Compound targeting CAIX and FAP as well as nuclide marker, preparation method and application thereof

Abstract

The invention discloses a compound targeting CAIX and FAP as well as a nuclide marker, a preparation method and application thereof, and belongs to the technical field of nuclear medicine. The structure of the CAIX and FAP targeting compound or the salt thereof is as shown in a formula I, and the structure of the radionuclide marker is as shown in a formula II. The preparation method of the compound in the formula I comprises the following steps: reacting a compound 3 with a compound 10 to generate a compound 11; and reacting the compound 11 with a compound 12 to generate the compound shown in the formula I. The preparation method of the radionuclide marker comprises the step of reacting a compound shown in a formula I with radionuclide salt to generate the radionuclide marker shown in a formula II. The invention discloses application of compounds shown in a formula I and a formula II in preparation of products for detecting and / or detecting cells and / or tissues expressing FAP receptors and CAIX receptors. The compound or the nuclide marker thereof is used for diagnosing or / and treating tumors expressing FAP receptors and CAIX receptors, and has the advantages of high affinity, high T / NT value, quick kidney clearance and the like.

Description

Technical Field

[0001] The present invention belongs to the field of nuclear medicine technology, and in particular, relates to a compound targeting CAIX and FAP, a radionuclide marker thereof, a preparation method and an application thereof. Background Art

[0002] Cancer, also known as malignant tumor, is a heterogeneous disease formed in an extremely complex microenvironment. According to the latest statistics, there will be 19,976,499 new cases of malignant tumors worldwide in 2022, an increase of nearly 700,000 from 2020. Among them, the malignant tumor with the highest incidence rate is lung cancer 2480675 (12.4%), which once again surpasses breast cancer. The incidence rates 2-6 are breast cancer, colorectal cancer, prostate cancer, gastric cancer, and liver cancer, respectively. The tumor microenvironment plays an important role in the occurrence, development, metastasis, and drug sensitivity of tumors. The inside of the tumor is like a highly systematized ecosystem, with not only tumor cells but also rich and diverse immune cells, tumor-associated fibroblasts (CAFs), endothelial cells (ECs) and other cell types. Fibroblast Activation Protein (FAP) is a membrane-bound serine protease of the dipeptidyl peptidase 4 (DPP4) family that is overexpressed in CAFs and is overexpressed in about 90% of epithelial tumors. Based on the fact that FAP protein is lowly expressed in normal tissues but highly expressed in the tumor microenvironment, nuclear medicine diagnosis and treatment targeting FAP have developed rapidly in recent years. 68 Ga-FAPI-04 has been used in the diagnosis of up to 28 types of tumors, including sarcoma, esophageal cancer, breast cancer, and lung cancer, but it has the disadvantages of low accuracy and low sensitivity.

[0003] Carbonic anhydrase IX (CAIX) plays an important role in the evolution of cancer. CAIX is a transmembrane protein composed of 459 amino acids, including five parts: a signal peptide exposed outside the cell, a mucin domain, a catalytic domain, a transmembrane fragment, and a short peptide in the cytoplasm. Recent studies have shown that CAIX is a transcription protein of the hypoxia-inducible factor-1α (HIF-1α) downstream gene. It is specifically overexpressed on the cell surface of many hypoxic malignant tumors, including breast cancer, lung cancer, ovarian cancer, head and neck cancer, bladder cancer, colon cancer, cervical cancer, and renal cancer, while its expression in normal tissues is very limited. Therefore, CAIX is expected to become a target for the diagnosis and treatment of tumors. Based on this, the construction of a molecular probe that dual-targets CAIX and FAP has certain research significance and clinical application value for the sensitivity of early diagnosis and detection of primary lesions and metastatic lesions of various tumors. Summary of the invention

[0004] The purpose of the present invention is to introduce another tumor overexpressed receptor CAIX as a second targeting group, and utilize the overexpression of CAIX receptors in the tumor microenvironment to assist in improving the early diagnosis accuracy and sensitivity of the former FAP probe, so as to overcome the problems of low diagnostic accuracy and low sensitivity of FAP-04 type broad-spectrum tumor imaging agents in the prior art. Based on this, the present invention provides a compound or a salt thereof targeting CAIX and FAP dual targets as shown in Formula I.

[0005] The second object of the present invention is to provide a radionuclide label of a compound or a salt thereof that targets both CAIX and FAP, the structure of which is shown in Formula II.

[0006] The third object of the present invention is to provide a method for preparing the compound or its salt targeting CAIX and FAP dual targets as shown in Formula I.

[0007] A fourth object of the present invention is to provide a method for preparing a radionuclide labeled compound or a salt thereof targeting both CAIX and FAP as shown in Formula II.

[0008] A fifth object of the present invention is to provide the use of a radionuclide label of a compound or a salt thereof targeting CAIX and FAP as shown in Formula I, or a compound or a salt thereof targeting CAIX and FAP as shown in Formula II.

[0009] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0010] The present invention discloses a compound or a salt thereof targeting CAIX and FAP, and its structure is shown in Formula I:

[0011]

[0012] The radionuclide label of the compound or salt thereof targeting CAIX and FAP disclosed in the present invention has a structure as shown in Formula II:

[0013]

[0014] Where A is a radionuclide.

[0015] In some embodiments of the present invention, the radionuclide comprises 68 Ga, 177 Lu, 99m Tc, 111 In, 67 Ga, 86 Y. 90 Y. 161 Tb, 186 Re,188 Re, 64 Cu, 67 Cu, 211 At 225 Ac, 18 F. 123 I. 124 I. 125 At least one of I;

[0016] Preferably, 68 Ga, 177 Lu, 99m Tc, 111I n. 64 Cu, 18 F or 225 At least one of Ac;

[0017] More preferably 68 Ga, 177 Lu or 225 At least one of Ac.

[0018] In some embodiments of the present invention, the radionuclide is 68 The structure of the Ga, radionuclide label is shown in Formula III:

[0019]

[0020] In some embodiments of the present invention, the radionuclide is 177 The structure of Lu, a radionuclide label, is shown in Formula IV:

[0021]

[0022] The preparation method of the compound targeting CAIX and FAP disclosed in the present invention comprises the following steps: compound 3 (compd3) reacts with compound 10 (compd10) to generate compound 11 (compd11); compound 11 (compd11) reacts with compound 12 (compd12) to generate a compound of formula I; the synthesis route is as follows:

[0023]

[0024] The method for preparing the radionuclide marker of the compound targeting CAIX and FAP disclosed in the present invention comprises the following steps: reacting the compound of formula I with a radionuclide salt to generate the radionuclide marker shown in formula II.

[0025] A pharmaceutical composition disclosed in the present invention comprises the above-mentioned compound targeting CAIX and FAP or a salt thereof; or comprises a radionuclide marker of the above-mentioned compound targeting CAIX and FAP or a salt thereof.

[0026] Use of the above-mentioned compound targeting CAIX and FAP or its salt, or the radionuclide label of the above-mentioned compound targeting CAIX and FAP or its salt disclosed in the present invention in the preparation of a product for detecting and / or detecting cells and / or tissues expressing FAP receptors and CAIX receptors;

[0027] Preferably, the product comprises a diagnostic tracer and / or a therapeutic agent;

[0028] More preferably, the diagnostic tracer is used for positron emission tomography, computed tomography, positron emission computed tomography, single photon emission tomography or single electron emission computed tomography.

[0029] The present invention discloses the use of the above-mentioned compound targeting CAIX and FAP or its salt, or the radionuclide label of the above-mentioned compound targeting CAIX and FAP or its salt in the preparation of products for diagnosing and / or treating prostate cancer, pre-metastatic prostate cancer, colon cancer, breast cancer, kidney cancer or bladder cancer.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] The invention is scientifically designed and ingeniously conceived. The compound of the invention can simultaneously target FAP receptors and CAIX receptors, overcoming the problems of low diagnostic accuracy and low sensitivity of tumor imaging agents in the prior art. Experimental results show that the radionuclide marker of the invention is relatively 68 Ga-FAP-04 has better uptake at the tumor site, higher sensitivity, longer uptake time at the tumor site, is more conducive to the diagnosis and treatment of the tumor, and has rapid renal clearance.

[0032] The compound of the present invention or its radionuclide marker is used for diagnosing and / or treating tumors expressing FAP receptors and CAIX receptors, and has the advantages of high affinity, high T / NT value and rapid renal clearance.

[0033] The Chinese name corresponding to the English abbreviation of the present invention is:

[0034] Sodium ascorbate: Ascorbic acid

[0035] DMF: N,N-dimethylformamide

[0036] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0037] DIEA: N,N-diisopropylethylamine

[0038] TFA: trifluoroacetic acid

[0039] Piperidine: Piperidine

[0040] EDCI: carbodiimide

[0041] HOOBt: 3-Hydroxy-1,2,3-benzotriazine-4(3H)-one

[0042] NMM: N-methylmorpholine BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 The synthetic route of the compound DOTA-CAIX-FAP of Example 1 of the present invention is shown in FIG.

[0044] Figure 2 This is the mass spectrum of DOTA-CAIX-FAP.

[0045] Figure 3 This is the UV spectrum of DOTA-CAIX-FAP.

[0046] Figure 4 for 68 Radio-HPLC spectrum of Ga-DOTA-CAIX-FAP.

[0047] Figure 5 for 177 Radio-TLC spectrum of Lu-DOTA-CAIX-FAP.

[0048] Figure 6 for 68 Radio-HPLC spectrum of Ga-FAP04.

[0049] Figure 7 for 68 PET / CT images of Ga-CAIX-FAP on U87MG model.

[0050] Figure 8 for 68 PET / CT images of Ga-FAPI-4 on U87MG model.

[0051] Fig. 9 for 177 SPETCT / CT images of Lu-CAIX-FAP on U87MG model.

[0052] Fig.10 for 68 The in vitro stability results of Ga-CAIX-FAP in PBS and 10% FBS.

[0053] Fig.11 This is a diagram showing the cell uptake experimental results of Experimental Example 4. DETAILED DESCRIPTION

[0054] To make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. If specific conditions are not specified in the examples, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified in the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0055] Example 1

[0056] This embodiment discloses the synthesis of the compound DOTA-CAIX-FAP of formula I of the present invention. The synthesis route is shown in the attached Figure 1 shown.

[0057] The specific steps are as follows:

[0058] 1. Compd 1 (1 eq) and Compd 2 (2 eq) were dissolved in 5 ml H2O / EtOH (V:V=2:3) solution, and CuSO45H2O (0.2 eq) and Sodium ascorbate (0.4 eq) were added under nitrogen protection. The reaction was carried out at room temperature for 3 hours. The reaction was completed by LC-MS monitoring. The product was concentrated and purified by reverse phase preparative liquid chromatography to obtain Compd 3 (yield: 90%).

[0059] 2. Compd 5 (1.2 eq) was dissolved in 10 ml DMF, HATU (1 eq) and DIEA (3 eq) were added, stirred for 5 minutes, and then Compd4 (4 eq) was added; the reaction was allowed to react overnight at room temperature, and the reaction was complete as monitored by LC-MS. The product was concentrated, 5 mL TFA was added, the reaction was allowed to react for 5 minutes at room temperature, 50 mL ether was added, the product was centrifuged, dried, and purified by reverse phase preparative liquid chromatography to obtain Compd 6 (yield: 62%).

[0060] 3. Compd 7 (1 eq) was dissolved in 10 ml DMF, HATU (1 eq) and DIEA (1 eq) were added, the reaction was continued for 5 minutes, and then Compd6 (1 eq) was added; the reaction was continued at room temperature for 2 hours, and the reaction was completed after monitoring by LC-MS. The product was concentrated, 5 mL of 20% piperidine / DMF was added, the reaction was continued at room temperature for 5 minutes, and then 50 mL of ether was added. The product was centrifuged and dried, and purified by reverse phase preparative liquid chromatography to obtain Compd 8 (Yield: 60%).

[0061] 4. Compd 9 (1 eq) was dissolved in 10 ml DCM, EDCI (1 eq) and HOOBt (1 eq) were added at 0°C, the reaction was continued for 10 minutes, and Compd 8 (1 eq) and NMM (3 eq) were added; the reaction was transferred to room temperature for 2 hours, and the reaction was completed after monitoring by LC-MS. The reaction was concentrated, 5 mL 20% piperidine / DMF was added, the reaction was continued at room temperature for 5 minutes, and 50 mL ether was added. The reaction was centrifuged and dried, and Compd 10 (yield: 29%) was obtained by reverse phase preparative liquid purification.

[0062] 5. Compd 3 (1 eq) was dissolved in 5 ml DCM, EDCI (1 eq) and HOOBt (1 eq) were added at 0°C, the reaction was allowed to proceed for 10 minutes, and Compd 10 (1 eq) and NMM (3 eq) were added; the reaction was transferred to room temperature and allowed to react overnight. The reaction was completed after monitoring by LC-MS, the reaction was concentrated, 5 ml TFA solution was added, the reaction was allowed to proceed at room temperature for 30 minutes, 50 mL ether was added, the reaction was centrifuged, the reaction was dried, and Compd 11 (Yield: 46%) was obtained by purification by reverse phase preparative liquid chromatography.

[0063] 6. Compd 11 (1 eq) and Cmpd 12 (1.2 eq) were dissolved in 5 ml DMF, and DIEA (3 eq) was added; the mixture was reacted at room temperature for 2 hours, concentrated, and purified by reverse phase preparative liquid phase to obtain the compound of formula I DOTA-CAIX-FAP (yield: 57%).

[0064] Its mass spectrum is as follows Figure 2 As shown, HPLC chart see Figure 3 shown.

[0065] Example 2

[0066] This embodiment discloses a radionuclide label of a compound of formula I 68 The preparation method of Ga-DOTA-CAIX-FAP is as follows:

[0067] Using DOTA-CAIX-FAP compound as a precursor, DOTA-CAIX-FAP was prepared into a 1 μg / μl precursor aqueous solution for standby use.

[0068] Take 30 μl of the above precursor solution and add it to 37 MBq 68 GaCl3 solution, and adjust pH to 4-5 with 0.25M sodium acetate buffer, react at 90℃ for 15min. Add 5ml of saline to the reaction solution and pass it through a C18 light column. Use 20ml of saline to wash the residual 68 The product in the C18 column was eluted with 1 ml of 50% ethanol solution, passed through a 0.22 μm sterile filter membrane, and finally the ethanol concentration was diluted to less than 10%.68 The radiochemical purity of Ga-DOTA-CAIX-FAP is >98%, as Figure 4 shown.

[0069] Example 3

[0070] This embodiment discloses 177 The preparation method of Lu-DOTA-CAIX-FAP is as follows:

[0071] Using DOTA-CAIX-FAP compound as a precursor, DOTA-CAIX-FAP was prepared into a 1 μg / μl aqueous solution for standby use.

[0072] Take 30 μl of the above precursor solution and add it to 370 MBq 177 LuCl3 solution, and adjust pH to 4-5 with 0.25M sodium acetate buffer, react at 90℃ for 15min. Add 5ml of saline to the reaction solution and pass it through a C18 light column. Use 20ml of saline to wash the remaining 177 LuCl3. The product in the C18 column was eluted with 2 ml of 50% ethanol solution, passed through a 0.22 um sterile filter membrane, and finally the ethanol concentration was diluted to less than 10%. 177 The radiochemical purity of Lu-DOTA-CAIX-FAP is >98%, as Figure 5 shown.

[0073] Comparative Example 1

[0074] This comparative ratio discloses 68 Preparation of Ga-FAPI-4. The FAPI-4 in this comparative example was provided by Ganzhou Tanzhen Biopharmaceutical Co., Ltd.

[0075] Using FAPI-4 compound as a precursor, FAPI-4 was prepared into a 1 μg / μl precursor aqueous solution for standby use.

[0076] Take 50 μl of the above precursor solution and add it to 370 MBq 68 GaCl3 solution, and adjust pH to 4-5 with 0.25M sodium acetate buffer, react at 90℃ for 15min. Add 5ml of saline to the reaction solution and pass it through a C18 light column. Use 20ml of saline to wash the residual 68 The product in the C18 column was eluted with 1 ml of 50% ethanol solution, passed through a 0.22 μm sterile filter membrane, and finally the ethanol concentration was diluted to less than 10%. 68 The radiochemical purity of Ga-FAPI-4 is >98%, such as Figure 6 shown.

[0077] Test Example 1

[0078] This test example discloses 68 Ga-DOTA-CAIX-FAP, 68 Ga-FAPI-4 and 177 PET / CT imaging experiment of Lu-DOTA-CAIX-FAP.

[0079] Establishment of U87MG animal model: U87MG cells expressing FAP were cultured in DMEM medium containing 10% FBS at 37°C, 5% CO2, and saturated humidity. After the cells grew to 70-80%, they were digested with trypsin and centrifuged before inoculation. After anesthetizing BALB / c-nu nude mice, they were subcutaneously inoculated in their axilla. The number of cells inoculated per BALB / c-nu nude mouse was 5*10 6 cell / piece / 0.1ml. When the tumor size grows to 400-500mm 3 It can be used for imaging experiments.

[0080] In this test example 68 Ga-DOTA-CAIX-FAP was prepared according to the method of Example 1; 177 Lu-DOTA-CAIX-FAP was prepared according to the method of Example 2; 68 Ga-FAPI-4 was prepared according to the method of Comparative Example 1. 100 μci of 68 Ga-DOTA-CAIX-FAP was injected into U87MG tumor-bearing mice with high FAP expression via the tail vein. PET / CT imaging was performed 0.5h, 1h, and 1.5h after injection. The results are as follows: Figure 7 shown.

[0081] Take 1.5mci 177 Lu-DOTA-CAIX-FAP was injected into U87MG tumor-bearing mice with high FAP expression via the tail vein. SPETCT / CT imaging was performed 4h, 24h, 48h, 96h, and 166h after injection. The results are as follows Fig. 9 shown.

[0082] Take 100μci 68 Ga-FAPI-4 was injected into U87MG tumor-bearing mice with high FAP expression via the tail vein. PET / CT imaging was performed 0.5h, 1h, and 1.5h after injection. The results are as follows: Figure 8 shown.

[0083] result:

[0084] (1) From Figure 6 It can be seen that the radionuclide label of the compound of formula I of the present invention 68Ga-DOTA-CAIX-FAP was specifically taken up in the U87MG tumor site, and the uptake in other organs was low.

[0085] (2) From Figure 7 It can be seen that the comparative example 1 68 The uptake of Ga-FAPI-4 in the U87MG tumor model was low at 0.5h, 1h, and 1.5h.

[0086] (3) From Figure 8 It can be seen that the radionuclide label of the compound of formula I of the present invention 177 Lu-DOTA-CAIX-FAP was specifically taken up in the U87MG tumor site, and the uptake was still high at 166h.

[0087] The above results show that the radionuclide label of the present invention is 68 Ga-FAPI-4 has better uptake at the tumor site, higher sensitivity, longer uptake time at the tumor site, is more conducive to the diagnosis and treatment of the tumor, and is cleared quickly by the kidneys.

[0088] Test Example 2

[0089] This test example discloses 68 Ga-DOTA-CAIX-FAP and 177 In vitro stability experimental data of Lu-DOTA-CAIX-FAP.

[0090] In this test example 68 Ga-DOTA-CAIX-FAP was prepared according to the method of Example 1; 177 Lu-DOTA-CAIX-FAP was prepared according to the method of Example 2.

[0091] The cells were analyzed by incubation in saline or 10% bovine serum albumin for 15, 30, 60, and 120 minutes in vitro. 68 In vitro stability of Ga-DOTA-CAIX-FAP. The radiochemical purity was analyzed by radio-HPLC. After incubation with saline or 10% bovine serum albumin, the radiochemical purity was greater than 95% within 2 hours. Fig. 9 shown.

[0092] Take 20 μL, 100 μci of marker in parallel 68Ga-DOTA-CAIX-FAP was dissolved in 3 vials of 180 μL PBS or 10% bovine serum albumin (FBS), incubated at 37°C for 15 min, 30 min, 60 min and 120 min, and samples were taken at each time point. The radiochemical purity was analyzed by radio-HPLC to investigate its in vitro stability.

[0093] Same method determination 177 The in vitro stability of Lu-DOTA-CAIX-FAP in PBS and 10% bovine serum albumin. The results showed that 68 Ga-DOTA-CAIX-FAP and 177 Lu-DOTA-CAIX-FAP has good in vitro stability, and the radiochemical purity is greater than 95% within 2 hours after incubation in PBS or 10% bovine serum albumin. Fig.10 shown.

[0094] Test Example 3

[0095] This test example discloses 68 The lipid-water partition coefficient of Ga-DOTA-CAIX-FAP was investigated. 68 Ga-DOTA-CAIX-FAP was prepared according to the method of Example 1.

[0096] 68 The lipid-water partition coefficient of Ga-DOTA-CAIX-FAP was tested by the following method: 68 Ga-DOTA-CAIX-FAP (50ul, 0.37Mbq) was added to a mixed solution of n-octanol and PBS, and the volume ratio of the organic phase to the aqueous phase was finally maintained at 1:1 (n=5). The mixture was vortexed for 3 minutes and centrifuged at 3000×rpm for 5 minutes. Then, 3 samples (50μL) were taken from each phase and the radioactive counts were determined using a γ counter (HIDEX,). The distribution coefficient was calculated as the counts in n-octanol divided by the counts in phosphate-buffered saline. 68 The lipid-water partition coefficient of Ga-DOTA-CAIX-FAP is logD7.4 = -3.89, indicating that 68 Ga-DOTA-CAIX-FAP has excellent hydrophilicity.

[0097] Test Example 4

[0098] This test example discloses 68 Ga-DOTA-CAIX-FAP cell uptake assay, in this test example 68 Ga-DOTA-CAIX-FAP was prepared according to the method of Example 1.

[0099] U87MG cells expressing FAP were cultured in DMEM medium containing 10% FBS. After the cells grew to 70-80%, they were digested with trypsin and inoculated into 24-well plates (about 1.5*10 5 Cell / well), and cultured overnight at 37°C, 5% CO2. The next day, the cells were starved with pure culture medium DMEM, and then about 50μl / 1μCi / well of radiolabeled product was added. The cells were placed in an incubator and cultured for 15min, 30min, 60min and 120min, and the cell uptake value at each time point was measured using a γ counter (n≥3). The data obtained are shown in Fig.11 .

[0100] Depend on Fig.11 It can be seen that 68 Ga-DOTA-CAIX-FAP had a high uptake in FAP-positive U87MG cells (>15% ID / 10 6 Cell), at 15min, 30min, 60min, and 120min, the cells 68 The uptake of Ga-DOTA-CAIX-FAP did not decrease, but showed a slowly increasing trend, proving that 68 Ga-DOTA-CAIX-FAP binds stably to the FAP target and is not prone to off-target effects.

[0101] FAPI-4FAPI-4 The embodiments described above are only some embodiments of the present invention, but not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

Claims

1. A compound or a salt thereof targeting CAIX and FAP, Features ,, its structure is shown in Formula I:

2. A radionuclide label of the compound targeting CAIX and FAP or a salt thereof as claimed in claim 1, It is characterized in that Its structure is shown in Formula II, Where A is a radionuclide.

3. The radionuclide label according to claim 2, It is characterized in that The radionuclides include 68 Ga, 177 Lu, 99m Tc, 111 In, 67 Ga, 86 Y. 90 Y. 161 Tb, 186 Re, 188 Re, 64 Cu, 67 Cu, 211 At 225 Ac, 18 F. 123 I. 124 I. 125 At least one of I; Preferably, 68 Ga, 177 Lu, 99m Tc, 111I n. 64 Cu, 18 F or 225 At least one of Ac; More preferably 68 Ga, 177 Lu or 225 At least one of Ac.

4. The radionuclide label according to claim 2, It is characterized in that The radionuclides are 68 The structure of the Ga, radionuclide label is shown in Formula III:

5. The radionuclide label according to claim 2, It is characterized in that The radionuclides are 177 The structure of Lu, a radionuclide label, is shown in Formula IV:

6. The method for preparing the compound targeting CAIX and FAP according to claim 1, It is characterized in that The method comprises the following steps: compound 3 reacts with compound 10 to generate compound 11; compound 11 reacts with compound 12 to generate a compound of formula I; the synthesis route is as follows:

7. The method for preparing the radionuclide label of the compound or salt thereof targeting CAIX and FAP according to claim 2, It is characterized in that The method comprises the following steps: reacting the compound of formula I with a radioactive nuclide salt to generate a radioactive nuclide marker shown in formula II.

8. A pharmaceutical composition, It is characterized in that A compound targeting CAIX and FAP or a salt thereof according to claim 1; Or a radionuclide label comprising the compound targeting CAIX and FAP or a salt thereof according to any one of claims 2 to 5.

9. Use of the compound targeting CAIX and FAP or its salt according to claim 1, or the radionuclide label of the compound targeting CAIX and FAP or its salt according to any one of claims 2 to 5 in the preparation of a product for detecting and / or detecting cells and / or tissues expressing FAP receptors and CAIX receptors; Preferably, the product comprises a diagnostic tracer and / or a therapeutic agent; More preferably, the diagnostic tracer is used for positron emission tomography, computed tomography, positron emission computed tomography, single photon emission tomography or single electron emission computed tomography.

10. Use of the compound targeting CAIX and FAP or its salt according to claim 1, or the radionuclide label of the compound targeting CAIX and FAP or its salt according to any one of claims 2 to 5 in the preparation of a product for diagnosing and / or treating prostate cancer, pre-metastatic prostate cancer, colon cancer, breast cancer, kidney cancer or bladder cancer.

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