Al18F-labeled PSMA radiopharmaceutical as well as preparation method and application of Al18F-labeled PSMA radiopharmaceutical

Abstract

The invention provides a preparation method of an Al18F-labeled PSMA radiopharmaceutical, according to the preparation method, through adjustment of a reaction system, the labeling time efficiency, the radiochemical purity of a final product, the radiochemical conversion rate and the product yield are ensured, meanwhile, the requirement for the fluorination reaction temperature in the labeling process is effectively reduced, and the product yield is improved. The preparation method of the Al18F-labeled PSMA radiopharmaceutical provided based on the method has good applicability and thorough reaction, new impurities are not introduced into a final product due to reduction of the reaction temperature or adjustment of a reaction system, the variety and content of the impurities in the final product can be further reduced and controlled, and the preparation method is suitable for industrial production. And the medication safety of a patient is further ensured. In addition, the final product obtained by the preparation method provided by the invention has good inter-batch uniformity, and has good stability under the storage conditions of 30 DEG C + / -2 DEG C and 40 DEG C + / -2 DEG C.

Description

Technical Field

[0001] The present invention relates to the field of radioactive drugs, and in particular to an Al 18 F-labeled PSMA radiopharmaceuticals and preparation methods and applications thereof. Background Art

[0002] With the intensification of the aging process of the population, the incidence of prostate cancer has ranked sixth among the incidence of male malignant tumors in my country. How to accurately detect prostate cancer at an early stage has become a problem that needs to be solved urgently in the clinic. Nuclear medicine imaging can non-invasively, visualize, qualitatively / quantitatively monitor and participate in the physiological and pathological processes of tumor occurrence and development at the molecular and cellular levels, and has become an important means of clinical tumor detection. PSMA (Prostate Specific Membrane Antigen) is highly expressed in prostate cancer cells as a specific target. PSMA is highly expressed in the late stage of prostate cancer and is also highly expressed in the cells of prostate cancer metastasis. Its expression level is significantly correlated with the degree of tumor differentiation, metastasis tendency and sensitivity to hormone therapy. At this stage, specific prostate cancer molecular probes targeting PSMA have become a hot topic of research.

[0003] PSMA-BCH is a compound composed of glutamic acid, lysine and naphthylalanine with PSMA targeting function, which has good application prospects in the diagnosis and treatment of prostate cancer [Reference 1: Liu T, Liu C, Xu X, Liu F, Guo X, Li N, Wang X, Yang J, Yang X, Zhu H, Yang Z. Preclinical Evaluation and Pilot Clinical Study of Al 18 F-PSMA-BCH for Prostate Cancer PET Imaging. JNucl Med. 2019 Sep;60(9):1284-1292.]. Currently, diagnostic probes for PSMA-targeted compounds are mainly based on 68 Ga and 18 F is mainly marked, relative to 68 For Ga (half-life is 68 minutes), 18 F (half-life 109.8 minutes) has a longer half-life and higher positron energy, and 18 F Comparable 68Ga showed a higher maximum standardized uptake value (SUVmax) and detection rate [Reference 2: Huang S, Ong S, McKenzie D, Mirabelli A, Chen DC, Chengodu T, Murphy DG, Hofman MS, Lawrentschuk N, Perera M. Comparison of 18F-based PSMA radiotracers with [ 68 Ga]Ga-PSMA-11 in PET / CT imaging of prostate cancer-a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2024 Dec;27(4):654-664.], which makes it more clinically preferred 18 F-labeled molecular probe. 18 Due to the decay characteristics of F nuclides, in order to ensure the normal use of drugs by patients, nuclear pharmacies need to produce drugs on the day of use. In addition, in order to ensure the timeliness of the drugs, the entire probe production preparation to shipment process generally needs to be controlled within 4 hours, and its production and distribution is also limited to a 3-4 hour driving radius, which has strict time constraints on the entire production process of molecular probes. In addition, traditional 18 The F labeling method also has some disadvantages such as long labeling time, high reaction temperature and low labeling rate, which restricts 18 Application of F molecular probes.

[0004] Literature 1 [Liu T, Liu C, Xu X, Liu F, Guo X, Li N, Wang X, Yang J, Yang X, Zhu H, Yang Z. Preclinical Evaluation and Pilot Clinical Study of Al 18 F-PSMA-BCH for Prostate Cancer PET Imaging. J Nucl Med. 2019 Sep;60(9):1284-1292.] A manual Al 18 F-labeled PSMA-BCH method, which is to add no carrier 18 F2 saline solution, sodium acetate buffer and AlCl3 are mixed in sodium acetate buffer to form Al 18F complex, PSMA-BCH was added and heated at 110°C for 15 minutes for fluorination reaction. This method is a manual labeling method, which will inevitably increase the probability of operators being exposed to radionuclides, thereby causing radiation damage to operators due to unnecessary overexposure. Patent application with publication number CN110938041A discloses an Al 18 The automatic labeling method of F-PSMA-BCH is to mix PSMA-BCH, AlCl3 and pH buffer first, and then capture 18 F is added to a fluorination reaction bottle loaded with an aqueous solution of PSMA-BCH, AlCl3 and pH buffer for fluorination reaction, the reaction temperature is 110 ° C, and the reaction time is 15min. Although this method can effectively reduce the contact probability between operators and radionuclides, its fluorination reaction temperature is relatively high, which leads to the need for the actual production process to be carried out in a high temperature environment. The high temperature reaction environment will theoretically produce more impurities, which will cause trouble for subsequent purification. In short, how to provide a labeling method with low exposure, mild reaction conditions, good labeling rate and low impurity rate is still a problem that needs to be solved in this field. Summary of the invention

[0005] In view of the above problems, the present invention provides a method for fluorinating a PSMA radiopharmaceutical intermediate, and further provides an Al 18 The invention discloses a method for preparing a PSMA radiopharmaceutical labeled with F. The fluorination method and the preparation method can effectively reduce the requirement for the fluorination reaction temperature during the labeling process by adjusting the reaction system while ensuring the radiochemical purity, radiochemical conversion rate and product yield of the final product.

[0006] Specifically, the present invention provides a method for fluorinating a PSMA radiopharmaceutical intermediate, which comprises the following steps: A potassium hydrogen phthalate solution containing aluminum chloride hexahydrate, a dimethyl sulfoxide solution containing a PSMA radiopharmaceutical intermediate, and a potassium hydrogen phthalate solution are simultaneously added to a fluorine-containing 18 F] ion solution in a reaction bottle, the reaction temperature is 75-85°C (such as 75°C, 76°C, 77°C, 78°C, 79°C, 80°C, 81°C, 82°C, 83°C, 84°C, 85°C), and the reaction time is 15 minutes.

[0007] The PSMA radiopharmaceutical intermediates described in the present invention are relative to the labeled PSMA radiopharmaceuticals, and specifically refer to those active structural parts that are not radiolabeled. For example, when the labeled PSMA radiopharmaceuticals are Al 18When F-PSMA-BCH, the PSMA radiopharmaceutical intermediate specifically refers to the PSMA-BCH structure.

[0008] Preferably, the molar ratio of the aluminum chlorohexahydrate to the PSMA radiopharmaceutical intermediate is 0.7-0.8:1 (such as 0.7:1, 0.71:1, 0.72:1, 0.73:1, 0.74:1, 0.75:1, 0.76:1, 0.77:1, 0.78:1, 0.79:1, 0.8:1); more preferably, the molar ratio of the aluminum chlorohexahydrate to the PSMA radiopharmaceutical intermediate is 0.73-0.77:1; even more preferably, the molar ratio of the aluminum chlorohexahydrate to the PSMA radiopharmaceutical intermediate is 0.75:1.

[0009] Preferably, the reaction temperature in the above fluorination reaction is 80-85°C (such as 80°C, 81°C, 82°C, 83°C, 84°C, 85°C); more preferably, the reaction temperature in the above fluorination reaction is 85°C.

[0010] Preferably, in the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate described in the fluorination reaction, the concentration of aluminum chloride hexahydrate is 0.6-0.9 mg / ml (such as 0.6 mg / ml, 0.61 mg / ml, 0.62 mg / ml, 0.63 mg / ml, 0.64 mg / ml, 0.65 mg / ml, 0.66 mg / ml, 0.67 mg / ml, 0.68 mg / ml, 0.69 mg / ml, 0.7 mg / ml, 0.71 mg / ml, 0.72 mg / ml, 0.73 mg / ml, 0.74 mg / ml, 0.75 mg / ml, 0.76 mg / ml, 0.77 mg / ml, 0.78 mg / ml, 0.79 mg / ml, 0.8 mg / ml, 0.81 mg / ml, 0.82 mg / ml, 0.83 mg / ml, 0.84 75 mg / ml, 0.76 mg / ml, 0.77 mg / ml, 0.78 mg / ml, 0.79 mg / ml, 0.8 mg / ml); more preferably, in the potassium hydrogen phthalate solution containing aluminum chlorohexahydrate described in the above fluorination reaction, the concentration of aluminum chlorohexahydrate is 0.7-0.8 mg / ml (such as 0.7 mg / ml, 0.71 mg / ml, 0.72 mg / ml, 0.73 mg / ml, 0.74 mg / ml, 0.75 mg / ml, 0.76 mg / ml, 0.77 mg / ml, 0.78 mg / ml, 0.79 mg / ml, 0.8 mg / ml); more preferably, in the potassium hydrogen phthalate solution containing aluminum chlorohexahydrate described in the above fluorination reaction, the concentration of aluminum chlorohexahydrate is 0.75-0.8 mg / ml (such as 0.75 mg / ml, 0.76 More preferably, the concentration of aluminum chloride hexahydrate in the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate in the above-mentioned fluorination reaction is 0.77 mg / ml.

[0011] Preferably, in the dimethyl sulfoxide solution containing the PSMA radiopharmaceutical intermediate described in the above fluorination reaction, the concentration of the PSMA radiopharmaceutical intermediate is 0.4-0.6 mg / ml (such as 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml); more preferably, in the dimethyl sulfoxide solution containing the PSMA radiopharmaceutical intermediate described in the above fluorination reaction, the concentration of the PSMA radiopharmaceutical intermediate is 0.5 mg / ml.

[0012] Preferably, the concentration of the potassium hydrogen phthalate solution in the fluorination reaction is 0.1-1M (such as 0.1M, 0.2M, 0.3M, 0.4M, 0.5M, 0.6M, 0.7M, 0.8M, 0.9M, 1M); more preferably, the concentration of the potassium hydrogen phthalate solution in the fluorination reaction is 0.4-0.6M (such as 0.4M, 0.5M, 0.6M); even more preferably, the concentration of the phthalic acid solution in the fluorination reaction is 0.5M.

[0013] Preferably, the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate described in the above fluorination reaction (volume is defined as V a ) and a dimethyl sulfoxide solution containing a PSMA radiopharmaceutical intermediate (volume defined as V b ) has a volume ratio of V a :V b =1:5-10 (such as 1:5, 1:6, 1:7, 1:8, 1:9, 1:10); More preferably, the volume ratio of the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate and the dimethyl sulfoxide solution containing the PSMA radiopharmaceutical intermediate in the above fluorination reaction is V a :V b =1:7-9 (such as 1:7, 1:8, 1:9); More preferably, the volume ratio of the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate and the dimethyl sulfoxide solution containing the PSMA radiopharmaceutical intermediate in the above fluorination reaction is V a :V b =1:8.

[0014] Preferably, the dimethyl sulfoxide solution (volume defined as V) containing the PSMA radiopharmaceutical intermediate in the above fluorination reaction is b ) and potassium hydrogen phthalate solution (volume defined as V c ) has a volume ratio of V b :V c =5-10:1 (such as 5:1, 6:1, 7:1, 8:1, 9:1, 10:1); More preferably, the volume ratio of the dimethyl sulfoxide solution containing the PSMA radiopharmaceutical intermediate and the potassium hydrogen phthalate solution in the above fluorination reaction is V b :V c =7-9:1 (such as 7:1, 8:1, 9:1); More preferably, the volume ratio of the dimethyl sulfoxide solution containing the PSMA radiopharmaceutical intermediate and the potassium hydrogen phthalate solution in the above fluorination reaction is V b :V c =8:1.

[0015] Preferably, the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate described in the above fluorination reaction (volume is defined as V a ), a dimethyl sulfoxide solution containing a PSMA radiopharmaceutical intermediate (volume is defined as V b ) and potassium hydrogen phthalate solution (volume defined as V c ) has a volume ratio of V a :V b :V c =1:7-9:1 (such as 1:7:1, 1:8:1, 1:9:1); More preferably, the volume ratio of the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate, the dimethyl sulfoxide solution containing the PSMA radiopharmaceutical intermediate and the potassium hydrogen phthalate solution in the above fluorination reaction is V a :V b :V c =1:8:1.

[0016] In some specific embodiments, the fluorination reaction comprises the following steps: adding a potassium hydrogen phthalate solution containing aluminum chlorohexahydrate (the concentration of aluminum chlorohexahydrate is 0.77 mg / ml, and the concentration of potassium hydrogen phthalate solution is 0.5 M), a dimethyl sulfoxide solution containing a PSMA radiopharmaceutical intermediate (the concentration of the PSMA radiopharmaceutical intermediate is 0.5 mg / ml), and a potassium hydrogen phthalate solution (the concentration of the potassium hydrogen phthalate solution is 0.5 M) to a fluorine-containing mixture; 18 F] ion solution in a reaction bottle for fluorination reaction, the fluorination reaction temperature is 85 ° C, the fluorination reaction time is 15 minutes, the reaction is completed, the reaction mixture is cooled to 50 ° C, and Al 18 F-PSMA radiopharmaceutical crude solution, containing aluminum chloride hexahydrate potassium hydrogen phthalate solution (V a ), dimethyl sulfoxide solution containing PSMA radiopharmaceutical intermediate (V b ), potassium hydrogen phthalate solution (V c )’s volume ratio is V1:V2:V3=1:8:1.

[0017] In another aspect, the present invention also provides an Al 18 A method for preparing a F-labeled PSMA radiopharmaceutical, the method comprising the fluorination method of the PSMA radiopharmaceutical intermediate described above.

[0018] Further, the Al provided by the present invention 18 The preparation method of F-labeled PSMA radiopharmaceuticals comprises the following steps: Step 1: Fluorine 18 F] ion preparation and transport; Step 2: Fluorine 18F] ion capture; Step 3: Radiolabeling of PSMA radiopharmaceutical intermediates; Step 4: Al 18 Purification of crude F-PSMA radiopharmaceutical; Step 5: Al 18 Preparation of F-PSMA radiopharmaceuticals.

[0019] Among them, the PSMA radiopharmaceutical intermediate described in the present invention is relative to Al 18 F-labeled PSMA radiopharmaceutical (i.e., Al 18 F-PSMA radiopharmaceuticals) are specifically those that have not been 18 F-labeled active structural parts, such as Al 18 F-labeled PSMA radiopharmaceutical (i.e., Al 18 F-PSMA radiopharmaceutical) has a specific structure of Al 18 When F-PSMA-BCH is used, the PSMA radiopharmaceutical intermediate specifically refers to the PSMA-BCH structural part.

[0020] In the above preparation method, the step three comprises the following steps: adding a potassium hydrogen phthalate solution containing aluminum chloride hexahydrate, a dimethyl sulfoxide solution containing a PSMA radiopharmaceutical intermediate, and a potassium hydrogen phthalate solution to a solution containing fluorine [ 18 F] ion solution in a reaction bottle for fluorination reaction, the fluorination reaction temperature is 75-85°C (such as 75°C, 76°C, 77°C, 78°C, 79°C, 80°C, 81°C, 82°C, 83°C, 84°C, 85°C), the fluorination reaction time is 15 minutes, the reaction is completed, the reaction mixture is cooled to 45-55°C (45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C), and Al 18 F-PSMA crude radiopharmaceutical solution.

[0021] Preferably, the molar ratio of the aluminum chlorohexahydrate and the PSMA radiopharmaceutical intermediate described in step 3 is 0.7-0.8:1 (such as 0.7:1, 0.71:1, 0.72:1, 0.73:1, 0.74:1, 0.75:1, 0.76:1, 0.77:1, 0.78:1, 0.79:1, 0.8:1); more preferably, the molar ratio of the aluminum chlorohexahydrate and the PSMA radiopharmaceutical intermediate described in step 3 is 0.73-0.77:1; more preferably, the molar ratio of the aluminum chlorohexahydrate and the PSMA radiopharmaceutical intermediate described in step 3 is 0.75:1.

[0022] Preferably, the fluorination reaction temperature in step three is 80-85°C (such as 80°C, 81°C, 82°C, 83°C, 84°C, 85°C); more preferably, the fluorination reaction temperature in step three is 85°C.

[0023] Preferably, in step three, the reaction mixture is cooled to 50-55°C (50°C, 51°C, 52°C, 53°C, 54°C, 55°C); more preferably, in step three, the reaction mixture is cooled to 50°C.

[0024] Preferably, in the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate described in step 3, the concentration of aluminum chloride hexahydrate is 0.6-0.9 mg / ml (such as 0.6 mg / ml, 0.61 mg / ml, 0.62 mg / ml, 0.63 mg / ml, 0.64 mg / ml, 0.65 mg / ml, 0.66 mg / ml, 0.67 mg / ml, 0.68 mg / ml, 0.69 mg / ml, 0.7 mg / ml, 0.71 mg / ml, 0.72 mg / ml, 0.73 mg / ml, 0.74 mg / ml, 0.75 mg / ml, 0.76 mg / ml, 0.77 mg / ml, 0.78 mg / ml, 0.79 mg / ml, 0.8 mg / ml, 0.81 mg / ml, 0.82 mg / ml, 0.83 mg / ml, 0.84 mg / ml, 0.85 75 mg / ml, 0.76 mg / ml, 0.77 mg / ml, 0.78 mg / ml, 0.79 mg / ml, 0.8 mg / ml); more preferably, in the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate described in step 3, the concentration of aluminum chloride hexahydrate is 0.7-0.8 mg / ml (such as 0.7 mg / ml, 0.71 mg / ml, 0.72 mg / ml, 0.73 mg / ml, 0.74 mg / ml, 0.75 mg / ml, 0.76 mg / ml, 0.77 mg / ml, 0.78 mg / ml, 0.79 mg / ml, 0.8 mg / ml); more preferably, in the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate described in step 3, the concentration of aluminum chloride hexahydrate is 0.75-0.8 mg / ml (such as 0.75 mg / ml, 0.76 mg / ml, 0.77 More preferably, in the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate in step 3, the concentration of aluminum chloride hexahydrate is 0.77 mg / ml.

[0025] Preferably, in the dimethyl sulfoxide solution containing the PSMA radiopharmaceutical intermediate described in step 3, the concentration of the PSMA radiopharmaceutical intermediate is 0.4-0.6 mg / ml (such as 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml); more preferably, in the dimethyl sulfoxide solution containing the PSMA radiopharmaceutical intermediate described in step 3, the concentration of the PSMA radiopharmaceutical intermediate is 0.5 mg / ml.

[0026] Preferably, the concentration of the potassium hydrogen phthalate solution described in step three is 0.1-1M (such as 0.1M, 0.2M, 0.3M, 0.4M, 0.5M, 0.6M, 0.7M, 0.8M, 0.9M, 1M); more preferably, the concentration of the potassium hydrogen phthalate solution described in step three is 0.4-0.6M (such as 0.4M, 0.5M, 0.6M); more preferably, the concentration of the phthalic acid solution described in step three is 0.5M.

[0027] Preferably, the volume ratio of the potassium hydrogen phthalate solution containing aluminum chlorohexahydrate (volume defined as V1) and the dimethyl sulfoxide solution containing the PSMA radiopharmaceutical intermediate (volume defined as V2) described in step 3 is V1: V2 = 1: 5-10 (such as 1: 5, 1: 6, 1: 7, 1: 8, 1: 9, 1: 10); More preferably, the volume ratio of the potassium hydrogen phthalate solution containing aluminum chlorohexahydrate and the dimethyl sulfoxide solution containing the PSMA radiopharmaceutical intermediate described in step 3 is V1: V2 = 1: 7-9 (such as 1: 7, 1: 8, 1: 9); More preferably, the volume ratio of the potassium hydrogen phthalate solution containing aluminum chlorohexahydrate and the dimethyl sulfoxide solution containing the PSMA radiopharmaceutical intermediate described in step 3 is V1: V2 = 1: 8.

[0028] Preferably, the volume ratio of the dimethyl sulfoxide solution containing the PSMA radiopharmaceutical intermediate (volume defined as V2) and the potassium hydrogen phthalate solution (volume defined as V3) described in step three is V2: V3 = 5-10: 1 (such as 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1); more preferably, the volume ratio of the dimethyl sulfoxide solution containing the PSMA radiopharmaceutical intermediate and the potassium hydrogen phthalate solution described in step three is V2: V3 = 7-9: 1 (such as 7: 1, 8: 1, 9: 1); more preferably, the volume ratio of the dimethyl sulfoxide solution containing the PSMA radiopharmaceutical intermediate and the potassium hydrogen phthalate solution described in step three is V2: V3 = 8: 1.

[0029] Preferably, the volume ratio of the potassium hydrogen phthalate solution containing aluminum chlorohexahydrate (volume defined as V1), the dimethyl sulfoxide solution containing the PSMA radiopharmaceutical intermediate (volume defined as V2), and the potassium hydrogen phthalate solution (volume defined as V3) described in step 3 is V1: V2: V3 = 1:7-9:1 (such as 1:7:1, 1:8:1, 1:9:1); More preferably, the volume ratio of the potassium hydrogen phthalate solution containing aluminum chlorohexahydrate, the dimethyl sulfoxide solution containing the PSMA radiopharmaceutical intermediate, and the potassium hydrogen phthalate solution described in step 3 is V1: V2: V3 = 1:8:1.

[0030] In some specific embodiments, the step three comprises the following steps: adding a potassium hydrogen phthalate solution containing aluminum chlorohexahydrate (the concentration of aluminum chlorohexahydrate is 0.77 mg / ml, and the concentration of potassium hydrogen phthalate solution is 0.5 M), a dimethyl sulfoxide solution containing a PSMA radiopharmaceutical intermediate (the concentration of the PSMA radiopharmaceutical intermediate is 0.5 mg / ml), and a potassium hydrogen phthalate solution (the concentration of the potassium hydrogen phthalate solution is 0.5 M) to a flask containing fluorine [ 18 F] ion solution in a reaction bottle for fluorination reaction, the fluorination reaction temperature is 85 ° C, the fluorination reaction time is 15 minutes, the reaction is completed, the reaction mixture is cooled to 50 ° C, and Al 18 The crude F-PSMA radiopharmaceutical solution comprises a potassium hydrogen phthalate solution containing aluminum chloride hexahydrate (V1), a dimethyl sulfoxide solution containing a PSMA radiopharmaceutical intermediate (V2), and a potassium hydrogen phthalate solution (V3), wherein the volume ratio V1:V2:V3 is 1:8:1.

[0031] Furthermore, the step 1 is to complete the fluorine [ 18 F] ion preparation and transport.

[0032] Furthermore, the fluorine produced in step 1 18 F] ions, the radioactivity of which is determined according to clinical needs.

[0033] Furthermore, the fluorine [ 18 The preparation of F] ions includes the following steps: using a cyclotron to load heavy oxygen ( 18 O) water, set the bombardment beam current (30-100 μA) and bombardment time (20-120 minutes), and bombard heavy oxygen ( 18 O) Water, through the occurrence 18 O(p,n) 18 F nuclear reaction produces fluorine [ 18 F] ions, after the bombardment, will contain fluorine [ 18 F] ion heavy oxygen (18 O) Water transfer to fluorine [ 18 F] ion V-shaped bottle, and then purged with helium gas [ 18 F] ion transfer pipeline, and turn off the accelerator after completion.

[0034] Furthermore, the fluorine [ 18 The transport of F] ions includes the following steps: dissolving in heavy oxygen ( 18 O) Fluoride in water 18 F] Ions flow from the V-shaped vial into a conical tube on the synthesizer cartridge.

[0035] Furthermore, the steps 2, 3 and 4 are completed in a synthesizer.

[0036] Furthermore, the step 2 comprises the following steps: transferring the heavy oxygen ( 18 O) Fluoride in water 18 The fluoride [F] ions are adsorbed onto the pre-activated QMA ion exchange column. After the QMA ion exchange column is cleaned with an appropriate amount of injection water, a mixture of an appropriate amount of sodium chloride injection and a sodium vitamin C aqueous solution is used to remove the fluoride [ 18 F] ions were eluted from the QMA ion exchange column.

[0037] Preferably, the concentration of the sodium vitamin C aqueous solution in step 2 is 80-120 mg / ml (such as 80 mg / ml, 90 mg / ml, 100 mg / ml, 110 mg / ml, 120 mg / ml); more preferably, the concentration of the sodium vitamin C aqueous solution is 90-110 mg / ml (such as 90 mg / ml, 100 mg / ml, 110 mg / ml); even more preferably, the concentration of the sodium vitamin C aqueous solution is 100 mg / ml.

[0038] Preferably, the volume ratio of the sodium chloride injection and the sodium vitamin C aqueous solution in step 2 is V 氯化钠注射液 :V 维生素C钠水溶液 =10-30:1 (e.g., 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1); More preferably, the volume ratio of the sodium chloride injection and the sodium vitamin C aqueous solution in step 2 is V 氯化钠注射液 :V 维生素C钠水溶液=15-25:1 (such as 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1); More preferably, the volume ratio of the sodium chloride injection and the sodium vitamin C aqueous solution in step 2 is V 氯化钠注射液 :V 维生素C钠水溶液 =20:1.

[0039] Furthermore, the step four comprises HPLC purification.

[0040] Furthermore, the HPLC purification described in step 4 comprises the following steps: 18 The crude F-PSMA radiopharmaceutical solution was diluted with an appropriate amount of mobile phase and separated and purified according to the following chromatographic conditions. A radioactivity detector was used to detect online and collect the Al 18 The component peak of F-PSMA radiopharmaceutical is then diluted with an appropriate amount of sterile water for injection. 18 HPLC purified fraction of F-PSMA radiopharmaceutical.

[0041] Table 1 HPLC purification parameters

[0042] Furthermore, the step four comprises HLB purification.

[0043] Furthermore, the HLB purification described in step 4 comprises the following steps: 18 The HPLC purified components of F-PSMA radiopharmaceuticals were adsorbed onto the HLB column. The impurities adsorbed on the HLB column were washed with an appropriate amount of sterile injection water, and then the residual liquid on the HLB column was purged and removed. Subsequently, the Al 18 F-PSMA radiopharmaceutical was eluted from the HLB column to obtain Al 18 F-PSMA radiopharmaceutical pure solution.

[0044] Furthermore, the step four comprises HPLC purification and HLB purification, the HPLC purification step is as described above, and the HLB purification step is as described above.

[0045] Further, the step five comprises the following steps: 18 The pure F-PSMA radiopharmaceutical solution was diluted with an appropriate amount of sodium chloride injection, filtered and sterilized, and aseptically packaged according to clinical demand to obtain Al 18 F-labeled PSMA radiopharmaceutical.

[0046] Preferably, the Al obtained by the preparation method provided by the present invention 18The F-labeled PSMA radiopharmaceutical is available as an injectable solution.

[0047] Preferably, the Al obtained by the preparation method provided by the present invention 18 The specification of F-labeled PSMA radiopharmaceutical injection solution is 37-1850 MBq / ml (i.e. 1.0-50.0 mCi / ml).

[0048] Preferably, the Al obtained by the preparation method provided by the present invention 18 The shelf life of the PSMA radiopharmaceutical labeled with F is within 8 hours from the end of synthesis, wherein the end of synthesis refers to the end of the radiolabeling reaction, i.e., the AlF-labeled PSMA radiopharmaceutical obtained by the preparation method provided by the present invention. 18 The shelf life of the F-labeled PSMA radiopharmaceutical is preferably within 8 hours from the end of the radiolabeling reaction.

[0049] In some specific embodiments, the Al obtained by the preparation method provided by the present invention 18 The batch formulation composition of F-labeled PSMA radiopharmaceutical (based on 22 ml) is shown below. It can be understood that the batch volume can be adjusted according to actual conditions (exemplary examples are 10 ml, 15 ml, 20 ml, 25 ml, etc.), and the components and their proportions will not change with changes in the batch volume.

[0050] Table 2 Al 18 Batch formulation composition of F-labeled PSMA radiopharmaceuticals

[0051] In another aspect, the present invention also provides a method for fluorinating the PSMA radiopharmaceutical intermediate described above or the Al 18 The use of the preparation method of F-labeled PSMA radiopharmaceuticals in the preparation of PSMA-type drugs, wherein the PSMA-type drugs specifically refer to drugs with PSMA (Prostate Specific Membrane Antigen) as a specific target, including but not limited to macromolecular drugs, polypeptide drugs (such as those composed of ≥15 or more amino acids), short peptide drugs (such as those composed of less than 15 amino acids), small molecule drugs, or a combination thereof targeting PSMA.

[0052] In another aspect, the present invention also provides a method for fluorinating the PSMA radiopharmaceutical intermediate described above or the Al 18 Preparation method of F-labeled PSMA radiopharmaceuticals 18 Application of F-labeled PSMA radiopharmaceuticals.

[0053] Furthermore, the Al 18 F-labeled PSMA radiopharmaceuticals are Al 18 F-labeled PSMA radiopharmaceutical injection.

[0054] Furthermore, the Al 18 The specification of F-labeled PSMA radiopharmaceutical injection solution is 37-1850 MBq / ml (i.e. 1.0-50.0 mCi / ml).

[0055] Further, the Al obtained by the fluorination method provided by the present invention 18 The shelf life of the F-labeled PSMA radiopharmaceutical is preferably within 8 hours from the end of the radiolabeling reaction.

[0056] In another aspect, the present invention also provides a method for fluorinating the PSMA radiopharmaceutical intermediate described above or the Al 18 The invention discloses a method for preparing a F-labeled PSMA radiopharmaceutical and its application in preparing an imaging drug for diagnosing prostate cancer patients.

[0057] In another aspect, the present invention also provides a method for fluorinating the PSMA radiopharmaceutical intermediate described above or the Al 18 The invention discloses a method for preparing F-labeled PSMA radiopharmaceuticals and their application in preparing imaging drugs for diagnosing prostate specific membrane antigen (PSMA) positive lesions in prostate cancer patients.

[0058] Furthermore, the aforementioned prostate cancer patients are prostate cancer patients suspected of having metastatic lesions after the initial radical treatment or prostate cancer patients with elevated serum prostate-specific antigen (PSA) levels and suspected biochemical recurrence.

[0059] In another aspect, the present invention also provides an Al 18 F-labeled PSMA radiopharmaceutical, the Al 18 The F-labeled PSMA radiopharmaceutical was prepared using the Al 18 The preparation method of F-labeled PSMA radiopharmaceuticals or the fluorination method of the above-mentioned PSMA radiopharmaceutical intermediates can be used to obtain the radiopharmaceutical.

[0060] Furthermore, the Al 18 The F-labeled PSMA radiopharmaceutical is available as an injectable solution.

[0061] Furthermore, the Al 18 The specification of F-labeled PSMA radiopharmaceutical injection solution is 37-1850 MBq / ml (i.e. 1.0-50.0 mCi / ml).

[0062] Furthermore, the Al 18 The effectiveness of F-labeled PSMA radiopharmaceuticals is preferably within 8 hours from the completion of the radiolabeling reaction.

[0063] In some specific embodiments, the Al provided by the present invention 18 The batch formulation composition of F-labeled PSMA radiopharmaceutical (based on 22 ml) is shown below. It can be understood that the batch volume can be adjusted according to actual conditions (exemplary examples are 10 ml, 15 ml, 20 ml, 25 ml, etc.), and the components and their proportions will not change with changes in the batch volume.

[0064] Table 3 Al 18 Batch formulation composition of F-labeled PSMA radiopharmaceuticals

[0065] In another aspect, the present invention also provides the Al 18 Use of F-labeled PSMA radiopharmaceuticals in the preparation of imaging drugs for diagnosing prostate cancer patients.

[0066] In another aspect, the present invention also provides the Al 18 Application of F-labeled PSMA radiopharmaceuticals in the preparation of imaging drugs for diagnosing prostate-specific membrane antigen (PSMA)-positive lesions in prostate cancer patients.

[0067] Furthermore, the aforementioned prostate cancer patients are prostate cancer patients suspected of having metastatic lesions after the initial radical treatment or prostate cancer patients with elevated serum prostate-specific antigen (PSA) levels and suspected biochemical recurrence.

[0068] In some specific embodiments, the PSMA radiopharmaceutical intermediate described above is PSMA-BCH, and its structure is shown in formula (I):

[0069] In some specific embodiments, the Al 18 F-labeled PSMA radiopharmaceuticals are Al 18 F-PSMA-BCH, whose structure is shown in formula (II):

[0070] In summary, the fluorination method of the PSMA radiopharmaceutical intermediate provided by the present invention adjusts the reaction system, while ensuring the labeling time, the radiochemical purity of the final product, the radiochemical conversion rate and the product yield, and effectively reduces the requirement for the fluorination reaction temperature during the labeling process. 18The preparation method of F-labeled PSMA radiopharmaceuticals has good applicability, a thorough reaction, and the final product does not introduce new impurities due to the reduction of reaction temperature or the adjustment of the reaction system. The preparation method can further reduce and control the types and contents of impurities in the final product, further ensuring the safety of medication for patients. In addition, the final product obtained by the fluorination method or preparation method provided by the present invention has good batch uniformity and good stability under storage conditions of 30°C ± 2°C and 40°C ± 2°C. DETAILED DESCRIPTION

[0071] Unless otherwise defined, the technical and scientific terms in this specification have the same meaning as those generally understood by those skilled in the art. Although similar or identical methods and materials as described herein may be used in experiments or practical applications, materials and methods are described herein below. In the event of a conflict, the present specification including the definitions therein shall prevail. In addition, materials, methods and examples are provided for illustration only and are not restrictive. The present application is further described below in conjunction with specific embodiments, but is not intended to limit the scope of the present application.

[0072] Unless the context requires otherwise, throughout the specification and the following claims, the word "comprise" and its variations such as "comprising", "containing" will be understood as implicitly including the integers or steps, or groups of integers or steps, but not excluding any other integers or steps, or groups of integers or steps. In the following paragraphs, the same aspects of the invention will be defined in more detail. Each aspect so defined can be combined with any other one or more aspects unless there is a clear indication to the contrary. In particular, any feature described as optional, preferred or advantageous can be combined with any other one or more features described as optional, preferred or advantageous.

[0073] The "appropriate amount" involved in the present invention refers to the required amount, temperature, volume, time and other amounts or conditions that are suitable and can meet the requirements of the reaction. Those skilled in the art can make reasonable judgments and choices based on the actual working environment, specific needs and conditions to achieve practical effects. Therefore, the "appropriate amount" described in the present invention is based on conditions that can meet the requirements of the reaction. The relevant conditions are understandable and known to those skilled in the art, and the relevant conditions should not be regarded as limitations on the present invention.

[0074] The embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention.

[0075] Example 1 Fluorination reaction of PSMA-BCH

[0076] In this embodiment, the following fluorination reaction process was designed: 111.2 μl of aluminum chloride hexahydrate solution (0.277 mg / ml, 0.128 nmol), 400 μl of anhydrous ethanol and 40 μl of acetic acid-sodium acetate buffer (pH=4) containing PSMA-BCH (5 mg / ml, 0.212 nmol) were added to a fluorine-containing 18 F] ion solution in a reaction bottle. Referring to the above process, this example explored the temperature of the fluorination reaction, selected three time points of 90°C, 110°C and 120°C, and investigated the reaction temperature and reaction time, as shown in Table 4.

[0077] Table 4 Exploration of fluorination reaction temperature

[0078] From the results, it can be seen that when the reaction temperature is 110°C and the reaction time is 15 minutes, the reaction yield is 8.1% and the total amount of impurities is 0.53 μg / ml (see Table 4 Batch YT-110). When the reaction temperature is lowered (such as lowered to 90°C, see Table 4 Batch YT-090), if a certain yield needs to be maintained, the reaction time needs to be delayed accordingly (such as the delayed reaction time is 20 minutes), which obviously increases the overall reaction time, which is for 18 F molecular probe production is not applicable. When the reaction temperature is only increased by 10°C in order to shorten the reaction time (such as reducing the reaction time to 5 minutes, see Table 4 Batch YT-120), the impurity content of the reaction increases significantly, which will obviously increase the subsequent purification process and difficulty of the drug and reduce the quality of the drug preparation. In addition, the above reaction system uses anhydrous ethanol, which will cause the vaporization of ethanol at a high temperature of 110°C, resulting in the inability of anhydrous ethanol to play an actual protective role.

[0079] For the above reasons, the present embodiment is based on the premise of keeping the reaction time unchanged, in line with the purpose of reducing the reaction temperature, the factors such as reaction feed ratio, buffer system are studied and adjusted again, such as adjusting the aluminum chlorohydrate / PSMA-BCH feed ratio (changed from the previous 0.6: 1 to 0.75: 1), using potassium hydrogen phthalate buffer system instead of acetate buffer system (PH remains unchanged, PH=4), the reaction temperature is reduced to 75 ° C, and the reaction parameters and results after adjustment are shown in Table 5 batches of YT-075. From the results, it can be seen that, while keeping the reaction time unchanged, seeking the demand for lower reaction temperature, after adjusting the feed ratio and buffer solution type of aluminum chlorohydrate / PSMA-BCH, the reaction can obtain a higher radiochemical conversion rate (42.3%). Based on the adjusted parameters, the present embodiment has been found to the yield of the reaction after studying again, and the adjusted process can not only obtain an ideal radiochemical conversion rate, but also its yield is significantly increased to 20.7% (see Table 5 batches of YT-075-1).

[0080] This example also explores the effects of the original buffer system and the current buffer system on the reaction. Based on the above adjusted parameters, the buffer system is readjusted from the potassium hydrogen phthalate buffer system (PH = 4) to the acetic acid-sodium acetate buffer (PH = 4). However, the results show that the reaction yield after readjustment to the acetic acid-sodium acetate buffer (PH = 4) is significantly reduced to only 9.6% (see Table 5 Batch YT-075-2), which indicates that the potassium hydrogen phthalate buffer system (PH = 4) has a great influence on the reaction.

[0081] In order to further improve the yield of the reaction, the temperature of the fluorination reaction was explored in this example. The reaction temperature was adjusted to 85°C and the reaction time was maintained at 15 min. Since the boiling point of anhydrous ethanol is 78°C, it is still easy to gasify in the reaction system. Therefore, the anhydrous ethanol in the reaction system was adjusted to dimethyl sulfoxide. The reaction process after adjustment was as follows: 50 μl of 0.5 M potassium hydrogen phthalate solution containing aluminum chloride hexahydrate (0.77 mg / ml, 0.16 nmol), 400 μl of dimethyl sulfoxide solution containing PSMA-BCH (0.5 mg / ml, 0.212 nmol) and 50 μl of 0.5 M potassium hydrogen phthalate solution were added to a fluorine-containing solution. 18 F] ion solution in a reaction bottle at 85°C for 15 minutes. The adjusted reaction yield was significantly increased to 29.7%, and the radiochemical purity was 99.3% (see Table 5 Batch YT-085).

[0082] Table 5 Exploration of fluorination reaction conditions

[0083] Note: Radiochemical conversion rate refers to fluorine [18 The conversion efficiency of the [F] ion in the reaction process was obtained by sampling the radioactively labeled reaction solution and injecting it into HPLC for analysis. 18 The ratio of the peak area of ​​F-PSMA-BCH to the sum of the peak areas was used as the calculation formula.

[0084] Based on the repeated feeding under the above reaction conditions, the yield and radiochemical purity remained consistent (26.1% and 99.4%, respectively, see Table 5 Batch YT-085-1), which shows that the fluorination method provided by the present invention has good batch stability and is suitable for production promotion.

[0085] Embodiment 2 A1 18 Preparation of F-PSMA-BCH drug

[0086] (1) Fluorine 18 Preparation and transport of [F] ions

[0087] The F-18 target was loaded with heavy oxygen ( 18 O) water, set the bombardment beam current (30-100 μA) and bombardment time (20-120 minutes). Start the accelerator program sequence and bombard the heavy oxygen ( 18 O) Water, through the occurrence 18 O(p,n) 18 F nuclear reaction produces fluorine [ 18 F] ions, after the bombardment, will contain fluorine [ 18 F] ion heavy oxygen ( 18 O) Water transfer to fluorine [ 18 F] ion V-shaped bottle, and then purged with helium gas [ 18 F] ion transfer pipeline, and turn off the accelerator after completion.

[0088] Dissolve in heavy oxygen ( 18 O) Fluoride in water 18 F] Ions flow from the V-shaped vial into a conical tube on the synthesizer (ORA, Neptisperform) cartridge.

[0089] (2) Fluorine 18 F] ion capture

[0090] Pre-activate the QMA ion exchange column (Cat. No. 186004540, specification 46 mg, filler manufacturer Waters Sep-Pak) with 30 ml of sterile injection water. 18 O) Fluoride in water 18The fluoride [F] ions were adsorbed onto the pre-activated QMA ion exchange column. After the QMA ion exchange column was washed with 20 ml of sterile injection water, a mixed solution of 300 μl of sodium chloride injection and 15 μl of sodium vitamin C aqueous solution (100 mg / ml) was used to adsorb the fluoride [ 18 F] ions were eluted from the QMA ion exchange column into the reaction vial.

[0091] (3) Radiolabeling of PSMA-BCH

[0092] 50 μl of 0.5 M potassium hydrogen phthalate solution containing aluminum chloride hexahydrate (0.77 mg / ml, 0.16 nmol), 400 μl of dimethyl sulfoxide solution containing PSMA-BCH (0.5 mg / ml, 0.212 nmol) and 50 μl of 0.5 M potassium hydrogen phthalate solution were added to a solution containing fluorine [ 18 F] ion solution in a reaction bottle at 85°C for 15 minutes. After the reaction is complete, the reaction mixture is cooled to 50°C to obtain Al 18 F-PSMA-BCH crude mixture.

[0093] (4) Al 18 Purification of crude F-PSMA-BCH

[0094] (a) HPLC purification

[0095] The Al in the reaction bottle 18 The crude F-PSMA-BCH mixture was diluted with the mobile phase in the table below, and then separated and purified using the chromatographic conditions in the table below. A radioactive detector was used to detect online and collect the radioactive substances containing Al 18 The component peak of F-PSMA-BCH was then diluted with about 50 ml of sterile injection water to collect Al 18 HPLC purified fractions of F-PSMA-BCH.

[0096] Table 6 HPLC purification parameters

[0097] (b) HLB column purification

[0098] The HLB column (Cat. No.: 186000132, specification 225 mg, manufacturer: Waters Corporation) was activated with 10 ml of anhydrous ethanol and 30 ml of sterile water for injection. 18 F-PSMA-BCH is adsorbed on the HLB column. After adsorption, the impurities adsorbed on the HLB column are washed with 20 ml of sterile injection water within 45 seconds, and then the residual liquid on the HLB column is removed within 10 seconds by purging with nitrogen at a negative pressure of -0.3 bar.

[0099] Then, 2 ml of 80% ethanol was used to 18 F-PSMA-BCH was eluted from the HLB column to obtain Al 18 F-PSMA-BCH pure solution.

[0100] ( 5)Al 18 Preparation of F-PSMA-BCH drug

[0101] The collected Al 18 The pure F-PSMA-BCH solution was diluted with 20 ml of sodium chloride injection solution. Under nitrogen pressure, it was sterilized and filtered through a 0.22 μm liquid filter, entered the product bottle, and aseptically dispensed into multiple sealed 10 ml sterile bottles to obtain Al 18 F-PSMA-BCH preparation (i.e. Al 18 F-PSMA-BCH injection), and the radioactivity content of each bottle was measured by activity meter.

[0102] Al 18 The specification of F-PSMA-BCH injection is 37-1850 MBq / ml (1.0-50.0 mCi / mL), and its validity period is preferably within 8 hours from the end of the radiolabeling reaction. The detailed batch prescription is shown in Table 7.

[0103] Table 7 Al 18 Composition of F-PSMA-BCH injection batch formula (22ml)

[0104] According to the above method, different batches of Al 18 Preparation of F-PSMA-BCH injection solution, its radiochemical purity is shown in Table 8.

[0105] Table 8 Three batches of Al 18 Radiochemical purity of F-PSMA-BCH injection

[0106] Embodiment 3 A1 18 Study on Impurities of F-PSMA-BCH Injection

[0107] Al 18 The active ingredient of F-PSMA-BCH injection is Al 18 F-PSMA-BCH,Al 18 The production process of F-PSMA-BCH mainly includes fluorine [ 18 F] production, Al 18The steps of F-PSMA-BCH synthesis, elution, dilution, sterilization filtration, etc., combined with the raw materials used in production, were used to evaluate the impurities that may be introduced or generated, as shown in Table 9.

[0108] Table 9 Al 18 Evaluation of Impurities in F-PSMA-BCH Injection

[0109] After evaluation, the Al obtained by the preparation method provided by the present invention 18 No mutagenic impurities were found in F-PSMA-BCH injection. The known impurities mainly included fluorine [ 19 F]PSMA-BCH, potassium hydrogen phthalate, sodium ascorbyl palmitate, residual solvents (acetonitrile, acetic acid and dimethyl sulfoxide). The detection method of residual acetonitrile refers to the third method of Part IV General Rules 0861 of the 2020 edition of the Chinese Pharmacopoeia. The detection methods of other impurities are as follows.

[0110] (1) Impurity fluorine 19 F] PSMA-BCH detection method

[0111] Test solution: Fluorine [ 18 F] PSMA-BCH injection

[0112] Reference stock solution: Take fluorine [ 19 [F] About 5 mg of PSMA-BCH reference substance is accurately weighed and placed in a 250 ml volumetric flask. Add appropriate amount of water to dissolve it, dilute it to the scale with water, and shake well to obtain it.

[0113] Al 18 F-PSMA-BCH stock solution: take Al 18 About 2 mg of F-PSMA-BCH reference substance is accurately weighed and placed in a 100 ml volumetric flask. An appropriate amount of water is added to dissolve it. Dilute it to the scale with water and shake well.

[0114] Separation solution: Accurately measure 5 ml of reference stock solution and Al 18 Place 2 ml of F-PSMA-BCH stock solution in a 20 ml volumetric flask, dilute to the mark with water, and shake well to obtain.

[0115] Reference substance solution: Accurately measure 5 ml of reference substance stock solution, place in a 20 ml volumetric flask, dilute to the mark with water, shake well, and obtain.

[0116] Chromatographic column: Octadecylsilane bonded silica as filler (such as Agilent Eclipse Plus C18 column, 250×4.6mm, 5μm)

[0117] Mobile phase A: 20 mM sodium acetate solution

[0118] Mobile phase B: acetonitrile

[0119] Flow rate: 1.0ml / min

[0120] Detection wavelength: 220nm

[0121] Injection volume: 20 μl

[0122] Table 10 Gradient elution program

[0123] After the chromatographic system is stable, inject the sample according to the following procedure:

[0124] (1) Blank solution, 1 injection

[0125] (2) Separation solution, 1 needle

[0126] (3) Reference solution, 3 injections

[0127] (4) Test solution, 1 injection. If there is a 60-minute interval between the last injection of reference solution, inject 1 injection of blank solution before starting the analysis of the test solution.

[0128] System suitability requirements:

[0129] (1) The chromatogram of the blank solution has no peaks or only unclear peaks within 20 minutes.

[0130] (2) Separation degree In the solution chromatogram, fluorine [ 19 F]PSMA-BCH and Al 18 The separation between F-PSMA-BCH should be ≥1.5.

[0131] (3) 3 consecutive injections of fluoride 19 The peak area RSD of the [F]PSMA-BCH reference solution was ≤5%.

[0132] Calculation results:

[0133]

[0134] Where:

[0135] C(X) is the fluorine content in the test solution. 19 F]PSMA-BCH concentration (μg / ml);

[0136] PA(X) is the fluorine content in the test solution. 19 F] peak area of ​​PSMA-BCH;

[0137] C (standard) is the fluorine content in the reference solution [ 19F]PSMA-BCH concentration (the concentration of the reference solution should be based on the fluorine [ 19 F] The actual purity value of PSMA-BCH reference substance was corrected);

[0138] PA (standard) is the fluorine content in the reference solution [ 19 F] Average peak area of ​​PSMA-BCH.

[0139] The standard stipulates: no more than 5.00µg / ml.

[0140] (2) Detection method of residual dimethyl sulfoxide

[0141] Instruments: Gas chromatograph, electronic balance

[0142] Reagent: Dimethyl sulfoxide

[0143] Test solution: Fluorine [ 18 F] PSMA-BCH injection

[0144] Reference solution: Weigh about 20 mg of dimethyl sulfoxide into a 50 ml volumetric flask, dilute to the mark with water, and shake well.

[0145] Chromatographic column: capillary column with 6% cyanopropylphenyl-94% dimethylpolysiloxane as stationary phase (such as DB-624 column, 0.32mm×30m, 1.8μm)

[0146] Carrier gas: Helium

[0147] Flow rate: 2ml / min

[0148] Column temperature: start at 40°C, maintain for 5 minutes, increase the temperature to 200°C at a rate of 20°C per minute, maintain for 3 minutes

[0149] Injector temperature: 200°C

[0150] Split ratio: 1:30

[0151] Detector Type: Flame Ionization Detector (FID)

[0152] Detector temperature: 250°C

[0153] Injection volume: 1 μl

[0154] Determination: Take samples of the reference solution and the test solution respectively, record the chromatogram, and calculate the residual amount of dimethyl sulfoxide by the peak area according to the external standard method.

[0155] (3) Detection method for residual potassium hydrogen phthalate and sodium vitamin C

[0156] Instruments: High performance liquid chromatograph, electronic balance

[0157] Reagents: Sodium vitamin C, potassium hydrogen phthalate, acetonitrile, trifluoroacetic acid

[0158] Blank solution: water

[0159] Test solution: Fluorine [ 18 F] PSMA-BCH injection

[0160] Vitamin C sodium stock solution: Weigh about 50 mg of vitamin C sodium, place in a 10 ml volumetric flask, dilute to the scale with water, and shake well.

[0161] Potassium hydrogen phthalate stock solution: Weigh about 50 mg of potassium hydrogen phthalate, place in a 10 ml volumetric flask, dilute to the mark with water, and shake well.

[0162] Reference substance mixed solution: Take 50 μl of sodium vitamin C stock solution, 50 μl of potassium hydrogen phthalate stock solution and 900 μl of water and mix well.

[0163] Chromatographic column: Shim-pack GIST C18-AQ (250mm×4.6mm, 5μm)

[0164] Mobile phase: water-acetonitrile-trifluoroacetic acid (900:100:2)

[0165] Flow rate: 0.6ml / min

[0166] Detection wavelength: 244nm

[0167] Injection volume: 5ml

[0168] Isocratic elution time: 45 min.

[0169] Column temperature: 30°C

[0170] After the chromatographic system is stable, inject the sample according to the following procedure:

[0171] (1) Blank solution, 1 injection

[0172] (2) Reference substance mixed solution, 3 injections

[0173] (3) Blank solution, 1 injection

[0174] (4) Test solution, 1 injection

[0175] System suitability requirements:

[0176] (1) The chromatogram of the blank solution has no obvious peaks.

[0177] (2) For the reference sample mixed solution, the RSD of the peak area of ​​sodium ascorbyl palmitate is ≤5%, and the RSD of the peak area of ​​potassium hydrogen phthalate is ≤5%.

[0178] Calculation results:

[0179] The contents of sodium vitamin C and potassium hydrogen phthalate in the test sample were calculated using the peak area according to the external standard method.

[0180] (4) Detection method of residual acetic acid

[0181] Instruments: High performance liquid chromatograph, electronic balance

[0182] Reagents: sodium acetate, acetonitrile

[0183] Blank solution: water

[0184] Test solution: Al 18 F-PSMA-BCH Injection

[0185] Glacial acetic acid stock solution: Take 500μl of glacial acetic acid, place it in a 10ml volumetric flask, dilute it to the scale with water, shake well, and you have it.

[0186] Glacial acetic acid reference solution: Mix 200 μl of glacial acetic acid stock solution and 800 μl of water.

[0187] Chromatographic column: Octadecylsilane bonded silica as filler (such as Agilent Eclipse Plus C18, 250×4.6mm, 5μm)

[0188] Mobile phase A: 20 mM sodium acetate solution

[0189] Mobile phase B: acetonitrile

[0190] Flow rate: 1.0ml / min

[0191] Detection wavelength: 220nm

[0192] Injection volume: 20 μl

[0193] Table 11 Gradient elution program

[0194] Determination: Take samples of the reference solution and the test solution respectively, record the chromatogram, and calculate the residual acetic acid by the peak area according to the external standard method.

[0195] This example evaluates the impurities in three batches of samples, and the results are as follows:

[0196] fluorine[ 19 The results of the impurity content test of F]PSMA-BCH are shown in Table 12. The results show that the impurity content of each batch of fluorine [ 19 The content of F]PSMA-BCH was no more than 5.00 μg / ml, and the difference was not large. During the stability process, the fluorine content of these samples was19 The content of F]PSMA-BCH remained basically unchanged.

[0197] Table 12 Fluorine content in three batches of samples 19 F]PSMA-BCH impurity content (µg / ml)

[0198] The test results of potassium hydrogen phthalate and sodium vitamin C are shown in Table 13. The results show that potassium hydrogen phthalate and sodium vitamin C were not detected in any batch (the detection limit of sodium vitamin C was 0.01 μg / ml, and the detection limit of potassium hydrogen phthalate was 0.10 μg / ml), indicating that in Al 18 F-PSMA-BCH can be effectively removed during the purification process.

[0199] Table 13 Test results of potassium hydrogen phthalate and sodium vitamin C in three batches of samples Note: “ND” stands for Not detected.

[0200] The test results of residual solvents (acetonitrile, acetic acid and dimethyl sulfoxide) are shown in Table 14. ICH Q3C stipulates that acetonitrile belongs to the second category of solvents with a limit of ≤410ppm, and acetic acid and dimethyl sulfoxide belong to the third category of solvents with a limit of ≤5000ppm. The results in Table 14 show that acetic acid and dimethyl sulfoxide were not detected in any batch (the detection limit of acetic acid was 52.07μg / ml, and the detection limit of dimethyl sulfoxide was 1.03μg / ml), indicating that they were present in Al 18 F-PSMA-BCH can be effectively removed during the purification process; the residual amount of acetonitrile is also far less than the required limit.

[0201] Table 14 Detection results of residual solvents (acetonitrile, acetic acid and dimethyl sulfoxide) in three batches of samples

[0202] Note: “ND” stands for Not detected.

[0203] In summary, it can be seen that the preparation method provided by the present invention, although the temperature of the fluorination reaction is reduced, the reaction is thorough and no new impurities are generated. In addition, although the preparation method provided by the present invention introduces a new solution system compared to the prior art, the system can effectively reduce or control the impurity residues in the final product, further ensuring the safety of drug application.

[0204] Example 4 Preparation Stability Study

[0205] For Al18 The long-term stability and accelerated stability of F-PSMA-BCH injection samples were studied, as shown in Table 15. The properties, pH, fluorine, and other characteristics of each batch of samples were investigated. 19 F] PSMA-BCH content, fluorine [ 19 F] PSMA-BCH and other chemical impurities, total content, bacterial endotoxin, sterility, radiochemical purity, radioactivity concentration and other indicators.

[0206] Table 15 Stability evaluation indicators

[0207] (1) Property (appearance) inspection method

[0208] Detection method: visual inspection.

[0209] This product should be a colorless, clear liquid.

[0210] (2) pH investigation method

[0211] Use pH test paper that meets the suitability requirements and place it in the surface dish of the protective box for later use. The operator stands in front of the lead glass of the protective box, takes 2μl of the sample to be tested, and drops it on the wide range pH test paper (4-10). Observe through the lead glass, compare the color on the test paper with the standard color plate, and read the pH value range of the sample to be tested. Take another 2μl of the sample to be tested and drop it on the precision pH test paper of the corresponding range. Observe through the lead glass, compare the color on the test paper with the standard color plate, and read the pH value of the sample to be tested.

[0212] The pH of this product should be 4.5-8.0.

[0213] (3) Impurity fluorine 19 F] PSMA-BCH content investigation method

[0214] The investigation method is shown in Example 3 (1) Impurity fluorine [ 19 F] PSMA-BCH detection method

[0215] The standard stipulates: no more than 5.00µg / ml.

[0216] (4) Impurity fluorine [ 19 F] Total content of PSMA-BCH and other chemical impurities

[0217] Instruments, reagents, solution preparation, chromatographic conditions, detection process, system suitability requirements: all the same as those in Example 3 (1) Impurity fluorine [ 19 F] Detection method of PSMA-BCH.

[0218] Calculation results:

[0219]

[0220]

[0221] Where: C(X) is the fluorine content in the test solution 19 F] PSMA-BCH concentration or chemical impurity concentration (μg / ml);

[0222] PA(X) is the fluorine content in the test solution. 19 F] peak area of ​​PSMA-BCH or peak area of ​​chemical impurities;

[0223] C (standard) is the fluorine content in the reference solution [ 19 F]PSMA-BCH concentration (the concentration of the reference solution should be based on the fluorine [ 19 F] The actual purity value of PSMA-BCH reference substance was corrected);

[0224] PA (standard) is the fluorine content in the reference solution [ 19 F] Average peak area of ​​PSMA-BCH.

[0225] The standard stipulates: no more than 10.00µg / ml.

[0226] (5) Radiochemical purity

[0227] Test solution: Al 18 F-PSMA-BCH injection.

[0228] Chromatographic conditions:

[0229] Chromatographic column: Octadecylsilane bonded silica as filler (such as Agilent Eclipse Plus C18 column, 250×4.6mm, 5μm)

[0230] Mobile phase A: 20 mM sodium acetate solution

[0231] Mobile phase B: acetonitrile

[0232] Flow rate: 1.0ml / min

[0233] Detector: Radioactivity detector

[0234] Injection volume: 20-100 μl (For determination of radiochemical purity (RCP), the injection volume of the test solution may need to be adjusted based on batches with low and / or high radioactivity concentrations to obtain a radioactivity concentration that is suitable for the detection range of the radioactivity detector).

[0235] Table 16 Gradient elution program

[0236] The standard stipulates that the purity of the main peak calculated by the area normalization method should be no less than 90.0%.

[0237] (6) Other project inspection methods

[0238] For the bacterial endotoxin test method, please refer to 1143 Method 1 Gel Method in the General Rules of Part IV of the 2020 Edition of the "Chinese Pharmacopoeia"; for the sterility test method, please refer to 1101 Sterility Test of Test Articles 2 Direct Inoculation Method in the General Rules of Part IV of the 2020 Edition of the "Chinese Pharmacopoeia"; for radioactivity concentration, please refer to 1401 General Rules of Part IV of the 2020 Edition of the "Chinese Pharmacopoeia".

[0239] In this example, three batches of Al 18 Long-term stability and accelerated stability studies were conducted on F-PSMA-BCH injection samples, and the results are shown in Tables 17-22, respectively.

[0240] Table 17 Accelerated test results of batch YT-085-A (batch: 409mCi)

[0241] Table 18 Accelerated test results of batch YT-085-B (batch: 101mCi)

[0242] Table 19 Accelerated test results of batch YT-085-C (batch: 411mCi)

[0243] Table 20 Long-term test results of batch YT-085-A (batch: 409mCi)

[0244] Table 21 Long-term test results of batch YT-085-B (batch: 101mCi)

[0245] Table 22 Long-term test results of batch YT-085-C (batch: 411mCi)

[0246] After 8 hours of long-term test and accelerated test, each batch of Al 18 All indicators of F-PSMA-BCH injection meet the quality standards, indicating that the Al 18 F-PSMA-BCH injection has good stability under storage conditions of 30℃±2℃ and 40℃±2℃. 18The data change trends of F-PSMA-BCH injection at various time points are basically consistent, and the batch-to-batch uniformity of the product is good, which indicates that the preparation method provided by the present invention also has good stability.

[0247] The above description is only a preferred embodiment, which is only used as an example and does not limit the combination of features necessary to implement the present invention. The titles provided are not intended to limit the various embodiments of the present invention. Terms such as "comprising", "including" and "including" are not intended to be limiting. In addition, unless otherwise specified, plural forms are included when there is no numeral modification, and "or" means "and / or". Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art.

[0248] All disclosures and patents mentioned in this application are incorporated herein by reference. Without departing from the scope and spirit of the present invention, multiple modifications and variants of the described method and composition of the present invention are apparent to those skilled in the art. Although the present invention has been described by specific preferred embodiments, it should be understood that the claimed invention should not be unduly limited to these specific embodiments. In fact, those multiple variants of the described mode for implementing the present invention that are apparent to those skilled in the relevant art are intended to be included in the scope of the appended claims.

Claims

1. Al of a PSMA radiopharmaceutical intermediate 18 F fluorination method, characterized in that The structure of the PSMA radiopharmaceutical intermediate is shown in formula (I): （I）， The fluorination method comprises the following steps: adding a potassium hydrogen phthalate solution containing aluminum chloride hexahydrate, a dimethyl sulfoxide solution containing a PSMA radiopharmaceutical intermediate, and a potassium hydrogen phthalate solution to a fluorine-containing 18 The reaction was carried out in a reaction bottle of the F] ion solution at a temperature of 75-85°C and a reaction time of 15 minutes.

2. The fluorination method according to claim 1, characterized in that The molar ratio of aluminum chloride hexahydrate to PSMA radioactive drug intermediate is 0.7-0.8:

1.

3. The fluorination method according to claim 1, characterized in that In the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate, the concentration of aluminum chloride hexahydrate is 0.6-0.9 mg / ml.

4. The fluorination method according to claim 1, characterized in that In the dimethyl sulfoxide solution containing the PSMA radioactive drug intermediate, the concentration of the PSMA radioactive drug intermediate is 0.4-0.6 mg / ml.

5. The fluorination method according to claim 1, characterized in that The concentration of the potassium hydrogen phthalate solution is 0.1-1M.

6. The fluorination method according to claim 1, characterized in that The volume ratio of the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate to the dimethyl sulfoxide solution containing the PSMA radioactive drug intermediate is 1:5-10.

7. The fluorination method according to claim 1, characterized in that The volume ratio of the dimethyl sulfoxide solution containing the PSMA radioactive drug intermediate to the potassium hydrogen phthalate solution is 5-10:

1.

8. Aluminum 18 The method for preparing a F-labeled PSMA radiopharmaceutical is characterized in that: The preparation method comprises the fluorination method of the PSMA radiopharmaceutical intermediate according to any one of claims 1 to 7.

9. The fluorination method according to any one of claims 1 to 7 or the preparation method according to claim 8 in the preparation of Al 18 Application of F-labeled PSMA radiopharmaceuticals.

10. Use of the fluorination method according to any one of claims 1 to 7 or the preparation method according to claim 8 in the preparation of an imaging drug for diagnosing prostate cancer patients or an imaging drug for diagnosing prostate-specific membrane antigen-positive lesions in prostate cancer patients.

11. Aluminum 18 The F-labeled PSMA radiopharmaceutical is characterized by: The Al 18 The F-labeled PSMA radiopharmaceutical is obtained by the fluorination method according to any one of claims 1 to 7 or the preparation method according to claim 8.

12. The radiopharmaceutical according to claim 11, characterized in that The radioactive drug is Al 18 F-labeled PSMA radiopharmaceutical injection.

13. The radiopharmaceutical according to claim 12, characterized in that The Al 18 The specifications of F-labeled PSMA radiopharmaceutical injection are 37-1850MBq / ml.

14. The Al according to any one of claims 11 to 13 18 The invention relates to the use of F-labeled PSMA radioactive drugs in the preparation of imaging drugs for diagnosing prostate cancer patients or imaging drugs for diagnosing prostate-specific membrane antigen-positive lesions in prostate cancer patients.

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