Carbonic anhydrase ix targeting compound and use thereof

Abstract

This invention belongs to the field of nuclear medicine and relates to a carbonic anhydrase IX targeting compound and its application. The carbonic anhydrase IX targeting compound has the structure shown in Formula I. ¹ This invention provides… 8 F-labeled CAIX-targeting molecular probes all achieved high-contrast imaging of CAIX-positive tumors in vivo. Each compound exhibited excellent tumor-to-kidney ratio, tumor-to-sarcoma ratio, tumor-to-liver ratio, and tumor-to-blood-pool ratio, demonstrating significant advantages in improving imaging clarity and reducing non-specific interference. These compounds are highly promising tumor PET imaging agents for CAIX targeting. In summary, 18 In addition to its excellent target / non-target ratio, F-T2 significantly reduces non-specific uptake in the stomach, making it more suitable for imaging CAIX-expressing lesions in abdominal organs and more conducive to the detection of small abdominal lesions.

Description

Technical Field

[0001] This invention belongs to the field of nuclear medicine, specifically relating to a carbonic anhydrase IX targeting compound and its application. Background Technology

[0002] Hypoxia is a key characteristic of the solid tumor microenvironment, caused by insufficient oxygen supply resulting from rapid tumor cell proliferation and abnormal tumor angiogenesis. Hypoxic tumor cells initiate metabolic reprogramming by mediating hypoxia-inducible factor-1α (HIF-1α), enhancing glycolysis and oxidative phosphorylation to maintain energy supply, while simultaneously leading to the release of lactate and protons (H+). + Tumor cells accumulate acidic metabolites such as carbon dioxide (CO2). To combat acidification stress and maintain pH homeostasis, tumor cells specifically activate related enzymes and transport proteins, among which carbonic anhydrase IX (CAIX) is a key regulatory enzyme.

[0003] CAIX is a transmembrane protein composed of acidic amino acids that catalyzes the hydration of CO2 to produce HCO3. - and H + CAIX maintains intracellular pH stability in tumor cells and promotes intercellular matrix acidification, thereby enhancing tumor cell migration, invasion, metastasis, and resistance to radiotherapy and chemotherapy. Studies have shown that CAIX exhibits varying degrees of positive expression in tissue microarrays of various tumors, and is closely related to tumor progression, patient prognosis, and treatment response—high CAIX expression is found in 25% of non-small cell lung cancer and ovarian cancer, 50% of breast cancer, 66% of pancreatic ductal carcinoma, 71% of bladder cancer, and 95% of renal clear cell carcinoma. Therefore, developing targeted molecular probes targeting CAIX has important theoretical basis.

[0004] Currently reported CAIX-targeted imaging agents still have limitations, primarily due to high gastric uptake and significant interference from normal tissue background, which can easily mask lesions in the stomach and adjacent areas, affecting the detection of micrometastases. Regarding radionuclide imaging... 68 Although Ga and other PET probes have been used in related research,¹ 8 F-labeled PET imaging agents offer higher spatial resolution and superior image quality, making them more suitable for precise tumor imaging. Optimizing the linker structure to improve probe distribution in vivo, reduce non-specific uptake, and enhance target specificity is crucial for overcoming current technological bottlenecks. Therefore, developing F-labeled PET imaging agents with high target affinity and excellent in vivo metabolic properties is essential.¹ 8 F-labeled CAIX targeted imaging reagents can provide a more reliable imaging tool for tumor monitoring and patient screening, and have broad application prospects in the field of precision oncology. Summary of the Invention

[0005] The purpose of this invention is to provide a novel carbonic anhydrase IX targeted imaging agent.

[0006] To achieve the above objectives, the present invention provides a carbonic anhydrase IX targeting compound having the structure shown in Formula I: Formula I In formula I, R1 is a chemical bond. , or ; R2 is .

[0007] Specifically, the carbonic anhydrase IX targeting compounds are compounds T1, T2, T3, and T4: Compound T1.

[0008] Compound T2.

[0009] Compound T3.

[0010] Compound T4.

[0011] The carbonic anhydrase IX-targeting compound of the present invention can be used to prepare nuclear medicine diagnostic probes or nuclear medicine therapeutic agents.

[0012] Specifically, the present invention provides a carbonic anhydrase IX targeted imaging reagent, wherein the carbonic anhydrase IX targeted imaging reagent is the above-mentioned carbonic anhydrase IX targeted compound labeled with a diagnostic radionuclide.

[0013] The diagnostic radionuclides include, but are not limited to, those used in the diagnosis of radioactive nuclides. 11 C 13 N、 18 F, 43 Sc、 44 Sc、 45 Ti、 47 Sc、 51 Cr 51 Mn, 52 Mn, 52 Fe、 55 Co、 57 Co、 58m Co、 59 Fe、 60 Cu、 61 Cu、 62 Cu、 63 Zn, 64 Cu、 67 Cu、 67 Ga、 68 Ga、75 Sc、 77 As、 82 Rb、 86 Y、 87 Y、 90 Y、 89 Zr、 94 Tc, 97 Ru、 99 Tc, 99m Tc, 101m Rh、 103m Rh、 105 Pd, 105 Rh、 111 Ag、 111 ln、 117m Sn、 119 Sb, 149 Pm, 149 Tb, 152 Tb, 153 Sm、 154-159 Gd, 161 Tb, 165 Dy、 166 Dy、 166 Ho、 169 Er、 169 Yb、 175 Yb、 175 Lu、 177 Lu、 186 Re、 188 Re、 189 Re、 191m Pt, 193m Pt, 195m Pt, 194 lr、 197 Pt, 198 Au、 199 Au、 211 At、 211 Pb, 212 Bi、 212 Pb, 213 Bi、 223 Ra、 224 Ra and 225 At least one of Ac.

[0014] The present invention also provides a carbonic anhydrase IX targeted therapeutic agent, wherein the carbonic anhydrase IX targeted therapeutic agent is the above-mentioned carbonic anhydrase IX targeted compound labeled with a radionuclide for therapeutic use.

[0015] The therapeutic radionuclides include, but are not limited to, those used in the treatment of radioactive nuclides. 47 Sc、 57 Co、 58m Co、60 Co、 61 Cu、、、 90 Y、 103 Pd, 103m Rh、 105 Rh、 106 Ru、 117m Sn、 119 Sb, 149 Tb, 149 Pm, 161 Ho、 165 Dy、 177 Lu、 177 Yb、 186 Re、 188 Re、 192 Ir、 193m Pt, 195m Pt, 197 Pt, 199 Au、 203 Pb、、 211 At、 212 Pb, 212 Bi、 213 Bi、 223 Ra、 224 Ra、 225 Ac、 226 Th、 227 Th and 229 At least one of Th.

[0016] The CAIX-targeting molecular probe of the present invention, after being labeled with a radionuclide, can be used as a carbonic anhydrase IX-targeting diagnostic and therapeutic agent, for example, in whole-body imaging. According to an embodiment of the present invention,¹ 8 F-T2 exhibits minimal gastric uptake within 1 hour and demonstrates excellent tumor-to-muscle ratio, tumor-to-liver ratio, and tumor-to-blood-pool ratio, making it particularly suitable for imaging and treatment of abdominal organs. Based on this, the present invention provides an application of a carbonic anhydrase IX targeted therapeutic agent in CAIX-targeted imaging or treatment of abdominal organs, wherein the carbonic anhydrase IX targeted therapeutic agent is a compound T2 labeled with a diagnostic radionuclide or a therapeutic radionuclide.

[0017] The present invention provides¹ 8 F-labeled CAIX-targeting molecular probes all achieved high-contrast imaging of CAIX-positive tumors in vivo. Each compound exhibited excellent tumor-to-kidney ratio, tumor-to-sarcoma ratio, tumor-to-liver ratio, and tumor-to-blood-pool ratio, demonstrating significant advantages in improving imaging clarity and reducing non-specific interference, making them highly promising tumor PET imaging agents for CAIX targeting. 18In addition to having an excellent target / non-target ratio, F-T2 significantly reduces non-specific uptake in the stomach, making it more suitable for imaging CAIX-expressing lesions in abdominal organs and more conducive to the detection of small abdominal lesions.

[0018] Other features and advantages of the present invention will be described in detail in the following detailed description section. Attached Figure Description

[0019] The above and other objects, features and advantages of the present invention will become more apparent from the more detailed description of exemplary embodiments of the invention in conjunction with the accompanying drawings.

[0020] Figure 1 The general preparation route for CAIX targeting probes T1-T4 is as follows.

[0021] Figure 2 The preparation route for the CAIX targeting probe T1 is shown.

[0022] Figure 3 This is the mass spectrum of the CAIX targeting probe T1.

[0023] Figure 4 The preparation route for the CAIX targeting probe T2 is shown.

[0024] Figure 5 This is the mass spectrum of the CAIX targeting probe T2.

[0025] Figure 6 The preparation route for the CAIX targeting probe T3 is shown.

[0026] Figure 7 This is the mass spectrum of the CAIX targeting probe T3.

[0027] Figure 8 The preparation route for the CAIX targeting probe T4 is shown.

[0028] Figure 9 This is the mass spectrum of the CAIX targeting probe T4.

[0029] Figure 10 for 18 PET / CT image of tumor-bearing mice with F-labeled T1.

[0030] Figure 11 for 18 PET / CT image of tumor-bearing mice with F-labeled T2.

[0031] Figure 12 for 18 PET / CT image of tumor-bearing mice with F-labeled T3.

[0032] Figure 13 for 18PET / CT image of tumor-bearing mice with F-labeled T4. Detailed Implementation

[0033] Preferred embodiments of the invention will now be described in more detail. While preferred embodiments of the invention are described below, it should be understood that the invention can be implemented in various forms and should not be limited to the embodiments set forth herein.

[0034] Example 1: Preparation of CAIX-targeting compounds T1, T2, T3, and T4

[0035] The synthesis steps of T1-T4 are as follows: Figure 1 As shown. The coupling of amino acids was carried out according to the standard Fmoc solid-phase synthesis method. Reaction conditions: (a) 20% piperidine DMF solution, Fmoc-R1-OH, HATU, HOBt and DIPEA DMF solution; or 20% piperidine DMF solution, Fmoc-R2-OH, HATU, HOBt and DIPEA DMF solution (b) 20% piperidine DMF solution, Fmoc-R2-OH, HATU, HOBt and DIPEA DMF solution (c) SnCl2·2H2O DMF solution (d) 1,4-sulfonylbutyric acid, HATU, HOBt and DIPEA DMF solution; 2, trifluoroacetic acid, water and triisopropylsilane (e) 1,3-di(bromomethyl)benzene, NH4HCO3, acetonitrile solution.

[0036] Preparation of T1:

[0037] T1 structural type

[0038] The synthesis steps of T1 are as follows: Figure 2 As shown. The coupling of amino acids was carried out according to the standard Fmoc solid-phase synthesis method. Reaction conditions: (a) DMF solution of 20% piperidine, DMF solution of 2-[4,7-bis[2-(tert-butoxy)-2-oxoethyl]-1,4,7-triazacyclononane-1-yl]acetic acid (NOTA-BIS), HBTU, HOBt and DIPEA; (c) DMF solution of SnCl2·2H2O; (d) DMF solution of 1,4-sulfonylbutyric acid, HATU, HOBt and DIPEA; 2, trifluoroacetic acid, water and triisopropylsilane; (e) 1,3-di(bromomethyl)benzene, acetonitrile and aqueous solution of NH4HCO3.

[0039] Specifically, a certain mass of resin 1 (0.05 mmol) was placed in a 10 mL solid-phase synthesis tube, and 2 mL of dichloromethane (DCM) was added to swell the resin. This process was repeated three times, each time for 5 minutes, followed by... N,NWash three times with dimethylformamide (DMF) for 5 minutes each time. Remove the amino protecting group Fmoc using a DMF solution (v / v) containing 20% ​​piperidine. Specifically, react 2 mL of 20% piperidine in DMF solution for 2 minutes, 10 minutes, and 10 minutes, followed by washing 3-5 times with 2 mL of DMF for 2 minutes each time. Add 5 times the stoichiometric amount of NOTA-bis(tBu)ester, activated with 5 times the stoichiometric amount of HATU in the presence of 10 times the stoichiometric amount of DIPEA relative to the resin (0.05 mmol), to the synthesis tube. React under electromagnetic stirring for 1 hour, followed by washing 3-5 times with 2 mL of DMF for 2 minutes each time. The nitro group attached to the phenylalanine residue was reduced to an amino group using SnCl2·2H2O. Specifically, a 1 M SnCl2·2H2O DMF solution (340 mg SnCl2·2H2O in 1.5 mL DMF) was added to the synthesis tube, and the reaction was carried out overnight with electromagnetic stirring. The tube was then washed 3-5 times with 2 mL DMF, 2 minutes each time. Five times the stoichiometric amount of 4-sulfonylbutyric acid (relative to 0.05 mmol of resin), activated with five times the stoichiometric amount of HATU in the presence of 10 times the stoichiometric amount of DIPEA, was added to the synthesis tube and acylated overnight with electromagnetic stirring. The tube was then washed 3-5 times with 2 mL DMF, 2 minutes each time. The ligand dissociation from the resin and the removal of Trt were completed by stirring 5 mL of trifluoroacetic acid / triisopropylsilane / water (95:2.5:2.5, v / v / v) for 2 hours. The resin was washed with 2 mL of trifluoroacetic acid, and all filtrates were collected. After removing trifluoroacetic acid under reduced pressure, the crude product was prepared by reverse HPLC and lyophilized to obtain intermediate 2. This intermediate was then diluted to 60 mL with acetonitrile / water (1:1, v / v), and 1,3-di(bromomethyl)benzene and ammonium bicarbonate were added. The mixture was stirred overnight, and the crude product was prepared by reverse HPLC and lyophilized to obtain the target compound T1. The ligand structure was identified by mass spectrometry, as shown below. Figure 3 As shown.

[0040] Preparation of T2:

[0041] T2 structural type

[0042] The synthesis steps of T2 are as follows: Figure 4As shown. The coupling of amino acids was carried out according to the standard Fmoc solid-phase synthesis method. Reaction conditions: (a) DMF solution of 20% piperidine, DMF solution of Fmoc-11-amino-3,6,9-trioxaundecanic acid, HBTU, HOBt and DIPEA; (b) DMF solution of 20% piperidine, DMF solution of 2-[4,7-bis[2-(tert-butoxy)-2-oxoethyl]-1,4,7-triazacyclononane-1-yl]acetic acid (NOTA-BIS), HBTU, HOBt and DIPEA; (c) DMF solution of SnCl2·2H2O; (d) DMF solution of 1,4-sulfonylbutyric acid, HATU, HOBt and DIPEA; 2, trifluoroacetic acid, water and triisopropylsilane; (e) 1,3-di(bromomethyl)benzene, acetonitrile and aqueous solution of NH4HCO3.

[0043] Specifically, a certain mass of resin 1 (0.05 mmol) was placed in a 10 mL solid-phase synthesis tube, and 2 mL of dichloromethane (DCM) was added to swell the resin. This process was repeated three times, each time for 5 minutes, followed by... N,NWash three times with dimethylformamide (DMF) for 5 minutes each time. Remove the amino protecting group Fmoc using a DMF solution (v / v) containing 20% ​​piperidine. Specifically, react 2 mL of 20% piperidine DMF solution for 2 minutes, 10 minutes, and 10 minutes, followed by washing 3-5 times with 2 mL DMF for 2 minutes each time. Add 5 times the stoichiometric amount of Fmoc-NH-PEG3-CH2COOH (relative to resin 0.05 mmol) activated with 5 times the stoichiometric amount of HATU in the presence of 10 times the stoichiometric amount of DIPEA to the synthesis tube, and react for 1 hour with electromagnetic stirring. Remove the amino protecting group Fmoc using a DMF solution (v / v) containing 20% ​​piperidine, followed by washing 3-5 times with 2 mL DMF for 2 minutes each time. Five times the stoichiometric amount of NOTA-bis(tBu)ester, activated with five times the stoichiometric amount of HATU in the presence of ten times the stoichiometric amount of DIPEA, was added to the synthesis tube and reacted under electromagnetic stirring for 1 hour, followed by washing 3-5 times with 2 mL DMF for 2 minutes each time. The nitro group attached to the phenylalanine residue was reduced to an amino group using SnCl2·2H2O. Specifically, a 1 M SnCl2·2H2O DMF solution (340 mg SnCl2·2H2O in 1.5 mL DMF) was added to the synthesis tube and reacted overnight under electromagnetic stirring, followed by washing 3-5 times with 2 mL DMF for 2 minutes each time. Five times the stoichiometric amount of 4-sulfonylbutyric acid, activated with five times the stoichiometric amount of HATU in the presence of ten times the stoichiometric amount of DIPEA, was added to the synthesis tube and reacted overnight under electromagnetic stirring for acylation, followed by washing 3-5 times with 2 mL DMF for 2 minutes each time. The ligand dissociation from the resin and the removal of Trt were completed by stirring 5 mL of trifluoroacetic acid / triisopropylsilane / water (95:2.5:2.5, v / v / v) for 2 hours. The resin was washed with 2 mL of trifluoroacetic acid, and all filtrates were collected. After removing trifluoroacetic acid under reduced pressure, the crude product was prepared by reverse HPLC and lyophilized to obtain intermediate 2. This intermediate was then diluted to 60 mL with acetonitrile / water (1:1, v / v), and 1,3-di(bromomethyl)benzene and ammonium bicarbonate were added. The mixture was stirred overnight, and the crude product was prepared by reverse HPLC and lyophilized to obtain the target compound T2. The ligand structure was identified by mass spectrometry, as shown below. Figure 5 As shown.

[0044] Preparation of T3:

[0045] T3 structural type

[0046] The synthesis steps of T3 are as follows: Figure 6As shown. The coupling of amino acids was carried out according to the standard Fmoc solid-phase synthesis method. Reaction conditions: (a) DMF solution of 20% piperidine, DMF solution of Fmoc-(4-aminomethyl)benzoic acid, HBTU, HOBt and DIPEA; (b) DMF solution of 20% piperidine, DMF solution of 2-[4,7-bis[2-(tert-butoxy)-2-oxoethyl]-1,4,7-triazacyclononane-1-yl]acetic acid (NOTA-BIS), HBTU, HOBt and DIPEA; (c) DMF solution of SnCl2·2H2O; (d) DMF solution of 1,4-sulfonylbutyric acid, HATU, HOBt and DIPEA; 2, trifluoroacetic acid, water and triisopropylsilane; (e) 1,3-di(bromomethyl)benzene, acetonitrile and aqueous solution of NH4HCO3.

[0047] Specifically, a certain mass of resin 1 (0.05 mmol) was placed in a 10 mL solid-phase synthesis tube, and 2 mL of dichloromethane (DCM) was added to swell the resin. This process was repeated three times, each time for 5 minutes, followed by... N,NWash three times with dimethylformamide (DMF) for 5 minutes each time. Remove the amino protecting group Fmoc using a DMF solution (v / v) containing 20% ​​piperidine. Specifically, react 2 mL of 20% piperidine in DMF solution for 2 minutes, 10 minutes, and 10 minutes, followed by washing 3-5 times with 2 mL of DMF for 2 minutes each time. Add 5 times the stoichiometric amount of Fmoc-L-phenylalanine (relative to resin, in the presence of 10 times the stoichiometric amount of DIPEA and activated with 5 times the stoichiometric amount of HATU) to the synthesis tube and react under electromagnetic stirring for 1 hour. Remove the amino protecting group Fmoc using a DMF solution (v / v) containing 20% ​​piperidine, followed by washing 3-5 times with 2 mL of DMF for 2 minutes each time. Five times the stoichiometric amount of NOTA-bis(tBu)ester, activated with five times the stoichiometric amount of HATU in the presence of ten times the stoichiometric amount of DIPEA, was added to the synthesis tube and reacted under electromagnetic stirring for 1 hour, followed by washing 3-5 times with 2 mL DMF for 2 minutes each time. The nitro group attached to the phenylalanine residue was reduced to an amino group using SnCl2·2H2O. Specifically, a 1 M SnCl2·2H2O DMF solution (340 mg SnCl2·2H2O in 1.5 mL DMF) was added to the synthesis tube and reacted overnight under electromagnetic stirring, followed by washing 3-5 times with 2 mL DMF for 2 minutes each time. Five times the stoichiometric amount of 4-sulfonylbutyric acid, activated with five times the stoichiometric amount of HATU in the presence of ten times the stoichiometric amount of DIPEA, was added to the synthesis tube and reacted overnight under electromagnetic stirring for acylation, followed by washing 3-5 times with 2 mL DMF for 2 minutes each time. The ligand dissociation from the resin and the removal of Trt were completed by stirring 5 mL of trifluoroacetic acid / triisopropylsilane / water (95:2.5:2.5, v / v / v) for 2 hours. The resin was washed with 2 mL of trifluoroacetic acid, and all filtrates were collected. After removing trifluoroacetic acid under reduced pressure, the crude product was prepared by reverse HPLC and lyophilized to obtain intermediate 2. This intermediate was then diluted to 60 mL with acetonitrile / water (1:1, v / v), and 1,3-di(bromomethyl)benzene and ammonium bicarbonate were added. The mixture was stirred overnight, and the crude product was prepared by reverse HPLC and lyophilized to obtain the target compound T3. The ligand structure was identified by mass spectrometry, as shown below. Figure 7 As shown.

[0048] Preparation of T4:

[0049] T4 structural

[0050] The synthesis steps of T4 are as follows: Figure 8As shown. The coupling of amino acids was carried out according to the standard Fmoc solid-phase synthesis method. Reaction conditions: (a) DMF solution of 20% piperidine, DMF solution of Fmoc-L-glycine, HBTU, HOBt and DIPEA; (b) DMF solution of 20% piperidine, DMF solution of 2-[4,7-bis[2-(tert-butoxy)-2-oxoethyl]-1,4,7-triazacyclononane-1-yl]acetic acid (NOTA-BIS), HBTU, HOBt and DIPEA; (c) DMF solution of SnCl2·2H2O; (d) DMF solution of 1,4-sulfonylbutyric acid, HATU, HOBt and DIPEA; 2, trifluoroacetic acid, water and triisopropylsilane; (e) 1,3-di(bromomethyl)benzene, acetonitrile and aqueous solution of NH4HCO3.

[0051] Specifically, a certain mass of resin 1 (0.05 mmol) was placed in a 10 mL solid-phase synthesis tube, and 2 mL of dichloromethane (DCM) was added to swell the resin. This process was repeated three times, each time for 5 minutes, followed by... N,NWash three times with dimethylformamide (DMF) for 5 minutes each time. Remove the amino protecting group Fmoc using a DMF solution (v / v) containing 20% ​​piperidine. Specifically, react 2 mL of 20% piperidine DMF solution for 2 minutes, 10 minutes, and 10 minutes, followed by washing 3-5 times with 2 mL DMF for 2 minutes each time. Add 5 times the stoichiometric amount of Fmoc-glycine (relative to resin 0.05 mmol) activated with 5 times the stoichiometric amount of HATU in the presence of 10 times the stoichiometric amount of DIPEA to the synthesis tube, and react under electromagnetic stirring for 1 hour. Remove the amino protecting group Fmoc using a DMF solution (v / v) containing 20% ​​piperidine, followed by washing 3-5 times with 2 mL DMF for 2 minutes each time. Five times the stoichiometric amount of NOTA-bis(tBu)ester, activated with five times the stoichiometric amount of HATU in the presence of ten times the stoichiometric amount of DIPEA, was added to the synthesis tube and reacted under electromagnetic stirring for 1 hour, followed by washing 3-5 times with 2 mL DMF for 2 minutes each time. The nitro group attached to the phenylalanine residue was reduced to an amino group using SnCl2·2H2O. Specifically, a 1 M SnCl2·2H2O DMF solution (340 mg SnCl2·2H2O in 1.5 mL DMF) was added to the synthesis tube and reacted overnight under electromagnetic stirring, followed by washing 3-5 times with 2 mL DMF for 2 minutes each time. Five times the stoichiometric amount of 4-sulfonylbutyric acid, activated with five times the stoichiometric amount of HATU in the presence of ten times the stoichiometric amount of DIPEA, was added to the synthesis tube and reacted overnight under electromagnetic stirring for acylation, followed by washing 3-5 times with 2 mL DMF for 2 minutes each time. The ligand dissociation from the resin and the removal of Trt were completed by stirring 5 mL of trifluoroacetic acid / triisopropylsilane / water (95:2.5:2.5, v / v / v) for 2 hours. The resin was washed with 2 mL of trifluoroacetic acid, and all filtrates were collected. After removing trifluoroacetic acid under reduced pressure, the crude product was prepared by reverse HPLC and lyophilized to obtain intermediate 2. This intermediate was then diluted to 60 mL with acetonitrile / water (1:1, v / v), and 1,3-di(bromomethyl)benzene and ammonium bicarbonate were added. The mixture was stirred overnight, and the crude product was prepared by reverse HPLC and lyophilized to obtain the target compound T4. The ligand structure was identified by mass spectrometry, as shown below. Figure 9 As shown.

[0052] Example 2: Labeling and Quality Control

[0053] mark: Accurately weigh a specific mass of ligands (T1-T4) into the sample, add DMSO (dimethyl sulfoxide) to dissolve them, and dilute the ligand concentration to 2 nmol / μL. Pipette 10 μL of the ligand solution, 9 μL of 50 mM AlCl3 solution, 27 μL of 0.5 M KHP solution, and 200 μL of physiological saline solution. 18 F - The mixture was placed in a vial and reacted at room temperature for 2 minutes. 150 μL of ethanol was added to the system, shaken well, and sealed. The mixture was then reacted at 100°C for 10 minutes. After cooling to room temperature, the solution was purified using a Sep-Pak C18 solid-phase extraction column and analyzed by HPLC for quality control.

[0054] Quality control: 18 The radiochemical purity of the F complex was determined by HPLC (high performance liquid chromatography) with an aqueous solution containing 20% ​​acetonitrile (containing 0.1% TFA) as the mobile phase. The radiochemical purity of all complexes was greater than 95%, and they were used for further study without purification.

[0055] Example 3 Imaging of the labeled product

[0056] Take 0.1 mL of freshly prepared 18 F-labeled complexes T1-T4 (5.6 MBq-7.4 MBq) were injected via the tail vein into female mice carrying the CAIX-transfected mouse renal cell carcinoma line Renca (CAIX) (tumor diameter approximately 1 cm). One hour later, the mice were anesthetized with isoflurane and subjected to small animal PET / CT (SUPER-NOVA, Ping Sheng Technology, China) imaging. The regions of interest were delineated using standard uptake values ​​(SUVs).

[0057] Table 1. SUVmax values ​​and ratios of the complexes in tumor and normal tissues (mean ± SD, n = 4)

[0058] Table 1 (continued)

[0059] like Figure 10 As shown in Table 1, after 1 hour 18 F-T1 complexes showed significant concentrations in the tumor region. The SUVmax ratio of tumor to kidney was 6.550±0.382, the SUVmax ratio of tumor to muscle was 434.150±159.542, the SUVmax ratio of tumor to liver was 45.858±7.478, and the SUVmax ratio of tumor to blood pool was 63.409±7.725. 18F-T1 shows significant advantages in terms of tumor-to-muscle ratio, tumor-to-liver ratio, and tumor-to-blood-pool ratio at 1 hour, making it a very promising treatment. 18 F-labeled CAIX targeting molecular probes.

[0060] like Figure 11 As shown in Table 1, after 1 hour 18 F-T2 complexes showed significant concentrations in the tumor region. The SUVmax of the stomach was 0.127±0.016, the ratio of tumor SUVmax to kidney SUVmax was 3.537±1.549, the ratio of tumor SUVmax to muscle SUVmax was 165.603±146.904, the ratio of tumor SUVmax to liver SUVmax was 30.160±7.125, and the ratio of tumor SUVmax to blood pool SUVmax was 37.625±11.225. Two hours later... 18 F-T2 complexes were significantly concentrated in the tumor area. The SUVmax of the stomach was 0.089±0.022. The ratio of the SUVmax of the tumor to that of the kidney was 3.741±1.960. The ratio of the SUVmax of the tumor to that of the muscle was 344.767±128.157. The ratio of the SUVmax of the tumor to that of the liver was 47.549±7.522. The ratio of the SUVmax of the tumor to that of the blood pool was 48.326±5.436. 18 F-T2 shows significant advantages in gastric uptake at 1 and 2 hours, with better tumor-to-kidney ratio, tumor-to-meat ratio, and tumor-to-blood pool ratio, making it a very promising candidate. 18 F-labeled CAIX targeting molecular probes.

[0061] like Figure 12 As shown in Table 1, after 1 hour 18 F-T3 complexes were significantly concentrated in the tumor area. The ratio of SUVmax between tumor and kidney was 3.634±1.134, the ratio between tumor and muscle was 78.770±49.191, the ratio between tumor and liver was 8.906±2.706, and the ratio between tumor and blood pool was 25.749±15.403. 18 F-T3 1-hour tumor-to-renal ratio slightly weaker than 18 F-T1, 1-hour tumor-to-tumor ratio, tumor-to-liver ratio, and tumor-to-blood-pool ratio are weaker than 18 F-T1 is a promising technology. 18 F-labeled CAIX targeting molecular probes.

[0062] like Figure 13 As shown in Table 1, after 1 hour 18F-T4 complexes showed significant concentrations in the tumor region. The SUVmax ratios of tumor to kidney were 1.041±0.584, tumor to muscle was 36.106±14.854, tumor to liver was 7.479±2.810, and tumor to blood pool was 8.205±3.461. At 1 hour, the tumor-kidney ratio, tumor-muscle ratio, tumor-liver ratio, and tumor-blood pool ratio were weaker than [previous data]. 18 F-T1 also has some application potential.

[0063] The various embodiments of the present invention have been described above. These descriptions are exemplary and not exhaustive, nor are they limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments.

Claims

1. A carbonic anhydrase IX-targeting compound, characterized in that, The carbonic anhydrase IX targeting compound has the structure shown in Formula I: Equation I In formula I, R1 is a chemical bond. , or ; R2 is .

2. The carbonic anhydrase IX-targeting compound according to claim 1, characterized in that, The carbonic anhydrase IX targeting compound is compound T1, compound T2, compound T3, or compound T4. Compound T1 Compound T2 Compound T3 Compound T4.

3. The use of the carbonic anhydrase IX targeting compound as described in claim 1 or 2 in the preparation of nuclear medicine diagnostic probes or nuclear medicine therapeutic agents.

4. A carbonic anhydrase IX targeted imaging reagent, characterized in that, The carbonic anhydrase IX targeted imaging reagent is a carbonic anhydrase IX targeted compound as described in claim 1 or 2, which is a diagnostic radionuclide-labeled compound.

5. The carbonic anhydrase IX targeted imaging reagent according to claim 4, characterized in that, The diagnostic radionuclide is 11 C 13 N、 18 F, 43 Sc、 44 Sc、 45 Ti、 47 Sc、 51 Cr 51 Mn, 52 Mn, 52 Fe、 55 Co、 57 Co、 58m Co、 59 Fe、 60 Cu、 61 Cu、 62 Cu、 63 Zn, 64 Cu、 67 Cu、 67 Ga、 68 Ga、 75 Sc、 77 As、 82 Rb、 86 Y、 87 Y、 90 Y、 89 Zr、 94 Tc, 97 Ru、 99 Tc, 99m Tc, 101m Rh、 103m Rh、 105 Pd, 105 Rh、 111 Ag、 111 ln、 117m Sn、 119 Sb, 149 Pm, 149 Tb, 152 Tb, 153 Sm、 154-159 Gd, 161 Tb, 165 Dy、 166 Dy、 166 Ho、 169 Er、 169 Yb、 175 Yb、 175 Lu、 177 Lu、 186 Re、 188 Re、 189 Re、 191m Pt, 193m Pt, 195m Pt, 194 lr、 197 Pt, 198 Au、 199 Au、 211 At、 211 Pb, 212 Bi、 212 Pb, 213 Bi、 223 Ra、 224 Ra and 225 At least one of Ac.

6. A carbonic anhydrase IX targeted therapeutic agent, characterized in that, The carbonic anhydrase IX targeted therapeutic agent is the carbonic anhydrase IX targeted compound of claim 1 or 2, which is radiolabeled for therapeutic use.

7. The carbonic anhydrase IX targeted imaging reagent according to claim 6, characterized in that, The therapeutic radionuclide is 47 Sc、 57 Co、 58m Co、 60 Co、 61 Cu、、、 90 Y、 103 Pd, 103m Rh、 105 Rh、 106 Ru、 117m Sn、 119 Sb, 149 Tb, 149 Pm, 161 Ho、 165 Dy、 177 Lu、 177 Yb、 186 Re、 188 Re、 192 Ir、 193m Pt, 195m Pt, 197 Pt, 199 Au、 203 Pb、、 211 At、 212 Pb, 212 Bi、 213 Bi、 223 Ra、 224 Ra、 225 Ac、 226 Th、 227 Th and 229 At least one of Th.

8. The application of a carbonic anhydrase IX targeted diagnostic agent in CAIX-targeted imaging or treatment of abdominal organs, characterized in that, The carbonic anhydrase IX targeted therapeutic agent is compound T2 labeled with a diagnostic radionuclide or a therapeutic radionuclide.

Images