeled prostate-specific membrane antigen-targeted complexes with high tumor uptake and long retention.

[0007] Another object of the present invention is to provide a method for preparing the radiolabeled prostate-specific membrane antigen-targeted complex with high tumor uptake and long retention.

[0008] Another object of the present invention is to provide the use of the complex in targeted radionuclide imaging and treatment of prostate cancer.

[0009] The technical solutions for achieving the above primary purpose of the present invention include the following two aspects: ligand synthesis and radioactive labeling.

[0010] In a first aspect, the present invention provides a dansylamide-modified PSMA-targeting compound with high tumor uptake and long retention. The molecular structure of the compound is composed of a linker group L connecting a dansylamide compound and a PSMA-targeting compound, as shown in the following formula A:

[0011] Alternatively, its molecular structure is composed of a linker group L connecting a dansylamide compound, a PSMA targeting compound, and a nuclide chelating group, and its structure is shown in the following formula I;

[0012] in:

[0013] L is -(X) n -(CH2) m -(Y) q -, wherein n is an integer from 0 to 10 (preferably an integer from 0 to 5), X and Y are independently selected from lysine, glutamic acid or a derivative structure containing lysine or glutamic acid, m is an integer from 0 to 20 (preferably an integer from 0 to 10), q is an integer from 0 to 6 (preferably an integer from 0 to 3), wherein each CH2 can be independently replaced with -OCH2-, -NH(CO)- or -(CO)-NH-

[0014] R1 is an amino acid analogue, including L-amino acids and D-amino acids and their derivatives Wherein R4 includes but is not limited to: (CH2) r -aryl, (CH2) r -heteroaryl, (CH2) r -COOH, (CH2) r -NH2, (CH2) r -OH, (CH2) r -SH, (CH2) r -naphthylmethyl, (CH2) r -Indolyl, (CH2) r -Benzothiazolyl, wherein r is an integer from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10). In a preferred embodiment, R1 can be specifically the following structure:

[0015] R2 is derived from a prostate-specific membrane antigen targeting compound, as shown in Formula II:

[0016] in:

[0017] a is an integer from 0 to 20 (preferably an integer from 0 to 10)

[0018] The X1 structures at different positions are the same or different and are independently selected from O, N, S or P;

[0019] Y1 is O, S, or NH;

[0020] Z is O, S, or NH;

[0021] Q is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkylaryl and cycloalkyl, preferably substituted or unsubstituted C5-C 14 Aryl, substituted or unsubstituted C5-C 14 -alkylaryl or substituted or unsubstituted C5-C 14 Cycloalkyl;

[0022] W is selected from -(CH2) b -aryl or -(CH2) b -heteroaryl, wherein b is an integer from 0 to 10 (specifically, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10).

[0023] Wherein R2 is derived from a prostate-specific membrane antigen targeting compound, preferably but not limited to the following structure

[0024] R3 is a nuclide chelating group, including but not limited to the following structures or structures derived from the following structures:

[0025] In the preferred embodiment of the present invention, R2 is R3 is That is, the structure of the compound of formula A is shown in formula B;

[0026] The structure of the compound of formula I is shown in the following formula III or formula III-1:

[0027] At this time, L is selected from:

[0028] Lys, -Lys-(CO)-CH2-(CO)-NH-CH2-(CO), -Lys-(CO)-CH2-(OCH2CH2)-O-CH2(CO)-NH-CH2-(CO), -Lys-(CO)-CH2-(OCH2CH2)3-O -CH2(CO)-NH-CH2-(CO), -(CO)-CH2-(CO)-Lys-, -(CO)-(OCH2CH2)-O-CH2(CO)-Lys-, or -(CO)-CH2-(OCH2CH2)3-O-CH2(CO)-Lys-.

[0029] In a more preferred embodiment of the present invention, R2 is R3 is L is Lys, that is, the structure of the compound of formula A is as shown in formula C;

[0030] The structure of the compound of formula I is shown in the following formula IV or formula IV':

[0031] R1 in the above formulas B, C, III, III-1, IV and IV' is an amino acid analogue, including L-amino acids and D-amino acids and their derivatives Wherein R4 includes but is not limited to: (CH2) r -aryl, (CH2) r -heteroaryl, (CH2) r -COOH, (CH2) r -NH2, (CH2) r -OH, (CH2) r -SH, (CH2) r -naphthylmethyl, (CH2) r -Indolyl, (CH2) r -Benzothiazolyl, wherein r is an integer from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10). In a preferred embodiment, R1 can be specifically the following structure:

[0032] In a further preferred embodiment of the present invention, the structure of the compound of formula A can be any one of the following formulas A-1 to A-12:

[0033] The present invention further provides a compound of any structure represented by Formula A'-1 to Formula A'-12:

[0034] R5 is a nuclide chelating group selected from any of the following structures:

[0035] The compound of formula I is any one of formulas IV-1 to IV-24:

[0036] or,

[0037] On this basis, the present invention also provides a method for preparing the compound represented by formula IV-1, comprising the following steps:

[0038] 5-(Dimethylamino)naphthalene-1-sulfonyl chloride reacts with amino acid amino groups to obtain a dansylamide derivative, which is then activated by NHS (N-hydroxysuccinimide) on the exposed carboxyl group of the amino acid, followed by an amide condensation reaction with Nε-Boc-L-lysine or (tert-butyloxycarbonyl)-L-lysine. This is followed by a reaction with PSMA-617 in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and NHS, followed by removal of the Boc protecting group by TFA, followed by a reaction with PSMA-617 in the presence of EDC and NHS. The Fmoc protection is then removed by piperazine, and finally, the compound is reacted with DOTA-NHS (hydroxysuccinimide-tetraazacyclododecanetetraacetic acid) to obtain the compound shown in Formula IV-1 below.

[0039] On the other hand, the present invention further provides a radiolabeled complex, which is a complex obtained by labeling a radionuclide with the compound of formula A'-1 to formula A'-12 or the compound of formula I of the present invention as a ligand. The radiolabeled complex can be used as a new type of tumor radiotherapy probe, that is, as a radionuclide diagnostic probe or a radionuclide therapeutic probe. The radionuclide is preferably 177 Lu, 18 F. 43 Sc, 44 Sc, 47 Sc, 55 Co、 57 Co、 68 Ga, 67 Ga, 62 Cu, 64 Cu, 67 Cu, 89 Zr, 86 Y. 90 Y. 99m Tc, 99 Tc, 90 ln、 111 ln、 89 Sr. 152 Gd, 153 Gd, 153 Sm, 149 Tb, 151 Tb, 161 Tb, 166 Ho, 166 Dy, 186 Re、 188 Re、212 Pb, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 226 Th, 227 Th or 211 Any of At.

[0040] The present invention also provides methods for preparing other compounds. The methods for preparing other compounds can specifically refer to the preparation of the compound represented by formula IV-1 above with necessary structural replacement.

[0041] In a preferred embodiment of the present invention, the structure of the radiolabeled complex is shown in Formula V below:

[0042] Where L is -(X) n -(CH2) m -(Y) q -, n is an integer from 0 to 10 (preferably an integer from 0 to 5), X and Y are independently selected from lysine, glutamic acid or a derivative structure containing lysine and glutamic acid, m is an integer from 0 to 20 (preferably an integer from 0 to 10), q is an integer from 0 to 6 (preferably an integer from 0 to 3), and each CH2 can be independently replaced with -OCH2-, -NH(CO)- or -(CO)-NH-;

[0043] R1 is an amino acid analogue, including L-amino acids and D-amino acids and their derivatives Wherein R4 includes but is not limited to: (CH2) r -aryl, (CH2) r -heteroaryl, (CH2) r -COOH, (CH2) r -NH2, (CH2) r -OH, (CH2) r -SH, (CH2) r -naphthylmethyl, (CH2) r -Indolyl, (CH2) r -Benzothiazolyl, wherein r is an integer from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10). In a preferred embodiment, R1 can be specifically the following structure:

[0044] R2 is derived from a prostate-specific membrane antigen targeting compound, as shown in Formula II:

[0045] in:

[0046] The X1 structures at different positions are the same or different and are independently selected from O, N, S or P;

[0047] Y1 is O, S, or NH;

[0048] Z is O, S, or NH;

[0049] a is an integer from 0 to 20; Q is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkylaryl or substituted or unsubstituted cycloalkyl;

[0050] W is selected from -(CH2) b -aryl or -(CH2) b -heteroaryl, wherein b is an integer from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).

[0051] In a preferred embodiment, R2 can be any of the following structures:

[0052] M is a radionuclide selected from 177 Lu, 18 F. 43 Sc, 44 Sc, 47 Sc, 55 Co、 57 Co、 68 Ga, 67 Ga, 62 Cu, 64 Cu, 67 Cu, 89 Zr, 86 Y. 90 Y. 99m Tc, 99 Tc, 90 ln、 111 ln、 89 Sr. 152 Gd, 153 Gd, 153 Sm, 149 Tb, 151 Tb, 161 Tb, 166 Ho, 166 Dy, 186 Re、 188 Re、 212 Pb, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 226 Th, 227 Th or 211 Any of At.

[0053] The remaining limitations are as stated above and will not be repeated here.

[0054] In some preferred embodiments, the compound described in the above formula V may also be replaced by a chelating agent, such as replacing DOTA with NOTA. The remaining limitations are as described above and will not be repeated here.

[0055] The radiolabeled complex of the present invention can be prepared by combining a compound containing a radionuclide with the compound of formula I of the present invention according to various existing labeling methods; the preferred labeling method of the present invention is the following wet method or freeze-drying method:

[0056] The wet method comprises the following steps: dissolving an appropriate amount of the compound of formula I described in the present invention in a buffer solution or deionized water, then adding a solution containing a radionuclide, reacting at room temperature to 100°C for 5 to 30 minutes, then diluting with physiological saline or water for injection, and filtering through a sterile filter membrane to produce a radionuclide-labeled complex injection.

[0057] The freeze-drying method comprises the following steps: dissolving an appropriate amount of the compound of formula I described in the present invention in a buffer solution or deionized water, dispensing the solution into freeze-drying containers, freeze-drying the solution, and sealing the freeze-dried drug kit. Relevant excipients, antioxidants, or acid-base regulators may be added to the freeze-dried drug kit as needed; adding deionized water or buffer solution to the freeze-dried drug kit to dissolve the solution, then adding a solution containing a radionuclide, reacting the solution at room temperature to 100° C. for 5 to 30 minutes, diluting the solution with physiological saline or water for injection, and filtering the solution through a sterile filter membrane to produce a radionuclide-labeled complex injection solution.

[0058] The present invention also provides the use of a radiolabeled complex represented by Formula V or other radiolabeled complexes (such as replacing DOTA in Formula V with NOTA or other chelating agents) in radionuclide therapy and imaging of PSMA-highly expressing tumors in mammals.

[0059] In the preferred application of the present invention, the complex is prepared into an injection and administered by intravenous injection to human patients or mammals with PSMA-highly expressed tumors.

[0060] The present invention provides a dansylamide-modified prostate-specific membrane antigen-targeting compound and its radionuclide-labeled complex, as well as methods for preparing and labeling such compounds. Biological test results demonstrate that these compounds exhibit a moderately prolonged blood circulation half-life and enhanced tumor uptake, enrichment, and retention. These novel properties, not currently possessed by other PSMA imaging agents, make them suitable for radionuclide therapy and imaging of PSMA-overexpressing tumors. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] FIG1 is a mass spectrum identification diagram of the compound of formula IV-1 of the present invention.

[0062] FIG2 is a mass spectrum identification diagram of the compound of formula IV-5 of the present invention.

[0063] FIG3 is a mass spectrum identification diagram of the compound of formula IV-9 of the present invention.

[0064] FIG4 is a mass spectrum identification diagram of the compound of formula IV-13A of the present invention.

[0065] FIG5 is a mass spectrum identification diagram of the compound of formula IV-13 of the present invention.

[0066] Figure 6 shows the compound of formula IV-1 of the present invention 68 Ga-labeled identification results.

[0067] FIG. 7 embodies the present invention 68 Ga-Normal saline and serum stability of the compound of formula IV-1.

[0068] FIG8 embodies the present invention 68 Stability of Ga-Formula IV-3 Compound in Physiological Saline and Serum.

[0069] FIG. 9 embodies the present invention 68 Stability of Ga-Formula IV-9 Compound in Physiological Saline and Serum.

[0070] FIG10 is a diagram of the present invention 68 Ga-compound of formula IV-1 and 68 Results of cellular uptake experiment and saturation binding experiment of Ga-PSMA617.

[0071] FIG. 11 embodies the present invention 68 MicroPET imaging of Ga-formula IV-1 compound in PC3-PIP model mice and quantification of its region of interest.

[0072] FIG. 12 embodies the present invention 68 Quantification of the region of interest in MicroPET imaging of Ga-formula IV-9 compound in PC3-PIP model mice.

[0073] FIG. 13 embodies the present invention 177 Biodistribution of Lu-Formula IV-1 compound in normal mice.

[0074] FIG14 is a diagram of the present invention 177 SPECT imaging of PC3-PIP model mice after administration of Lu-Formula IV-1 compound.

[0075] FIG. 15 embodies the present invention 177 Tissue uptake results of Lu-Formula IV-1 compound after administration to PC3-PIP model mice.

[0076] FIG16 is a diagram of the present invention 68 PET images of a prostate cancer patient after administration of the compound of formula IV-1.

[0077] FIG. 17 embodies the present invention 68 Quantification of regions of interest after administration of Ga-compound of formula IV-1 to prostate cancer patients.

[0078] FIG18 is a diagram of the present invention 68 PET imaging results after administration of Ga-formula IV-9 compound to prostate cancer patients.

[0079] FIG. 19 embodies the present invention 68 Quantification of regions of interest after administration of Ga-formula IV-9 compound to prostate cancer patients. DETAILED DESCRIPTION

[0080] The technical solution of the present invention is further illustrated and described below through specific implementation methods in conjunction with the accompanying drawings.

[0081] Example 1: Preparation of compound of formula IV-1

[0082] The synthetic route is as follows:

[0083] The specific steps are as follows:

[0084] Synthesis of compound 2-1:

[0085] L-phenylalanine (1.69 g, 10 mmol) was dissolved in 20 mL of 10% sodium carbonate solution. 5-(Dimethylamino)naphthalene-1-sulfonyl chloride (2.69 g, 10 mmol) was then dissolved in 20 mL of 1,4-dioxane. The mixture was added dropwise to the L-phenylalanine in an ice bath and allowed to react at room temperature for 4 h. After the reaction, 1 M dilute hydrochloric acid was added to adjust the pH to approximately 4. Extraction was performed, and the organic phase was evaporated under reduced pressure to remove the solvent. The crude product was purified on a silica gel column to afford Compound 2-1 as a pale yellow solid in 81% yield.

[0086] Synthesis of compound 3-1:

[0087] Compound 2-1 (400 mg, 1 mmol) and NHS (230 mg, 2 mmol) were dissolved in 10 mL of tetrahydrofuran. Dicyclohexylcarbodiimide (DCC) (412 mg, 2 mmol) was added dropwise in an ice bath. The mixture was allowed to react overnight at room temperature. After the reaction, the filtrate was filtered and the solvent removed by vacuum distillation to obtain a crude product. Purification on a silica gel column afforded compound 3-1 as a pale yellow solid in a 34% yield.

[0088] Synthesis of compound 4-1:

[0089] Compound 3-1 (495 mg, 1 mmol) and (tert-butyloxycarbonyl)-L-lysine (246 mg, 1 mmol) were dissolved in 10 mL of DMSO (dimethyl sulfoxide). Triethylamine (505 mg, 5 mmol) was added and allowed to react overnight at room temperature. After the reaction, dilute hydrochloric acid was added and extracted three times. The organic phase filtrate was evaporated under reduced pressure to remove the solvent to obtain a crude product. Purification on a silica gel column afforded compound 4-1 as a pale yellow solid in a 76% yield.

[0090] Synthesis of compound 5-1:

[0091] In a 10 mL flask, compound 4-1 (112 mg, 0.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40 mg, 0.2 mmol), N-hydroxysuccinimide (23 mg, 0.2 mmol), and 5 mL of N,N-dimethylformamide were placed. After 4 h of reaction, N,N-diisopropylethylamine (60 mg, 0.5 mmol) and PSMA-617 (130 mg, 0.2 mmol) were added. The resulting mixture was stirred and the reaction was monitored for completion by HPLC. The solvent was removed by distillation under reduced pressure to obtain a crude product. The crude product was purified by reverse phase column chromatography and freeze-dried to obtain pure compound 5-1 in a 59% yield.

[0092] Synthesis of compound 6-1:

[0093] 120 mg of compound 5-1 was dissolved in 5 mL of 2M hydrochloric acid-ethyl acetate solution and stirred at room temperature for 4 h. After the reaction, the insoluble matter was filtered and washed with ethyl acetate three times to obtain compound 6-1 with a yield of 92%.

[0094] Synthesis of compound IV-1:

[0095] Compound 6-1 (5.5 mg, 5 μmol), DOTA-NHS (hydroxysuccinimide-tetraazacyclododecanetetraacetic acid) (8 mg, 2 μmol), and N,N-diisopropylethylamine (3.2 mg, 25 μmol) were added sequentially to 1 ml of N,N-dimethylformamide. The reaction system was stirred at room temperature and monitored by HPLC until completion. The crude product was purified by HPLC and freeze-dried to obtain pure compound IV-1 in a 52% yield. The structural representation is shown in Figure 1.

[0096] Example 2. Preparation of compound of formula IV-3

[0097] The synthetic route of this embodiment is as follows:

[0098] This example refers to Example 1, and the L-phenylalanine reacted with 5-(dimethylamino)naphthalene-1-sulfonyl chloride in Example 1 is replaced with L-aspartic acid to obtain compound 2-3. Then, referring to the process for preparing compound 3-1 in Example 1, the compound 2-1 in the above process is replaced with compound 2-3 to obtain compound 3-3. Further referring to the process from preparing compound 4-1 to compound IV-1 in Example 1, the compound of formula IV-3 is finally obtained.

[0099] Example 3. Preparation of compound of formula IV-5

[0100] The synthetic route of this embodiment is as follows:

[0101] The above preparation steps of this embodiment refer to Example 1, and the L-phenylalanine reacted with 5-(dimethylamino)naphthalene-1-sulfonyl chloride in Example 1 is replaced with L-norvaline to obtain compound 2-5. Then, referring to the process of preparing compound 3-1 in Example 1, the compound 2-1 in the above process is replaced with compound 2-5 to obtain compound 3-5. Further referring to the process from preparing compound 4-1 to compound IV-1 in Example 1, the compound of formula IV-5 is finally obtained, and its structural representation is shown in Figure 2.

[0102] Example 4: Preparation of Formula IV-7 Compound

[0103] The synthetic route of this embodiment is as follows:

[0104] The above preparation steps of this embodiment refer to Example 1, and the L-phenylalanine reacted with 5-(dimethylamino)naphthalene-1-sulfonyl chloride in Example 1 is replaced with L-lysine to obtain compound 2-7. Then, referring to the process of preparing compound 3-1 in Example 1, the compound 2-1 in the above process is replaced with compound 2-7 to obtain compound 3-7. Further referring to the process from preparing compound 4-1 to compound IV-1 in Example 1, the compound of formula IV-7 is finally obtained.

[0105] Example 5. Preparation of compound of formula IV-9

[0106] The synthetic route of this embodiment is as follows:

[0107] The above preparation steps of this embodiment refer to Example 1, and the L-phenylalanine reacted with 5-(dimethylamino)naphthalene-1-sulfonyl chloride in Example 1 is replaced with L-glycine to obtain compound 2-9. Then, referring to the process of preparing compound 3-1 in Example 1, the compound 2-1 in the above process is replaced with compound 2-9 to obtain compound 3-9. Further referring to the process from preparing compound 4-1 to compound IV-1 in Example 1, the compound of formula IV-9 is finally obtained. The structural representation is shown in Figure 3.

[0108] Example 6. Preparation of compound of formula IV-2

[0109] Referring to Example 1, the (tert-butyloxycarbonyl)-L-lysine reacted with compound 3-1 in Example 1 is replaced with Nε-Boc-L-lysine, and compound 4-2, compound 5-2, and compound 6-2 can be prepared in sequence, and finally the compound of formula IV-2 can be obtained.

[0110] The reaction route is as follows:

[0111] Example 7. Preparation of compound of formula IV-4

[0112] Referring to Example 2, the (tert-butyloxycarbonyl)-L-lysine reacted with compound 3-3 in Example 2 is replaced with Nε-Boc-L-lysine, and compound 4-4, compound 5-4, and compound 6-4 can be prepared in sequence, and finally the compound of formula IV-4 can be obtained.

[0113] The reaction route is as follows:

[0114] Example 8. Preparation of compound of formula IV-6

[0115] Referring to Example 3, the (tert-butyloxycarbonyl)-L-lysine reacted with compound 3-5 in Example 3 is replaced with Nε-Boc-L-lysine, and compound 4-6, compound 5-6, and compound 6-6 can be prepared in sequence, and finally the compound of formula IV-6 can be obtained.

[0116] The reaction route is as follows:

[0117] Example 9. Preparation of compound of formula IV-8

[0118] Referring to Example 4, the (tert-butyloxycarbonyl)-L-lysine reacted with compound 3-7 in Example 4 was replaced with Nε-Boc-L-lysine, and compound 4-8, compound 5-8, and compound 6-8 were prepared in sequence, and finally the compound of formula IV-8 was obtained.

[0119] The reaction route is as follows:

[0120] Example 10. Preparation of compound of formula IV-10

[0121] Referring to Example 5, the (tert-butyloxycarbonyl)-L-lysine reacted with compound 3-9 in Example 5 is replaced with Nε-Boc-L-lysine, and compound 4-10, compound 5-10, and compound 6-10 can be prepared in sequence, and finally the compound of formula IV-10 can be obtained.

[0122] The reaction route is as follows:

[0123] Example 11-Example 12: Preparation of compounds of formula IV-11 and formula IV-12

[0124] Their preparation methods can refer to Examples 1-10. For example, based on Example 1, the Lys reacted with compound 3-1 is replaced with Lys-PEG2-COOH or Lys-PEG4-COOH, respectively, to obtain the following corresponding structures:

[0125] Example 13. Preparation of compound of formula IV-13

[0126] The synthetic route of this embodiment is as follows:

[0127] The specific steps are as follows:

[0128] Dissolve NOTA-Bis(t-BuEster) in DMF, add DIPEA, cool to 10°C, then add HBTU and incubate for 30 minutes. Add DIPEA to the compound of Formula 6-1 prepared in Example 1 to form a suspension, which is then added to the above reaction solution. After stirring for 1 hour, MTBE is added dropwise to the reaction solution to precipitate a solid. After standing, the supernatant is decanted and purified to obtain Compound IV-13A, the structural representation of which is shown in Figure 4.

[0129] Compound IV-13A was dissolved in a solution of TFA:water = 100:5, reacted at 30°C for 3 h, and then MTBE was added dropwise to the reaction solution to precipitate a solid. After filtration, the solid was purified and freeze-dried to obtain the compound of formula IV-13. The structural representation is shown in Figure 5.

[0130] Refer to the methods provided in Examples 1-13 to prepare other compounds provided by the present invention, such as IV-14, IV-15, IV-16, IV-17, IV-18, IV-19, IV-20, IV-21, IV-22, IV-23, and IV-24.

[0131] Example 14. Preparation of radionuclides 68 Ga-labeled complexes

[0132] 68 The Ga nuclide labeling process is as follows:

[0133] Wet method: about 37~3700MBq 68 GaCl3 hydrochloric acid solution (eluted from the gallium germanium generator) is added to a centrifuge tube containing a solution of the compound to be labeled (the solution of the compound to be labeled is 0.5-2 mL of acetic acid-acetate solution, which contains 20-200 μg of each compound prepared in Example 1 to Example 13), placed at room temperature to 100°C for 20 minutes, and then cooled to room temperature, diluted with physiological saline or water for injection, and sterile filtered to obtain a labeled compound injection, which is recorded as " 68 Ga-Formula IV”.

[0134] Lyophilization method: a certain amount of buffer and about 37-3700MBq 68 GaCl3 hydrochloric acid solution (eluted from the gallium germanium generator) is added to a freeze-dried drug box containing 20-200 μg of the compound to be labeled (the compound to be labeled is the compound prepared in Example 1 to Example 13), mixed and dissolved, and then placed at room temperature to 100°C for 20 minutes, cooled to room temperature, diluted with physiological saline or water for injection, and sterile filtered to obtain the labeled compound injection, which is recorded as " 68 Ga-Formula IV”.

[0135] Taking the labeling of the compound of formula IV-1 prepared in Example 1 as an example, the processes of the above two labeling methods are shown as follows:

[0136] If the radiochemical purity is less than 95%, purification is required. The purification steps are as follows: Take a Sep-Pak C18 separation column and activate it by eluting it with 10 mL of anhydrous ethanol and 10 mL of water. Dilute the labeled solution with 10 mL of water and load it onto the separation column. Rinse the separation column with water to remove unreacted 68Ga ions, and then washed with ethanol solution to obtain purified 68 The organic solvent was removed by nitrogen blowing, and the labeled compound injection was obtained by dilution with physiological saline and sterile filtration.

[0137] The compound of formula IV-1 in Example 1 was labeled according to the above method, and the identification results are shown in FIG6 . 68 Ga-formula IV-1 has a high labeling rate and specific activity, and the nuclide is easily available and simple to operate, which is conducive to large-scale clinical application.

[0138] The present invention also adopts 68 Ga-labeled other compounds, including but not limited to 68 Ga-Formula IV-2, 68 Ga-Formula IV-3, 68 Ga-Formula IV-4, 68 Ga-Formula IV-5, 68 Ga-Formula IV-6, 68 Ga-Formula IV-7, 68 Ga-Formula IV-8, 68 Ga-Formula IV-9, 68 Ga-Formula IV-10, 68 Ga-Formula IV-11, 68 Ga-formula IV-12, etc. Experiments have shown that the compounds provided by the present invention have a high labeling rate and specific activity, and the nuclides are easily available and simple to operate, which is conducive to large-scale clinical application.

[0139] Example 15. In vitro stability test

[0140] According to the labeling method of Example 14, the compounds IV-1, IV-3 and IV-9 prepared in Examples 1, 3 and 9 were labeled to obtain 68 The Ga-labeled complexes are respectively denoted as “ 68 Ga-Formula IV-1"," 68 Ga-Formula IV-3" and " 68 Ga-formula IV-9". Use physiological saline to dissolve the radiochemical purity of more than 95% 68 Ga-Formula IV-1, 68 Ga-formula IV-3 and 68 The Ga-formula IV-9 solution was placed at room temperature for different time periods, and samples were taken for analysis by HPLC. At the time points tested, each probe still maintained a radiochemical purity of >95%, indicating that it was stable in the specified solution and not easily decomposed. 68 Ga-Formula IV-1, 68 Ga-formula IV-3 and 68The HPLC identification results of the in vitro physiological saline stability of the Ga-formula IV-9 solution are shown in part A of Figures 7 to 9, indicating that it still maintains a high stability (>95%) in the physiological saline system for 2 hours.

[0141] The radiochemical purity of the above-mentioned 68 Ga-Formula IV-1, 68 Ga-formula IV-3 and 68 Solutions of Ga-Formula IV-9 were incubated with serum at room temperature for various periods of time. Acetonitrile was added for protein removal, and the supernatant was centrifuged and sampled for analysis by HPLC. At all time points tested, each probe maintained a radiochemical purity >95%, demonstrating its stability in the specified solution. 68 Ga-Formula IV-1, 68 Ga-formula IV-3 and 68 The in vitro serum stability HPLC identification results of Ga-Formula IV-9 are shown in Part B of FIG. 7 to FIG. 9 , indicating that it still maintains a high stability (>95%) in physiological saline, i.e., serum system, for 2 h.

[0142] Example 16. Preparation of radionuclides 177 Lu-labeled complexes

[0143] Wet method: about 18.5~1850MBq 177 LuCl3 sodium acetate solution was added to the centrifuge tube containing the solution of the compound to be labeled (the solution of the compound to be labeled was 0.5-2 mL of acetic acid-acetate solution, which contained 20-200 μg of each compound prepared in Example 1-Example 13), placed at 90°C for reaction for 20 minutes, cooled to room temperature, diluted with physiological saline or water for injection, and sterile filtered to obtain the labeled compound injection, which was recorded as " 177 Lu-Formula IV".

[0144] Lyophilization method: a certain amount of buffer and about 37-3700MBq 177 LuCl3 is added to a freeze-dried kit containing 20-200 μg of the compound to be labeled (the compound to be labeled is the compound provided by the present invention, including but not limited to the compounds prepared in Examples 1 to 13), mixed and dissolved, and then placed at room temperature to 100°C for 20 minutes, cooled to room temperature, diluted with physiological saline or water for injection, and sterile filtered to obtain the labeled compound injection, which is recorded as " 177 Lu-Formula IV".

[0145] If the radiochemical purity is less than 95%, purification is required. The purification steps are as follows: Take a Sep-Pak C18 separation column and activate it by eluting it with 10 mL of anhydrous ethanol and 10 mL of water. Dilute the labeled solution with 10 mL of water and load it onto the separation column. Rinse the separation column with water to remove unreacted 177 Lu ions, and then eluted with ethanol solution to obtain purified 177 The Lu-labeled complex was purified by nitrogen purge to remove the organic solvent, diluted with physiological saline, and then sterile filtered to obtain the labeled compound injection.

[0146] The present invention also adopts 177 Lu-labeled other compounds, including but not limited to 177 Lu-Formula IV-1, 177 Lu-Formula IV-2, 177 Lu-Formula IV-3, 177 Lu-Formula IV-4, 177 Lu-Formula IV-5, 177 Lu-Formula IV-6, 177 Lu-Formula IV-7, 177 Lu-Formula IV-8, 177 Lu-Formula IV-9, 177 Lu-Formula IV-10, 177 Lu-Formula IV-11, 177 Lu-Formula IV-12, etc.

[0147] The compounds provided by the present invention can also be labeled with reference to other labeling methods involved in the prior art, such as 18 F-Formula IV-13, 18 F-Formula IV-14, 18 F-Formula IV-15, 18 F-Formula IV-16, 18 F-Formula IV-17, 18 F-Formula IV-18, 18 F-Formula IV-19, 18 F-Formula IV-20, 18 F-Formula IV-21, 18 F-Formula IV-22, 18 F-Formula IV-23, 18 F-Formula IV-24, etc.

[0148] In addition, the radioactive nuclide-labeled compound provided by the present invention can also be labeled with reference to other labeling methods provided by the prior art (including but not limited to the method provided by the present invention), and the radioactive nuclides include but are not limited to: 18 F. 51 Cr, 64 Cu,67 Cu, 67 Ga, 68 Ga, 89 Zr, 111 In, 99 mTc, 186 Re、 188 Re、 139 La, 140 La, 175 Yb, 153 Sm, 166 Ho, 86 Y. 90 Y. 149 Pm, 165 Dy, 169 Second, 177 Lu, 47 Sc, 142 Pr, 159 Gd, 212 Bi, 213 Bi, 72 As、 72 Se, 97 Such as 109 Pd, 105 Rh, 101 mRh, 119 Sb, 128 Ba, 123 I. 124 I. 131 I. 197 Hg, 211 At 151 Eu, 153 Eu, 169 Eu, 201 Tl, 203 Pb, 212 Pb, 198 Au, 225 Ac, 227 Th or 199 Ag et al.

[0149] Example 17. Cellular uptake experiment

[0150] Tumor cell uptake experiment: one day before the experiment, 2×10 5 PC3-PIP cells were cultured overnight. The cells were divided into three groups: total binding group, internalization group, and inhibition group, with four wells in each group. First, a 100-fold excess of PSMA617 was added to the inhibition group wells as an inhibitor. Then, 500 μL of serum-free medium-diluted PSMA617 prepared according to the method of Example 14 with a radiochemical purity greater than 95% was added to all wells. 68Ga-formula IV-1 solution (18.5kBq / well) was covered and incubated in a cell culture incubator at 37°C. For the total binding group and the internalization group, the cells were removed from the incubator at 10, 30, 60 and 120 minutes after incubation, and the cells were rinsed 3 times with PBS. The internalization group was washed once with eluent, and then the cells were digested with 1 mL of digestive solution. For the inhibition group, after incubation at 37°C for 10, 30, 60 and 120 minutes, the cells were washed twice with ice-cold PBS (pH 7.4), and then the cells were digested with digestive solution. Aspirate all the solutions and cells in the well plate and place them in a well-marked tube. Take 3 portions of 500 μL of the serum-free medium diluted with the 68 Ga-Formula IV-1 solution was added, and the total radioactive dose added to each well was calculated. The radioactive count was measured using a γ counter, and the cell binding rate and internalization rate at each time point were calculated.

[0151] Cell receptor saturation competition binding experiment: Based on the results of the cell uptake experiment, cells with high cell binding rate are selected as cells for measuring receptor affinity, and the affinity and specificity of the labeled probe are screened to guide and optimize the probe design. Briefly: before the experiment begins, 50 μL PC3-PIP (2×10 6 / mL) of serum-free medium. Increasing concentrations of the radiolabeled substance to be tested (18 kBq / well) were added, and the final reaction volume in all wells was adjusted to 200 μL. The reaction solution was agitated on a shaker at room temperature for 4 hours, then drained and air-dried. The filter membrane was collected and the radioactivity count was measured using a gamma counter. K was calculated using Graph-Pad Prism software. d value.

[0152] The experimental results are shown in Figure 10. 68 Ga-K of formula IV-1 d Value and 68 Ga-PSMA617 is comparable (see curves in parts B and D), but within 2 hours 68 The cellular uptake of Ga-formula IV-1 was much higher than 68 Ga-PSMA617 (see the bar graphs in parts A and C).

[0153] Example 18. 68 MicroPET imaging of Ga-formulated IV-1 tumor model mice

[0154] Prepared according to the labeling method of Example 14 with a radiochemical purity greater than 95% 68 Ga-formula IV-1, PC3-PIP tumor-bearing mice were randomly divided into experimental and control groups, and 0.2 mL (about 7.4 MBq) was taken 68 Ga-formula IV-1 solution was injected into the experimental group mice through the tail vein, while the control group mice were injected68 Ga-PSMA 617. MicroPET imaging was performed at 1h, 2h, and 4h after injection. The imaging results are shown in Figure 11. The arrow in part A indicates the tumor location. 68 The tumor uptake of Ga-PSMA 617 was about 20% ID / g 4 h after injection (see the image in part B and the vertical stripe bar graph in part C of FIG11 ), while the 68 The tumor uptake of Ga-formula IV-1 was about 50% ID / g 4 hours after injection, which was much higher than that of the control group. 68 The Ga-formula IV-1 complex has significantly enhanced tumor uptake and retention time (see the image in part A and the grid bar graph in part C in Figure 11). 68 Ga-Formula IV-1 can achieve a higher target to non-target ratio (tumor / flesh ratio, tumor / heart ratio and tumor / kidney ratio) within 1 hour, and the target to non-target ratio gradually increases with time (see the bar graph in part D of Figure 11).

[0155] In summary, the present invention 68 On the one hand, Ga-formula IV-1 facilitates longer-term imaging. Under the guarantee of high imaging contrast, the diagnosis of primary micro-lesions will be more accurate, which is conducive to the delineation of the target area. On the other hand, the high uptake and long retention of radionuclide-labeled probes in the tumor site will lay the foundation for radionuclide targeted therapy.

[0156] Example 19. 68 MicroPET imaging of tumor model mice using Ga-formula IV-9 complex

[0157] Prepared according to the labeling method of Example 14 with a radiochemical purity greater than 95% 68 Ga-formula IV-9 solution, PC3-PIP tumor-bearing mice were randomly divided into experimental and control groups, and 0.2 mL (about 7.4 MBq) was taken 68 Ga-formula IV-9 solution was injected into the experimental group mice through the tail vein, while the control group mice were injected 68 Ga-PSMA 617. MicroPET imaging was performed at 1h, 2h, and 4h after injection. The imaging results are shown in Figure 12. The arrow in part A indicates the tumor location. 68 The tumor uptake of Ga-PSMA 617 was about 20% ID / g 4 h after injection (see parts B and C of FIG11 ), while the 68 The tumor uptake of Ga-formula IV-9 complex was about 50% ID / g 4 hours after injection, which was much higher than that of the control group. 68Ga-Formula IV-9 can achieve a higher target to non-target ratio (tumor / meat ratio, tumor / heart ratio and tumor / kidney ratio) within 1 hour, and the target to non-target ratio gradually increases with time (see the bar graph in part B of Figure 12).

[0158] Example 20. 177 Biodistribution of Lu-labeled complexes in normal mice

[0159] Compound IV-1 prepared in Example 1 was labeled according to the labeling method of Example 16 to obtain a radiochemical purity greater than 95%. 177 Lu-Formula IV-1, 0.2 mL (about 1.85 MBq) was injected through the tail vein of normal mice. The mice were sacrificed at 4, 12, 24, and 48 hours after injection, and the organs of interest were measured using a γ-counter. As shown in Figure 13, 177 The blood uptake value of Lu-Formula IV-1 remained at a high level at 4 hours, and as time went on, the radioactivity was gradually cleared from the blood. 177 Lu-labeled IV-1 has the ability to moderately enhance blood circulation time, which is beneficial for enhancing tumor uptake while avoiding the problem of excessive drug circulation in the body.

[0160] Example 21. 177 SPECT imaging of Lu-formula IV-1 tumor model mice

[0161] Prepared according to Example 16 with a radiochemical purity greater than 95% 177 0.2 mL (about 37 MBq) of Lu-Formula IV-1 solution was injected into the tail vein of mice bearing PC3-PIP tumors, and SPECT imaging was performed at 2, 4, 12, 24, 48, and 72 hours after injection. The imaging results are shown in Figure 14. The arrows in Figure 14 indicate the tumor location. The imaging results show that the present invention 177 Lu-Formula IV-1 exhibits significantly enhanced tumor uptake and retention at the tumor site. The high uptake and prolonged retention of radionuclide-labeled probes at tumor sites will pave the way for radionuclide-targeted therapy. As shown in Figure 15 , the tissue uptake results after administration demonstrate high target-to-nontarget ratios (tumor-to-muscle, tumor-to-heart, and tumor-to-kidney) within 2 hours, and these ratios gradually increase over time.

[0162] Example 22. 68 Ga-labeled complexes for MicroPET imaging of prostate cancer patients

[0163] Subject selection criteria:

[0164] 1) Patients who are highly suspected of prostate cancer based on clinical symptoms, laboratory tests, and other imaging examinations (CT, MRI);

[0165] 2) Aged 18-80 years; eligible for surgery or biopsy to obtain a pathological diagnosis;

[0166] 3) Patients with renal failure (serum Cr>3mg / dl) were excluded; patients whose condition was too severe to receive further diagnosis and treatment were also excluded.

[0167] Prepared according to the labeling method of Example 14 with a radiochemical purity greater than 95% 68 Ga-formula IV-1 solution and 68 Subjects received an intravenous injection of a Ga-formula IV-9 solution at a radiotracer dose of 1.85–2.22 MBq / kg. PET / CT imaging was performed using an integrated PET / CT scanner (Polestar m660, Sino Union, China) 60, 120, 180, and 240 minutes after injection. Low-dose CT scans (120 kV, 35 mAs) from the tip of the skull to the mid-thigh were performed for attenuation correction and anatomical reference. Whole-body PET / CT was performed in 5–6 beds (2 minutes per bed). Images were reconstructed using the ordered subset expectation-maximization algorithm.

[0168] All images were transferred to MIM software (version 7.1.4, MIM Software, Inc., Cleveland, TN, USA), and regions of interest (ROIs) were drawn on the CT images using PET margins. Positive lesions were defined as those with significantly increased tracer uptake compared with surrounding normal prostate tissue. Standardized uptake values ​​(SUVs) were used to quantitatively assess radioactivity accumulation.

[0169] As shown in Figures 16 to 19, 68 Ga-formula IV-1 solution and 68 Analyze PET / CT images 1h, 2h, 3h, and 4h after injection of Ga-formula IV-9 solution, and measure the SUVmean of whole body organs and SUVmax of tumors. 68 The imaging results of Ga-Formula IV-1 are shown in Figures 16 and 17. 68 The imaging results of Ga-Formula IV-9 are shown in Figures 18 and 19. The imaging results show that as time goes by, the radioactivity concentration of the two complexes of the present invention in the cardiac blood pool and organs with rich blood supply such as the liver and spleen gradually decreases, while gradually increases in the tumor. The uptake value is the highest after 4 hours, and has a high target-to-substance ratio. This shows that the radioactivity of the two complexes of the present invention is 68 Ga-labeled complexes not only have high diagnostic efficacy, but also can play an advantage in the application of therapeutic nuclides with long half-lives.

Claims

1. A dansylamide-modified PSMA targeting compound, characterized in that: Its structure is shown in the following formula A or formula I in: L is -(X) n -(CH2) m -(Y) q -, wherein n is an integer from 0 to 10, X and Y are independently selected from lysine, glutamic acid or a derivative structure containing a lysine or glutamic acid structure, m is an integer from 0 to 20, q is an integer from 0 to 6, wherein each CH2 can be independently replaced with -OCH2-, -NH(CO)- or -(CO)-NH-; R1 is a structure The amino acid analog structure includes L-type amino acids or D-type amino acids or derivatives thereof, wherein R4 is selected from: (CH2) r -Aryl, (CH2) r -heteroaryl, (CH2) r -COOH, (CH2) r -NH2, (CH2) r -OH, (CH2) r -SH, (CH2) r -Naphthylmethyl, (CH2) r -Indolyl or (CH2) r -benzothiazolyl, wherein r is an integer from 0 to 10; R2 is a structure that targets prostate-specific membrane antigen; R3 is a nuclide chelating group selected from any of the following structures:

2. The dansylamide-modified PSMA targeting compound according to claim 1, characterized in that: The R1 is the following structure:

3. The dansylamide-modified PSMA targeting compound according to claim 1, characterized in that: R2 in Formula I is a prostate-specific membrane antigen targeting structure shown in the following Formula II, in: The X1 structures at different positions are the same or different and are independently selected from O, N, S or P; Y1 is O, S, NH; Z is O, S, or NH; a is an integer from 0 to 20; Q is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkylaryl or substituted or unsubstituted cycloalkyl; W is selected from -(CH2) b -Aryl or -(CH2) b -heteroaryl, wherein b is an integer of 0-10.

4. The dansylamide-modified PSMA targeting compound according to claim 3, characterized in that: The R2 is any of the following structures:

5. The dansylamide-modified PSMA targeting compound according to claim 3, characterized in that: Q in Formula II is selected from substituted or unsubstituted C5-C 14 Aryl, substituted or unsubstituted C5-C 14 -alkylaryl or substituted or unsubstituted C5-C 14 Cycloalkyl.

6. The dansylamide-modified PSMA-targeting compound according to any one of claims 1, 3 or 4, characterized in that: The R2 is R3 is That is, the structure of the compound of formula A is shown in formula B; the compound of formula I is shown in formula III or formula III-1: Wherein L is selected from: Lys, -Lys-(CO)-CH2-(CO)-NH-CH2-(CO), -Lys-(CO)-CH2-(OCH2CH2)-O-CH2(CO)-NH-CH2-(CO), -Lys-(CO)-CH2-(OCH2CH2)3-O -CH2(CO)-NH-CH2-(CO), -(CO)-CH2-(CO)-Lys-, -(CO)-(OCH2CH2)-O-CH2(CO)-Lys-, or -(CO)-CH2-(OCH2CH2)3-O-CH2(CO)-Lys-.

7. The dansylamide-modified PSMA targeting compound according to any one of claims 1, 3 or 4, characterized in that: The R2 is R3 is L is a Lys structure, that is, the structure of the compound of formula A is shown in formula C, and the structure of the compound of formula I is shown in formula IV or formula IV':

8. The dansylamide-modified PSMA targeting compound according to claim 1, characterized in that: The compound of formula A is any one of the following formulas A-1 to A-12; The compound of formula I is any one of the following formulas IV-1 to IV-24:

9. A radionuclide-labeled PSMA-targeting compound, characterized in that: It is a complex obtained by using the PSMA targeting compound modified by dansylamide of the structure shown in formula I as described in any one of claims 1 to 8 as a ligand labeled with a radionuclide; the radionuclide is selected from 177 Lu, 18 F. 43 Sc, 44 Sc, 47 Sc, 55 Co. 57 Co. 68 Ga, 67 Ga, 62 Cu, 64 Cu, 67 Cu, 89 Zr, 86 Y. 90 Y. 99m Tc, 99 Tc, 90 ln, 111 ln, 89 Sr. 152 Gd, 153 Gd, 153 Sm, 149 Tb, 151 Tb, 161 Tb, 166 Ho, 166 Dy, 186 Re, 188 Re, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 226 Th, 227 Th or 211 Any one of At.

10. A pharmaceutical composition, characterized in that: It comprises the dansylamide-modified PSMA targeting compound according to any one of claims 1 to 8 or the radionuclide-labeled PSMA targeting compound according to claim 9, and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition according to claim 10, characterized in that: The pharmaceutically acceptable carrier is selected from a binder, a buffer, a colorant, a diluent, a disintegrant, an emulsifier, a flavoring agent, a glidant, a lubricant, a preservative, a stabilizer, a surfactant, a tabletting agent or a wetting agent, or a combination thereof.

12. Use of the radionuclide-labeled PSMA-targeting compound of claim 9 in the preparation of a therapeutic or diagnostic drug for a cancer with high PSMA expression in a mammal; the cancer is prostate cancer, lung cancer, liver cancer, gastric cancer, breast cancer, colorectal cancer, renal cell carcinoma, bladder cancer, brain tumor, thyroid cancer or adenoid cystic carcinoma; in the use, the radioactively labeled PSMA-targeting compound of claim 9 is combined with one or more other active ingredients in an amount having a diagnostic or therapeutic effect on the mammal.

13. Use of the pharmaceutical composition of claim 10 in preparing a therapeutic or diagnostic drug for a cancer with high PSMA expression in a mammal; the cancer is prostate cancer, lung cancer, liver cancer, gastric cancer, breast cancer, colorectal cancer, renal cell carcinoma, bladder cancer, brain tumor, thyroid cancer or adenoid cystic carcinoma; in the use, the pharmaceutical composition of claim 10 is combined with one or more other active ingredients in an amount having a diagnostic or therapeutic effect on the mammal.

14. The use according to any one of claims 12-13, characterized in that: The one or more other active ingredients are selected from anti-cancer therapeutic compounds.

15. The use according to claim 14, characterized in that: The anticancer therapeutic compound is selected from any one or a combination of two or more of doxorubicin, paclitaxel, docetaxel, cisplatin, camptothecin, temozolomide, Avastin, Herceptin or Erbitux.

Images