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

Abstract

The invention provides a fluorination method of a PSMA radiopharmaceutical intermediate, and further provides a preparation method of an Al18F-labeled PSMA radiopharmaceutical preparation based on the fluorination method, and the fluorination method and the preparation method have the advantages that through adjustment of a reaction system, the purity of the PSMA radiopharmaceutical intermediate is improved, and the purity of the PSMA radiopharmaceutical preparation is improved. The preparation method of the PSMA radiopharmaceutical preparation marked by the Al18F has the advantages that marking time efficiency, radiochemical purity of a final product, radiochemical conversion rate and product yield are guaranteed, requirements on fluorination reaction temperature in a marking process are effectively lowered, and the preparation method of the PSMA radiopharmaceutical preparation marked by the Al18F based on the fluorination method is good in applicability, thorough in reaction and high in yield. New impurities are not introduced into the final product due to reduction of the reaction temperature or adjustment of a reaction system, and the preparation method can further reduce and control the variety and content of the impurities in the final product, so that the medication safety of patients is further ensured. In addition, the final product preparation product obtained by the fluorination method or 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] This invention relates to the field of radiopharmaceuticals, and more particularly to an Al 18 F-labeled PSMA radiopharmaceuticals, their preparation methods, and applications. Background Technology

[0002] With the increasing aging of the population, prostate cancer has become the sixth most common malignant tumor among men in my country. Early and accurate detection of prostate cancer has become a pressing clinical challenge. Nuclear medicine imaging, which provides non-invasive, visual, qualitative / quantitative monitoring at the molecular and cellular levels, and participates in the physiological and pathological processes of tumor development, has become an important tool for clinical tumor detection. PSMA (Prostate Specific Membrane Antigen) is a specific target highly expressed in prostate cancer cells, exhibiting high expression in advanced prostate cancer and also showing specific high expression in cells of metastatic prostate cancer lesions. Furthermore, its expression level is significantly correlated with tumor differentiation, metastatic tendency, and sensitivity to hormone therapy. Currently, specific prostate cancer molecular probes targeting PSMA have become a major research focus.

[0003] PSMA-BCH is a compound composed of glutamic acid, lysine, and naphthylalanine with PSMA-targeting function, and it shows promising 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. J Nucl Med. 2019 Sep;60(9):1284-1292.]. Currently, diagnostic probes targeting PSMA compounds mainly use... 68 Ga and 18 The F-mark is dominant, relative to 68 For Ga (with a half-life of 68 minutes), 18 F (with a half-life of 109.8 minutes) has a longer half-life and a higher positron energy, and 18 F comparable 68Ga showed higher maximum normalized uptake (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 to choose 18 F-labeled molecular probes. 18 Due to the decay characteristics of F radionuclides, to ensure patients receive timely medication, nuclear pharmacy facilities need to produce the probes immediately on the day of administration. Furthermore, to guarantee the drug's timeliness, the entire probe production, preparation, and shipping process generally needs to be controlled within 4 hours, with a 3-4 hour vehicle radius limitation for production and delivery. This imposes strict time constraints on the entire molecular probe production process. Additionally, traditional... 18 The F labeling method also suffers from drawbacks such as long labeling time, high reaction temperature, and low labeling rate, all of which limit its application. 18 Applications 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 was disclosed on page 1285. 18 The F-labeled PSMA-BCH method, which involves adding no vector... 18 F2 salt solution, sodium acetate buffer, and AlCl3 are mixed in sodium acetate buffer to form Al 18After the F complex is formed, PSMA-BCH is added, and the mixture is heated at 110°C for 15 minutes to carry out a fluorination reaction. This method is a manual labeling method, which will inevitably increase the probability of operators coming into contact with radioactive nuclides, thereby causing radiation damage to operators due to unnecessary overexposure. Patent application CN110938041A discloses an Al in lines

[0066] -

[0080] of the specification. 18 An automatic labeling method for F-PSMA-BCH involves first mixing PSMA-BCH, AlCl3, and a pH buffer, and then capturing the... 18 F was added to a fluorination reaction flask containing an aqueous solution of PSMA-BCH, AlCl3, and pH buffer for fluorination at 110°C for 15 minutes. While this method effectively reduces the chance of operator contact with radionuclides, the high fluorination temperature necessitates a high-temperature environment in actual production. Theoretically, this high temperature environment will generate more impurities, complicating subsequent purification. In conclusion, providing a labeling method with low exposure, mild reaction conditions, good labeling efficiency, and low impurity rate remains a pressing challenge in this field. Summary of the Invention

[0005] To address the above problems, this invention provides a fluorination method for PSMA radiopharmaceutical intermediates, and further provides an Al based on this fluorination method. 18 A method for preparing F-labeled PSMA radiopharmaceuticals, through adjustments to the reaction system, effectively reduces the temperature requirements for the fluorination reaction during the labeling process while ensuring the radiochemical purity, radiochemical conversion rate, and product yield of the final product.

[0006] Specifically, this invention provides a method for fluorinating a PSMA radiopharmaceutical intermediate, comprising 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 were simultaneously added to a solution containing fluorine. 18 The reaction is carried out in a reaction flask containing F ion solution at a temperature of approximately 75-85℃ (e.g., 75℃, 76℃, 77℃, 78℃, 79℃, 80℃, 81℃, 82℃, 83℃, 84℃, 85℃) for 15 minutes.

[0007] The PSMA radiopharmaceutical intermediates described in this invention are relative to the labeled PSMA radiopharmaceutical, specifically referring to the unlabeled active structural portions, such as when the labeled PSMA radiopharmaceutical is Al. 18When F-PSMA-BCH is used, the PSMA radiopharmaceutical intermediate specifically refers to the PSMA-BCH structure.

[0008] Preferably, the molar ratio of aluminum chloride hexahydrate to the PSMA radiopharmaceutical intermediate is 0.7-0.8:1 (e.g., 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 aluminum chloride hexahydrate to the PSMA radiopharmaceutical intermediate is 0.73-0.77:1; even more preferably, the molar ratio of aluminum chloride hexahydrate to the PSMA radiopharmaceutical intermediate is 0.75:1.

[0009] Preferably, the reaction temperature in the above fluorination reaction is about 80-85℃ (e.g., 80℃, 81℃, 82℃, 83℃, 84℃, 85℃); more preferably, the reaction temperature in the above fluorination reaction is 85℃.

[0010] Preferably, in the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate described in the above fluorination reaction, the concentration of aluminum chloride hexahydrate is approximately 0.6-0.9 mg / ml (e.g., 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). More preferably, in the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate described in the above fluorination reaction, the concentration of aluminum chloride hexahydrate is approximately 0.7-0.8 mg / ml (e.g., 0.7 mg / ml, 0.85 mg / ml, 0.86 mg / ml, 0.87 mg / ml, 0.88 mg / ml, 0.89 mg / ml, 0.9 mg / ml); even more preferably, in the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate described in the above fluorination reaction, the concentration of aluminum chloride hexahydrate is approximately 0.7-0.8 mg / ml (e.g., 0.75 mg / ml, 0.76 mg / ml, 0.77 mg / ml, 0.78 mg / ml, 0.79 mg / ml, 0.8 mg / ml); and even more preferably, in the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate described in the above fluorination reaction, the concentration of aluminum chloride hexahydrate is approximately 0.75-0.8 mg / ml (e.g., 0.75 mg / ml, 0.76 mg / ml, 0.87 mg / ml, 0.88 mg / ml, 0.89 ... (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 the above fluorination reaction, the concentration of aluminum chloride hexahydrate is 0.77 mg / ml.

[0011] Preferably, in the dimethyl sulfoxide solution containing the PSMA radiopharmaceutical intermediate in the above fluorination reaction, the concentration of the PSMA radiopharmaceutical intermediate is about 0.4-0.6 mg / ml (e.g., 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml); more preferably, in the dimethyl sulfoxide solution containing the PSMA radiopharmaceutical intermediate 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 above fluorination reaction is about 0.1-1M (e.g., 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 above fluorination reaction is about 0.4-0.6M (e.g., 0.4M, 0.5M, 0.6M); and even more preferably, the concentration of the phthalic acid solution in the above fluorination reaction is 0.5M.

[0013] Preferably, the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate (defined by volume V) mentioned in the above fluorination reaction a ) and a dimethyl sulfoxide solution containing a PSMA radiopharmaceutical intermediate (volume defined as V) b The volume ratio of ) is approximately V a V b =1:5-10 (e.g., 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 approximately V. a V b =1:7-9 (e.g., 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 containing the PSMA radiopharmaceutical intermediate in the above fluorination reaction (volume defined as V) b ) and potassium hydrogen phthalate solution (volume defined as V) c The volume ratio of ) is approximately V b V c =5-10:1 (e.g., 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 approximately V b V c =7-9:1 (e.g., 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 (defined by volume V) mentioned in the above fluorination reaction a ), a dimethyl sulfoxide solution containing PSMA radiopharmaceutical intermediates (volume defined as V) b ) and potassium hydrogen phthalate solution (volume defined as V) c The volume ratio of ) is approximately V a V b V c =1:7-9:1 (e.g., 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 above fluorination reaction includes the following steps: adding a potassium hydrogen phthalate solution containing aluminum chloride hexahydrate (the concentration of aluminum chloride hexahydrate 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 potassium hydrogen phthalate solution is 0.5 M) to a solution containing fluorine [ 18 The fluorination reaction was carried out in a reaction flask containing the F] ion solution at a temperature of 85°C for 15 minutes. After the reaction was completed, the reaction mixture was cooled to 50°C to obtain Al. 18 F-PSMA crude radiopharmaceutical solution, containing potassium hydrogen phthalate solution of aluminum chloride hexahydrate (V a ), dimethyl sulfoxide solution containing PSMA radiopharmaceutical intermediate (V b ), potassium hydrogen phthalate solution (V c The volume ratio V a V b V c =1:8:1.

[0017] Furthermore, the present invention also provides an Al 18 A method for preparing F-labeled PSMA radiopharmaceuticals, wherein the preparation method includes the fluorination method of the PSMA radiopharmaceutical intermediate described in any of the above-mentioned methods.

[0018] Furthermore, the Al provided by the present invention 18 The preparation method of F-labeled PSMA radiopharmaceutical includes the following steps: Step 1: Fluorine [ 18Preparation and transport of F ions; Step 2: Fluorine [ 18 Capture of F ions; 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] In this invention, the PSMA radiopharmaceutical intermediate is relative to Al. 18 F-labeled PSMA radiopharmaceutical (i.e., Al) 18 In the context of F-PSMA radiopharmaceuticals, it specifically refers to those that have not been treated by Al 18 The active structural part labeled with F, such as when Al 18 F-labeled PSMA radiopharmaceutical (i.e., Al) 18 The specific structure of F-PSMA radiopharmaceutical is Al 18 In the case of F-PSMA-BCH, the PSMA radiopharmaceutical intermediate specifically refers to the PSMA-BCH structural portion.

[0020] In the above preparation method, step three includes the following steps: adding a potassium hydrogen phthalate solution containing aluminum chloride hexahydrate, a dimethyl sulfoxide solution containing a PSMA radiopharmaceutical intermediate, and the potassium hydrogen phthalate solution to a solution containing fluorine […]. 18 The fluorination reaction is carried out in a reaction flask containing the F ion solution at a temperature of approximately 75-85℃ (e.g., 75℃, 76℃, 77℃, 78℃, 79℃, 80℃, 81℃, 82℃, 83℃, 84℃, 85℃) for 15 minutes. After the reaction is complete, the reaction mixture is cooled to approximately 45-55℃ (45℃, 46℃, 47℃, 48℃, 49℃, 50℃, 51℃, 52℃, 53℃, 54℃, 55℃) to obtain Al. 18 F-PSMA crude radiopharmaceutical solution.

[0021] Preferably, the molar ratio of aluminum chloride hexahydrate to the PSMA radiopharmaceutical intermediate in step three is 0.7-0.8:1 (e.g., 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 aluminum chloride hexahydrate to the PSMA radiopharmaceutical intermediate in step three is 0.73-0.77:1; even more preferably, the molar ratio of aluminum chloride hexahydrate to the PSMA radiopharmaceutical intermediate in step three is 0.75:1.

[0022] Preferably, the fluorination reaction temperature in step three is about 80-85°C (e.g., 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 approximately 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 three, the concentration of aluminum chloride hexahydrate is approximately 0.6-0.9 mg / ml (e.g., 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). More preferably, in the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate described in step three, the concentration of aluminum chloride hexahydrate is approximately 0.7-0.8 mg / ml (e.g., 0.7 mg / ml, 0.85 mg / ml, 0.86 mg / ml, 0.87 mg / ml, 0.88 mg / ml, 0.89 mg / ml, 0.9 mg / ml); even more preferably, in the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate described in step three, the concentration of aluminum chloride hexahydrate is approximately 0.75-0.8 mg / ml (e.g., 0.75 mg / ml, 0.86 mg / ml, 0.87 mg / ml, 0.88 mg / ml, 0.89 mg / ml, 0.9 mg / ml); (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 three, 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 three, the concentration of the PSMA radiopharmaceutical intermediate is approximately 0.4-0.6 mg / ml (e.g., 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 three, the concentration of the PSMA radiopharmaceutical intermediate is 0.5 mg / ml.

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

[0027] Preferably, the volume ratio of the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate (volume defined as V1) and the dimethyl sulfoxide solution containing the PSMA radiopharmaceutical intermediate (volume defined as V2) in step three is approximately V1:V2=1:5-10 (e.g., 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 step three is approximately V1:V2=1:7-9 (e.g., 1:7, 1:8, 1:9); even 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 step three is V1:V2=1:8.

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

[0029] Preferably, the volume ratio of the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate (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) in step three is approximately V1:V2:V3=1:7-9:1 (e.g., 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 step three is V1:V2:V3=1:8:1.

[0030] In some specific embodiments, step three includes the following steps: adding a potassium hydrogen phthalate solution containing aluminum chloride hexahydrate (the concentration of aluminum chloride hexahydrate 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 potassium hydrogen phthalate solution is 0.5 M) to a solution containing fluorine [ 18 The fluorination reaction was carried out in a reaction flask containing the F] ion solution at a temperature of 85°C for 15 minutes. After the reaction was completed, the reaction mixture was cooled to 50°C to obtain Al. 18 The crude F-PSMA radiopharmaceutical solution contains a potassium hydrogen phthalate solution (V1) containing aluminum chloride hexahydrate, a dimethyl sulfoxide solution (V2) containing PSMA radiopharmaceutical intermediates, and a potassium hydrogen phthalate solution (V3) in a volume ratio of V1:V2:V3=1:8:1.

[0031] Furthermore, step one is completed in a cyclotron with fluorine […]. 18 Preparation and transport of F ions.

[0032] Furthermore, the fluorine produced in step one... 18 The radioactivity of F ions is determined based on clinical needs.

[0033] Furthermore, the fluorine mentioned in step one... 18 The preparation of F] ions includes the following steps: loading heavy oxygen (F) into an F-18 target using a cyclotron. 18 O) water, set the bombardment beam (30-100 μA) and bombardment time (20-120 minutes), and bombard the heavy oxygen (O) according to the preset beam and time. 18 O) Water, through the occurrence of 18 O(p, n) 18 F nuclear reaction produces fluorine [ 18 F] ions, after bombardment, will contain fluorine [ 18 F] ions deuterium (18 O) Water is transported to fluoride [ 18 F] ion was placed in a V-shaped flask, and then fluorine was purged with helium. 18 F] Ion transport pipeline, shut down the accelerator after completion.

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

[0035] Furthermore, steps two, three, and four are completed in the synthesizer.

[0036] Furthermore, step two includes the following steps: transferring the heavy oxygen (from step one) 18 Fluoride in water [O) 18 F] ions are adsorbed onto a pre-activated QMA ion exchange column. After washing the QMA ion exchange column with an appropriate amount of water for injection, the fluoride ions are then removed with a mixed solution of sodium chloride injection and sodium vitamin C aqueous solution. 18 F] ions were eluted from the QMA ion exchange column.

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

[0038] Preferably, the volume ratio of sodium chloride injection solution and sodium vitamin C aqueous solution in step two is approximately 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 sodium chloride injection solution and vitamin C sodium aqueous solution in step two is approximately V 氯化钠注射液 :V 维生素C钠水溶液=15-25:1 (e.g., 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 sodium chloride injection and sodium vitamin C aqueous solution in step two is V 氯化钠注射液 V 维生素C钠水溶液 =20:1.

[0039] Furthermore, step four includes HPLC purification.

[0040] Furthermore, the HPLC purification described in step four includes the following steps: [The text abruptly shifts to a seemingly unrelated topic about Al purification.] 18 The crude F-PSMA radiopharmaceutical solution was diluted with an appropriate amount of mobile phase and purified under the following chromatographic conditions. The presence of Al was detected and collected online using a radioactive detector. 18 The component peaks of the F-PSMA radiopharmaceutical were then diluted with an appropriate amount of sterile water for injection. 18 HPLC purified fraction of F-PSMA radiopharmaceutical.

[0041] project Parameter range Preparative chromatography column Agilent ZORBAX Eclipse XDB-C18 inner diameter 5µm length 9.4 x 250mm Flow rate 3ml / min mobile phase 17% acetonitrile and 83% 20mM sodium acetate buffer (pH≈6) UV detection wavelength 220nm

[0042] Furthermore, step four includes HLB purification.

[0043] Furthermore, the HLB purification described in step four includes the following steps: Al 18 The HPLC-purified fraction of the F-PSMA radiopharmaceutical was adsorbed onto an HLB column. Impurities adsorbed on the HLB column were washed with an appropriate amount of sterile water for injection, and then residual liquid on the HLB column was purged. Finally, Al was removed with an appropriate amount of 80% ethanol. 18 F-PSMA radiopharmaceutical was eluted from the HLB column to obtain Al 18 F-PSMA radiopharmaceutical pure solution.

[0044] Furthermore, step four includes HPLC purification and HLB purification, wherein the HPLC purification steps are as described in any of the preceding descriptions, and the HLB purification steps are as described in any of the preceding descriptions.

[0045] Furthermore, step five includes the following steps: taking the Al obtained in step four... 18 The F-PSMA radiopharmaceutical purified solution was diluted with an appropriate amount of sodium chloride injection, filtered for sterilization, and aseptically dispensed according to clinical requirements to obtain Al. 18 F-labeled PSMA radiopharmaceutical.

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

[0047] Preferably, the Al obtained using the preparation method provided by the present invention 18 The specifications for F-labeled PSMA radiopharmaceutical injections are 37-1850 MBq / ml (i.e., 1.0-50.0 mCi / ml).

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

[0049] In some specific embodiments, Al obtained using the preparation method provided by the present invention 18 The batch formulation composition (in 22 ml) of the F-labeled PSMA radiopharmaceutical is shown below. It is understood that the batch volume can be adjusted as needed (e.g., 10 ml, 15 ml, 20 ml, 25 ml, etc.), and the components and their proportions do not change with the batch volume. Element content Function <![CDATA[Al 18 F-labeled PSMA radiopharmaceutical 37-1850 MBq / ml Active ingredients Sodium chloride injection 20ml Osmotic pressure regulator; solvent Sterile water for injection 0.4ml solvent Anhydrous ethanol 1.6ml solvent

[0050] In another aspect, the present invention also provides a method for fluorinating the PSMA radiopharmaceutical intermediate as described in any of the preceding claims, or an Al method as described in any of the preceding claims. 18 The method for preparing F-labeled PSMA radiopharmaceuticals is applied in the preparation of PSMA-type drugs, wherein the PSMA-type drugs specifically refer to drugs that target PSMA (Prostate Specific Membrane Antigen), including but not limited to macromolecular drugs, peptide drugs (such as those composed of ≥15 amino acids), short peptide drugs (such as those composed of less than 15 amino acids), small molecule drugs, or combinations thereof that target PSMA.

[0051] In another aspect, the present invention also provides a method for fluorinating the PSMA radiopharmaceutical intermediate as described in any of the preceding claims, or an Al method as described in any of the preceding claims. 18 The preparation method of F-labeled PSMA radiopharmaceuticals in the preparation of Al 18 Application of F-labeled PSMA radiopharmaceuticals.

[0052] Furthermore, the aforementioned Al 18 F-labeled PSMA radiopharmaceutical is Al 18F-labeled PSMA radiopharmaceutical injection.

[0053] Furthermore, the aforementioned Al 18 The specifications for F-labeled PSMA radiopharmaceutical injections are 37-1850 MBq / ml (i.e., 1.0-50.0 mCi / ml).

[0054] Furthermore, Al obtained using the fluorination method provided by this invention 18 The shelf life of F-labeled PSMA radiopharmaceuticals is preferably within 8 hours from the end of the radiolabeling reaction.

[0055] In another aspect, the present invention also provides a method for fluorinating the PSMA radiopharmaceutical intermediate as described in any of the preceding claims, or an Al method as described in any of the preceding claims. 18 Application of the preparation method of F-labeled PSMA radiopharmaceutical in the preparation of imaging drugs for diagnosing prostate cancer patients.

[0056] In another aspect, the present invention also provides a method for fluorinating the PSMA radiopharmaceutical intermediate as described in any of the preceding claims, or an Al method as described in any of the preceding claims. 18 The preparation method of F-labeled PSMA radiopharmaceuticals is used in the preparation of imaging drugs for diagnosing prostate-specific membrane antigen (PSMA) positive lesions in prostate cancer patients.

[0057] Furthermore, any of the aforementioned prostate cancer patients are those suspected of having metastases after undergoing initial radical treatment or those with elevated serum prostate-specific antigen (PSA) levels, suggesting biochemical recurrence.

[0058] Furthermore, the present invention also provides an Al 18 F-labeled PSMA radiopharmaceutical, the Al 18 F-labeled PSMA radiopharmaceuticals utilize any of the above-described Al 18 The PSMA radiopharmaceutical is obtained by the preparation method of F-labeled PSMA or by the fluorination method of the PSMA radiopharmaceutical intermediate described in any of the above-mentioned methods.

[0059] Furthermore, the Al mentioned above 18 The F-labeled PSMA radiopharmaceutical is an injectable solution.

[0060] Furthermore, the Al mentioned above 18 The specifications for F-labeled PSMA radiopharmaceutical injections are 37-1850 MBq / ml (i.e., 1.0-50.0 mCi / ml).

[0061] Furthermore, the Al mentioned above 18For F-labeled PSMA radiopharmaceuticals, the optimal time for use is within 8 hours of the end of the radiolabeling reaction.

[0062] In some specific embodiments, the Al provided by the present invention 18 The batch formulation composition (in 22 ml) of the F-labeled PSMA radiopharmaceutical is shown below. It is understood that the batch volume can be adjusted as needed (e.g., 10 ml, 15 ml, 20 ml, 25 ml, etc.), and the components and their proportions do not change with the batch volume. Element content Function <![CDATA[Al 18 F-labeled PSMA radiopharmaceutical 37-1850 MBq / ml Active ingredients Sodium chloride injection 20ml Osmotic pressure regulator; solvent Sterile water for injection 0.4ml solvent Anhydrous ethanol 1.6ml solvent

[0063] In another aspect, the present invention also provides the Al described in any of the above claims. 18 Application of F-labeled PSMA radiopharmaceuticals in the preparation of imaging drugs for diagnosing prostate cancer patients.

[0064] In another aspect, the present invention also provides the Al described in any of the above claims. 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.

[0065] Furthermore, any of the aforementioned prostate cancer patients are those suspected of having metastases after undergoing initial radical treatment or those with elevated serum prostate-specific antigen (PSA) levels, suggesting biochemical recurrence.

[0066] In some specific embodiments, the PSMA radiopharmaceutical intermediate described in any of the above claims is PSMA-BCH, and its structure is shown in formula (I): (I)

[0067] In some specific embodiments, the Al described in any of the above claims 18 F-labeled PSMA radiopharmaceutical is Al 18 F-PSMA-BCH, its structure is shown in equation (II): (II)

[0068] In summary, the fluorination method for PSMA radiopharmaceutical intermediates provided by this invention, through adjustments to the reaction system, effectively reduces the requirements for fluorination reaction temperature during the labeling process while ensuring labeling aging, final product radiochemical purity, radiochemical conversion rate, and product yield. This invention provides Al based on this fluorination method. 18The method for preparing F-labeled PSMA radiopharmaceuticals has good applicability, the reaction is thorough, and no new impurities are introduced into the final product due to the decrease in reaction temperature or the adjustment of the reaction system. Furthermore, this preparation method can further reduce and control the types and amounts of impurities in the final product, further ensuring patient medication safety. In addition, the final product formulations obtained using the fluorination method or preparation method provided by this invention exhibit good batch-to-batch homogeneity and good stability under storage conditions of 30℃±2℃ and 40℃±2℃. Detailed Implementation

[0069] Unless otherwise defined, technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art. While similar or identical methods and materials may be applied in experimental or practical applications, materials and methods are described herein. In case of conflict, the definitions included herein shall prevail. Furthermore, materials, methods, and examples are for illustrative purposes only and are not intended to be limiting. The present application is further described below with reference to specific embodiments, but is not intended to limit the scope of the application.

[0070] Unless the context otherwise requires, throughout this specification and the following claims, the word "comprising" and its variations such as "including" or "containing" will be understood to implicitly include the stated integers or steps, or groups of integers or steps, but not exclude 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 thus defined may be combined with any other one or more aspects unless expressly indicated to the contrary. In particular, any of the optional, preferred, or advantageous features may be combined with any other optional, preferred, or advantageous feature.

[0071] In this invention, the term "approximately" generally refers to an approximate value of a number, or a result after some approximation. In actual calculations, if the mass of a compound is 5.7 grams, and a solvent with a mass-to-volume ratio of 1:3 needs to be added, for practical production applications, the actual amount used is often measured by rounding. That is, based on the calculated value of 17.1 ml, 17 ml is actually measured by rounding. Similarly, if the mass of a compound is 6.8 grams, and a solvent with a mass-to-volume ratio of 1:7 needs to be added, for practical production applications, the actual amount used is often measured by rounding. That is, based on the calculated value of 47.6 ml, 48 ml is actually measured by rounding. Therefore, it can be understood that in such cases, appropriate adjustments have been made within a certain range for the convenience and controllability of practical production applications, and these adjustments are still within the numerical range provided in this patent.

[0072] In this invention, "appropriate amount" refers to the required amount, temperature, volume, time, etc., which 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, in order to achieve the actual effect. Therefore, "appropriate amount" in any one of the present invention refers to conditions that can meet the requirements of the reaction. The relevant conditions are those that those skilled in the art can grasp and know, and the relevant conditions should not be regarded as a limitation of the present invention.

[0073] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are only for illustrating the present invention and should not be regarded as limiting the scope of the present invention.

[0074] Example 1: Fluorination reaction of PSMA-BCH

[0075] This embodiment first designed the following fluorination reaction process: 111.2 μl of an aluminum chloride hexahydrate solution (0.277 mg / ml, 0.128 nmol), 400 μl of anhydrous ethanol, and 40 μl of an acetate-sodium acetate buffer solution (pH=4) containing PSMA-BCH (5 mg / ml, 0.212 nmol) were added to a solution containing fluorine. 18 The reaction flask contained the F] ion solution. Referring to the above process, this embodiment explored the temperature of the fluorination reaction, selecting three time points: 90℃, 110℃, and 120℃, and investigated the reaction temperature and reaction time, as shown in Table 1.

[0076] Table 1. Exploration of fluorination reaction temperature

[0077] The results show that when the reaction temperature is 110℃ and the reaction time is 15 min, the yield is 8.1% and the total impurity content is 0.53 μg / ml (see Table 1, batch YT-110). However, when the reaction temperature is lowered (e.g., to 90℃, see Table 1, batch YT-090), to maintain a certain yield, a corresponding delay in reaction time is required (e.g., a delay of 20 min). This obviously increases the overall reaction time, which is detrimental to... 18 The production of the F molecular probe is not suitable. Furthermore, when the reaction temperature is increased by only 10°C to shorten the reaction time (e.g., reducing it to 5 minutes, see batch YT-120 in Table 1), the impurity content increases significantly. This obviously increases the difficulty and complexity of subsequent drug purification and reduces the quality of the drug formulation. In addition, the above reaction system uses anhydrous ethanol, which will vaporize at 110°C, rendering the anhydrous ethanol ineffective in providing protection.

[0078] Based on the above reasons, this embodiment, while maintaining the reaction time unchanged, and aiming to reduce the reaction temperature, re-examined and adjusted factors such as the reaction feed ratio and buffer system. For example, the feed ratio of aluminum chloride hexahydrate / PSMA-BCH was adjusted (from 0.6:1 to 0.75:1), potassium hydrogen phthalate buffer system was used instead of acetate buffer system (pH remained unchanged, pH=4), and the reaction temperature was reduced to 75℃. The adjusted reaction parameters and results are shown in Table 2 for batch YT-075. The results show that, while maintaining the reaction time and seeking a lower reaction temperature, adjusting the feed ratio of aluminum chloride hexahydrate / PSMA-BCH and the type of buffer solution resulted in a higher radiochemical conversion rate (42.3%). Based on these adjusted parameters, this embodiment further studied the reaction yield and found that the adjusted process not only achieved the ideal radiochemical conversion rate but also significantly increased the yield to 20.7% (see Table 2 for batch YT-075-1).

[0079] This embodiment also investigated the effects of the original and new buffer systems on the reaction. Based on the adjusted parameters, the buffer system was readjusted from potassium hydrogen phthalate buffer (pH=4) to an acetate-sodium acetate buffer (pH=4). However, the results showed that the reaction yield was significantly reduced when the buffer was readjusted to acetate-sodium acetate buffer (pH=4), to only 9.6% (see Table 2, batch YT-075-2). This indicates that the potassium hydrogen phthalate buffer system (pH=4) has a significant impact on the reaction.

[0080] To further improve the reaction yield, this embodiment investigated the temperature of the fluorination reaction, adjusting it to 85°C and maintaining the reaction time at 15 min. Since anhydrous ethanol has a boiling point of 78°C and is still prone to vaporization in the reaction system, the anhydrous ethanol in the reaction system was replaced with dimethyl sulfoxide. The adjusted reaction process was as follows: 50 μl of a 0.5 M potassium hydrogen phthalate solution containing aluminum chloride hexahydrate (0.77 mg / ml, 0.16 nmol), 400 μl of a dimethyl sulfoxide solution containing PSMA-BCH (0.5 mg / ml, 0.212 nmol), and 50 μl of the 0.5 M potassium hydrogen phthalate solution were added to the fluorine-containing... 18 In the reaction flask of the F] ion solution, the reaction was carried out 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 2, batch YT-085).

[0081] Table 2. Exploration of fluorination reaction conditions

[0082] When the above reaction conditions are repeated, the yield and radiochemical purity remain consistent (26.1% and 99.4%, respectively, see Table 2 for batch YT-085-1). This indicates that the fluorination method provided by this invention has good batch-to-batch stability and is suitable for production and promotion.

[0083] Example 2 Al 18 Preparation of F-PSMA-BCH formulation

[0084] (1) Fluorine 18 Preparation and transport of F ions

[0085] Using the Sumitomo cyclotron (HM-12S), heavy oxygen was loaded into the F-18 target. 18 O) water, set the bombardment beam (30-100 μA) and bombardment time (20-120 minutes). Start the accelerator program sequence and bombard the heavy oxygen (O) water according to the preset beam and time. 18 O) Water, through the occurrence of 18 O(p, n) 18 F nuclear reaction produces fluorine [ 18 F] ions, after bombardment, will contain fluorine [ 18 F] ions deuterium ( 18 O) Water is transported to fluoride [ 18 F] ion was placed in a V-shaped flask, and then fluorine was purged with helium. 18 F] Ion transport pipeline, shut down the accelerator after completion.

[0086] Dissolved in heavy oxygen ( 18 Fluoride in water [O) 18 F ions flow from the V-shaped bottle into the conical tube on the ferrule of the synthesizer (ORA, Neptisperform).

[0087] (2) Fluorine 18 Capture of F ions

[0088] The QMA ion exchange column (catalog number 186004540, specification 46 mg, manufacturer: Waters Sep-Pak) was pre-activated with 30 ml of sterile water for injection. Heavy oxygen (…) 18 Fluoride in water [O) 18 F] ions are adsorbed onto a pre-activated QMA ion exchange column. After rinsing the QMA ion exchange column with 20 ml of sterile water for injection, the fluoride ions are then removed with a mixed solution of 300 μl of sodium chloride injection and 15 μl of sodium vitamin C aqueous solution (100 mg / ml). 18 F ions were eluted from the QMA ion exchange column into the reaction flask.

[0089] (3) Radiolabeling of PSMA-BCH

[0090] Add 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 to a solution containing fluorine. 18 In a reaction flask containing the F] ion solution, the reaction was carried out at 85°C for 15 minutes. After the reaction was completed, the reaction mixture was cooled to 50°C to obtain Al. 18 F-PSMA-BCH crude mixture.

[0091] (4) Al 18 Purification of F-PSMA-BCH crude product

[0092] (a) HPLC purification

[0093] Al in the reaction flask 18 The crude F-PSMA-BCH mixture was diluted with the mobile phase shown in the table below, and then separated and purified using the chromatographic conditions shown in the table below. The presence of Al was detected and collected online using a radiometric detector. 18 The component peaks of F-PSMA-BCH were then diluted with approximately 50 ml of sterile water for injection and collected in Al. 18 F-PSMA-BCH-HPLC purified components. project Parameter range Preparative chromatography column Agilent ZORBAX Eclipse XDB-C18 inner diameter 5µm length 9.4 x 250mm Flow rate 3ml / min mobile phase 17% acetonitrile and 83% 20mM sodium acetate buffer (pH adjusted to 6 with glacial acetic acid) UV detection wavelength 220nm

[0094] (b) HLB column purification

[0095] The HLB column (catalog number: 186000132, specification: 225mg, manufacturer: Waters Corporation) was pre-activated with 10ml of anhydrous ethanol and 30ml of sterile water for injection. Al 18 F-PSMA-BCH was adsorbed onto the HLB column. After adsorption was complete, the impurities adsorbed on the HLB column were rinsed with 20 ml of sterile water for injection within 45 seconds, and then the column was purged with nitrogen gas at a negative pressure of -0.3 bar for 10 seconds to remove the residual liquid on the HLB column.

[0096] Then use 2 ml of 80% ethanol to remove Al 18 F-PSMA-BCH was eluted from the HLB column to obtain Al 18 F-PSMA-BCH pure solution.

[0097] (5)Al 18 Preparation of F-PSMA-BCH formulation

[0098] Collected Al 18F-PSMA-BCH purified solution was diluted with 20 ml of sodium chloride injection. Under nitrogen pressure, it was sterilely filtered through a 0.22 μm liquid filter and dispensed into product vials. The aseptically dispensed vials were then filled into multiple sealed 10 ml sterile vials to obtain Al. 18 F-PSMA-BCH formulation (i.e., Al) 18 The radioactivity content of each vial of F-PSMA-BCH injection was determined by an activity meter.

[0099] Al 18 The F-PSMA-BCH injection solution has a strength of 37-1850 MBq / ml (1.0-50.0 mCi / mL), and its shelf life is preferably within 8 hours from the end of the radiolabeling reaction. For detailed batch prescriptions, please refer to Table 3.

[0100] Table 3 Al 18 Composition of F-PSMA-BCH injection batch formulation (22ml) Element content <![CDATA[Al 18 F-PSMA-BCH]]> 37-1850 MBq / ml Sodium chloride injection 20ml Sterile water for injection 0.4ml Anhydrous ethanol 1.6ml

[0101] Different batches of Al were processed using the method described above. 18 The preparation of F-PSMA-BCH injection solution and its radiochemical purity are shown in Table 4.

[0102] Table 4. Three batches of Al 18 F-PSMA-BCH injection radiochemical purity serial number batch Radiochemical purity (%) YT-085-A 409mCi 99.45% YT-085-B 101mCi 98.70% YT-085-C 411mCi 98.39%

[0103] Example 3 Al 18 Impurity Study of F-PSMA-BCH Injection

[0104] Al 18 The active ingredient in 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 18 The F-PSMA-BCH synthesis, elution, dilution, and sterilization filtration processes, along with the raw materials used in production, assess potential impurities that may be introduced or generated, as detailed in Table 5.

[0105] Table 5 Al 18 Impurity assessment in F-PSMA-BCH injection Serial Number Material Name Specification Process steps and functions Possible impurities 1 Oxygenated water 50g, 97% atom <![CDATA[Fluorine 18 raw material for the production of F] ions]]> <![CDATA[Fluorine 19 F]PSMA - BCH]]> 2 helium No less than 99.9999% Accelerator gas none 3 hydrogen No less than 99.999% Accelerator gas none 4 Nitrogen No less than 99.999% Drying of the synthesis module none 5 Anhydrous ethanol 500ml pharmaceutical excipient grade auxiliary materials none 6 Acetonitrile 5L analytical grade HPLC mobile phase Acetonitrile 7 Dimethyl sulfoxide 100ml or less 99.9% reaction solvent Dimethyl sulfoxide 8 Potassium hydrogen phthalate 500g analytical grade Preparation of buffer solution Potassium hydrogen phthalate 9 Sodium Vitamin C 25kg pharmaceutical excipient grade <![CDATA[Leaching fluorine 18 F] ion]]> Sodium Vitamin C 10 glacial acetic acid 500ml pharmaceutical excipient grade Preparation of semi-preparative HPLC mobile phase acetic acid 11 Sodium acetate trihydrate 500g analytical grade Preparation of semi-preparative HPLC mobile phase acetic acid 12 Aluminum chloride hexahydrate 500g analytical grade Radiolabeled reagents none 13 Sodium chloride injection 50ml, concentration 0.9% <![CDATA[Leaching fluorine 18 F] ions, excipients]]> none 14 Sterile water for injection 500ml HPLC mobile phase, solvent, and excipients none

[0106] After evaluation, the Al obtained by the preparation method provided by this invention... 18 No mutagenic impurities were found in F-PSMA-BCH injection. The main known impurities present are fluorine.19 F]PSMA-BCH, potassium hydrogen phthalate, sodium vitamin C, residual solvents (acetonitrile, acetic acid and dimethyl sulfoxide). For the detection method of residual acetonitrile, please refer to the General Chapter 0861, Method III of the 2020 edition of the Chinese Pharmacopoeia. The detection methods of other impurities are as follows.

[0107] (1) Impurity fluorine [ 19 F]PSMA-BCH detection method

[0108] Test solution: Fluorine [ 18 F] PSMA-BCH Injection

[0109] Reference stock solution: Take fluoride [ 19 Weigh approximately 5 mg of F]PSMA-BCH reference standard accurately, place it in a 250 ml volumetric flask, add an appropriate amount of water to dissolve it, dilute with water to the mark, and shake well.

[0110] Al 18 F-PSMA-BCH stock solution: Take Al 18 Weigh approximately 2 mg of F-PSMA-BCH reference standard accurately, place it in a 100 ml volumetric flask, add an appropriate amount of water to dissolve it, dilute with water to the mark, and shake well.

[0111] Separation solution: Accurately measure 5 ml of the reference stock solution and Al 18 Take 2 ml of F-PSMA-BCH stock solution and place it in a 20 ml volumetric flask. Dilute with water to the mark and shake well.

[0112] Reference solution: Accurately measure 5 ml of the reference stock solution, place it in a 20 ml volumetric flask, dilute with water to the mark, and shake well to obtain the solution.

[0113] Chromatographic column: Octadecylsilane-bonded silica gel as the packing material (e.g., Agilent Eclipse Plus C18 column, 250 × 4.6 mm, 5 μm)

[0114] Mobile phase A: 20 mM sodium acetate solution

[0115] Mobile phase B: Acetonitrile

[0116] Flow rate: 1.0 ml / min

[0117] Detection wavelength: 220nm

[0118] Injection volume: 20 μl

[0119] Gradient elution procedure: Time (min) Mobile phase A (%) Mobile phase B (%) 0 95 5 5.0 95 5 25.0 50 50 30.0 50 50 30.1 95 5 35.0 95 5

[0120] After the chromatographic system has stabilized, inject the sample according to the following procedure:

[0121] (1) Blank solution, 1 injection

[0122] (2) Separability solution, 1 injection

[0123] (3) Reference solution, 3 injections

[0124] (4) Test solution, 1 injection. If there is a 60-minute interval between the last injection of the reference solution and the last injection of the test solution, inject 1 injection of blank solution before starting the analysis of the test solution.

[0125] System applicability requirements:

[0126] (1) The chromatogram of the blank solution has no peaks or only inconspicuous peaks within 20 minutes.

[0127] (2) In the chromatogram of the solution with high resolution, fluorine [ 19 F]PSMA-BCH and Al 18 The resolution between F-PSMA-BCH should be ≥1.5.

[0128] (3) Three consecutive injections of fluoride [ 19 The peak area RSD of the F]PSMA-BCH reference solution is ≤5%.

[0129] Result calculation:

[0130]

[0131] In the formula:

[0132] C(X) represents the fluorine concentration in the test solution. 19 F]PSMA-BCH concentration (μg / ml);

[0133] PA(X) represents the fluorine concentration in the test solution. 19 Peak area of ​​F]PSMA-BCH;

[0134] C (standard) is the fluoride content in the reference solution. 19 F]PSMA-BCH concentration (the concentration of the reference solution should be based on fluorine [ 19 (The actual purity value of the F]PSMA-BCH reference standard was corrected);

[0135] PA (standard) is the fluoride content in the reference solution. 19 F]PSMA-BCH average peak area.

[0136] The standard specifies that the concentration should not exceed 5.00 µg / ml.

[0137] (2) Detection method for residual dimethyl sulfoxide

[0138] Instruments: Gas chromatograph, electronic balance

[0139] Reagent: Dimethyl sulfoxide

[0140] Test solution: Fluorine [ 18 F] PSMA-BCH Injection

[0141] Reference solution: Weigh about 20 mg of dimethyl sulfoxide, place it in a 50 ml volumetric flask, dilute with water to the mark, and shake well.

[0142] Chromatographic column: Capillary column with 6% cyanopropylphenyl-94% dimethylpolysiloxane as the stationary phase (e.g., DB-624 column, 0.32mm × 30m, 1.8μm).

[0143] Carrier gas: Helium

[0144] Flow rate: 2 ml / min

[0145] Column temperature: Initial temperature 40℃, maintain for 5 minutes, then increase to 200℃ at a rate of 20℃ per minute, maintain for 3 minutes.

[0146] Injector temperature: 200℃

[0147] Flow split ratio: 1:30

[0148] Detector type: Flame ionization detector (FID)

[0149] Detector temperature: 250℃

[0150] Injection volume: 1 μl

[0151] Determination: Inject the reference solution and the test solution separately, record the chromatograms, and calculate the residual amount of dimethyl sulfoxide by peak area using the external standard method.

[0152] (3) Detection methods for residual potassium hydrogen phthalate and sodium vitamin C

[0153] Instruments: High-performance liquid chromatograph, electronic balance

[0154] Reagents: Sodium vitamin C, potassium hydrogen phthalate, acetonitrile, trifluoroacetic acid

[0155] Blank solution: water

[0156] Test solution: Fluorine [ 18 F] PSMA-BCH Injection

[0157] Sodium Vitamin C Stock Solution: Weigh approximately 50 mg of sodium vitamin C, place it in a 10 ml volumetric flask, dilute with water to the mark, and shake well.

[0158] Potassium hydrogen phthalate stock solution: Weigh about 50 mg of potassium hydrogen phthalate, place it in a 10 ml volumetric flask, dilute with water to the mark, and shake well.

[0159] Reference solution: Mix 50 μl of sodium vitamin C stock solution, 50 μl of potassium hydrogen phthalate stock solution and 900 μl of water to obtain the solution.

[0160] Column: Shim-pack GIST C18-AQ (250mm × 4.6mm, 5μm)

[0161] Mobile phase: water-acetonitrile-trifluoroacetic acid (900:100:2)

[0162] Flow rate: 0.6 ml / min

[0163] Detection wavelength: 244nm

[0164] Injection volume: 5ml

[0165] Isocratic elution time: 45 min

[0166] Column temperature: 30℃

[0167] After the chromatographic system has stabilized, inject the sample according to the following procedure:

[0168] (1) Blank solution, 1 injection

[0169] (2) Reference solution, 3 injections

[0170] (3) Blank solution, 1 injection

[0171] (4) Test solution, 1 injection

[0172] System applicability requirements:

[0173] (1) The chromatogram of the blank solution showed no obvious peaks.

[0174] (2)3 For the reference solution, the peak area of ​​sodium vitamin C is RSD≤5% and the peak area of ​​potassium hydrogen phthalate is RSD≤5%.

[0175] Result calculation:

[0176] The content of sodium vitamin C and potassium hydrogen phthalate in the test sample was calculated based on peak area using the external standard method.

[0177] (4) Detection method for residual acetic acid

[0178] Instruments: High-performance liquid chromatograph, electronic balance

[0179] Reagents: Sodium acetate, acetonitrile

[0180] Blank solution: water

[0181] Test solution: Al 18 F-PSMA-BCH Injection

[0182] Glacial acetic acid stock solution: Take 500 μl of glacial acetic acid, place it in a 10 ml volumetric flask, dilute with water to the mark, and shake well to obtain the solution.

[0183] Glacial acetic acid reference solution: Mix 200 μl of glacial acetic acid stock solution with 800 μl of water to obtain the solution.

[0184] Chromatographic column: Octadecylsilane-bonded silica gel as the packing material (e.g., Agilent Eclipse Plus C18, 250 × 4.6 mm, 5 μm)

[0185] Mobile phase A: 20 mM sodium acetate solution

[0186] Mobile phase B: Acetonitrile

[0187] Flow rate: 1.0 ml / min

[0188] Detection wavelength: 220nm

[0189] Injection volume: 20 μl

[0190] Gradient elution procedure: Time (min) Mobile phase A (%) Mobile phase B (%) 0 95 5 5.0 95 5 25.0 50 50 30.0 50 50 30.1 95 5 35.0 95 5

[0191] Determination: Inject the reference solution and the test solution separately, record the chromatograms, and calculate the residual acetic acid by peak area using the external standard method.

[0192] This embodiment evaluated the impurities in three batches of samples, and the results are as follows:

[0193] fluorine[ 19 The results of the fluorine [F]PSMA-BCH impurity content test are shown in Table 6. The results show that the fluorine [F] in each batch... 19 The fluorine content of PSMA-BCH in these samples was not greater than 5.00 µg / ml, and the differences were not significant. Furthermore, during the stability process, the fluorine content in these samples decreased. 19 The content of F]PSMA-BCH also remained basically unchanged.

[0194] Table 6. Fluorine content in three batches of samples 19 F]PSMA-BCH impurity content (µg / ml) project YT-085-A YT-085-B YT-085-C <![CDATA[Fluorine 19 F]PSMA-BCH]]> 0.44 0.28 0.37

[0195] The detection results for potassium hydrogen phthalate and sodium vitamin C are shown in Table 7. The results showed that potassium hydrogen phthalate and sodium vitamin C were not detected in any batch (the detection limit for sodium vitamin C was 0.01 μg / ml, and the detection limit for potassium hydrogen phthalate was 0.10 μg / ml), indicating that in Al... 18 F-PSMA-BCH can be effectively removed during the purification process.

[0196] Table 7. Detection results of potassium hydrogen phthalate and sodium vitamin C in three batches of samples. project YT-085-A YT-085-B YT-085-C Potassium hydrogen phthalate ND ND ND Sodium Vitamin C ND ND ND Note: "ND" means Not detected.

[0197] The results of residual solvent detection (acetonitrile, acetic acid, and dimethyl sulfoxide) are shown in Table 8. ICH Q3C specifies acetonitrile as a Group II solvent with a limit of ≤410 ppm, while acetic acid and dimethyl sulfoxide are Group III solvents with a limit of ≤5000 ppm. Table 8 shows that acetic acid and dimethyl sulfoxide were not detected in any batches (the detection limit for acetic acid was 52.07 μg / ml, and the detection limit for dimethyl sulfoxide was 1.03 μg / ml), indicating that they are not present in Al₂O₃. 18 The F-PSMA-BCH can be effectively removed during the purification process; the residual amount of acetonitrile is also far less than the required limit.

[0198] Table 8. Detection results of residual solvents (acetonitrile, acetic acid, and dimethyl sulfoxide) in three batches of samples. project YT-085-A YT-085-B YT-085-C Acetonitrile 73µg / ml 83µg / ml 83µg / ml acetic acid ND ND ND Dimethyl sulfoxide ND ND ND .

[0199] Note: "ND" means Not detected.

[0200] In summary, the preparation method provided by this invention, although lowering the temperature of the fluorination reaction, ensures a complete reaction without generating new impurities. Furthermore, while the preparation method introduced by this invention employs a new solution system compared to existing technologies, this system effectively reduces or controls residual impurities in the final product, further guaranteeing the safety of drug application.

[0201] Example 4: Formulation Stability Study

[0202] For Al 18 The long-term stability and accelerated stability studies of F-PSMA-BCH injection samples were conducted (Table 9), examining the properties, pH, and fluoride content of each batch of samples. 19 F] PSMA-BCH content, fluorine [ 19 F] The total content of PSMA-BCH and other chemical impurities, bacterial endotoxins, sterility, radiochemical purity, and radioactivity concentration are among the indicators.

[0203] Table 9 Stable evaluation indicators

[0204] (1) Methods for examining physical characteristics (appearance)

[0205] Detection method: Visual inspection.

[0206] This product should be a colorless, clear liquid.

[0207] (2) pH test method

[0208] Prepare pH test strips that meet the suitability requirements by placing them in a petri dish within the protective enclosure. The operator stands in front of the lead glass of the enclosure, takes 2 μl of the sample to be tested, and drops it onto a wide-range pH test strip (4-10). Observe through the lead glass and compare the color development on the test strip with the standard color chart to read the pH range of the sample. Then, take another 2 μl of the sample to be tested and drop it onto a precision pH test strip of the corresponding range. Observe through the lead glass and compare the color development on the test strip with the standard color chart to read the pH value of the sample.

[0209] The pH of this product should be 4.5-8.0.

[0210] (3) Impurity fluorine [ 19 F] Methods for investigating PSMA-BCH content

[0211] For the method of investigation, please refer to Example 3 (1) Impurity Fluorine [ 19 F]PSMA-BCH detection method

[0212] The standard specifies that the concentration should not exceed 5.00 µg / ml.

[0213] (4) Impurity fluorine [ 19 F] Total content of PSMA-BCH and other chemical impurities

[0214] Instruments, reagents, solution preparation, chromatographic conditions, detection process, and system suitability requirements: all are the same as in Example 3 (1) regarding impurity fluorine. 19 F]PSMA-BCH detection method.

[0215] Result calculation:

[0216]

[0217]

[0218] In the formula: C(X) represents the fluorine concentration in the test solution. 19 F]PSMA-BCH concentration or chemical impurity concentration (μg / ml);

[0219] PA(X) represents the fluorine concentration in the test solution. 19 The peak area of ​​F]PSMA-BCH or the peak area of ​​chemical impurities;

[0220] C (standard) is the fluoride content in the reference solution. 19 F]PSMA-BCH concentration (the concentration of the reference solution should be based on fluorine [ 19 (The actual purity value of the F]PSMA-BCH reference standard was corrected);

[0221] PA (standard) is the fluoride content in the reference solution. 19 F]PSMA-BCH average peak area.

[0222] The standard specifies that the concentration should not exceed 10.00 µg / ml.

[0223] (5) Radiochemical purity

[0224] Test solution: Al 18 F-PSMA-BCH injection.

[0225] Chromatographic conditions:

[0226] Chromatographic column: Octadecylsilane-bonded silica gel as the packing material (e.g., Agilent Eclipse Plus C18 column, 250 × 4.6 mm, 5 μm)

[0227] Mobile phase A: 20 mM sodium acetate solution

[0228] Mobile phase B: Acetonitrile

[0229] Flow rate: 1.0 ml / min

[0230] Detector: Radioactive detector

[0231] Injection volume: 20-100 μl (For determining radiochemical purity (RCP), the injection volume of the test solution may need to be adjusted according to batches with low and / or high radioactivity concentrations to obtain a radioactivity concentration suitable for the detection range of the radioactivity detector).

[0232] Gradient elution procedure: Time (min) Mobile phase A (%) Mobile phase B (%) 0 95 5 5.0 95 5 25.0 50 50 30.0 50 50 30.1 95 5 35.0 95 5

[0233] The standard stipulates that the purity of the main peak, calculated using the area normalization method, should not be less than 90.0%.

[0234] (6) Other project assessment methods

[0235] For the bacterial endotoxin test, refer to Method 1, Gel Method, Part IV, General Chapter 1143, Chinese Pharmacopoeia 2020 Edition; for the sterility test, refer to Method 2, Direct Inoculation Method, Part IV, General Chapter 1101, Direct Inoculation Method, Chinese Pharmacopoeia 2020 Edition; for the radioactivity concentration test, refer to Method 1401, General Chapter IV, Chinese Pharmacopoeia 2020 Edition.

[0236] This embodiment applies to three batches of Al. 18 The long-term stability and accelerated stability studies of the F-PSMA-BCH injection samples are shown in Tables 10-15.

[0237] Table 10 shows the accelerated test results for batch YT-085-A (batch size: 409 mCi).

[0238] Table 11 Accelerated Test Results for Batch YT-085-B (Batch Size: 101 mCi)

[0239] Table 12 Accelerated Test Results for Batch YT-085-C (Batch Size: 411 mCi)

[0240] Table 13 Long-term test results for batch YT-085-A (batch size: 409 mCi)

[0241] Table 14. Long-term test results for batch YT-085-B (batch size: 101 mCi)

[0242] Table 15. Long-term test results for batch YT-085-C (batch size: 411 mCi)

[0243] After 8 hours of long-term and accelerated testing, each batch of Al 18 All indicators of F-PSMA-BCH injection meet the quality standards, indicating that the Al obtained using the preparation method provided by this invention... 18 F-PSMA-BCH injection exhibits good stability under storage conditions of 30℃±2℃ and 40℃±2℃. Furthermore, the results above also show that each batch of Al... 18 The data trends of F-PSMA-BCH injection at various time points were basically consistent, and the batch-to-batch homogeneity of the product was good, which indicates that the preparation method provided by the present invention also has good stability.

[0244] The above description represents only preferred embodiments and is provided as an example only, not as a limitation on the combination of features necessary for carrying out the invention. The provided headings are not intended to limit the various embodiments of the invention. Terms such as “comprising,” “including,” and “including” are not intended to be limiting. Furthermore, unless otherwise stated, the plural form is included when not modified by a numeral, and “or” or “or” means “and / or.” Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0245] All disclosures and patents mentioned in this application are incorporated herein by reference. Various modifications and variations of the methods and compositions described herein will be apparent to those skilled in the art without departing from the scope and spirit of the invention. While the invention has been described through specific preferred embodiments, it should be understood that the claimed invention should not be unduly limited to these specific embodiments. In fact, various variations of the described modes of carrying out the invention that will be apparent to those skilled in the art are intended to be included within the scope of the appended claims.

Claims

1. An Al 18 A method for preparing F-labeled PSMA radiopharmaceuticals, characterized in that, The radiopharmaceutical mentioned above contains Al 18 An injection solution of an F-labeled PSMA radiopharmaceutical intermediate, wherein the structure of the PSMA radiopharmaceutical intermediate is shown in formula (I), and the preparation method comprises the following fluorination process: （I） A potassium hydrogen phthalate solution containing aluminum chloride hexahydrate, a dimethyl sulfoxide solution containing a PSMA radiopharmaceutical intermediate, and a potassium hydrogen phthalate solution were added to a solution containing fluorine. 18 The reaction is carried out in a reaction vessel containing the F] ion solution at a temperature of approximately 75-85°C for 15 minutes. The molar ratio of aluminum chloride hexahydrate to the PSMA radiopharmaceutical intermediate is 0.7-0.8:

1. The specification of the injection solution is 37-1850 MBq / ml.

2. The preparation 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 approximately 0.6-0.9 mg / ml.

3. The preparation method according to claim 1, characterized in that, In the dimethyl sulfoxide solution containing the PSMA radiopharmaceutical intermediate, the concentration of the PSMA radiopharmaceutical intermediate is approximately 0.4-0.6 mg / ml.

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

5. The preparation 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 radiopharmaceutical intermediate is 1:5-10.

6. The preparation method according to claim 1, characterized in that, The volume ratio of the dimethyl sulfoxide solution containing the PSMA radiopharmaceutical intermediate to the potassium hydrogen phthalate solution is approximately 5-10:

1.

7. The preparation method according to claim 1, characterized in that, The Al 18 F-labeled PSMA radiopharmaceuticals also contain sterile water for injection and anhydrous ethanol.

8. The preparation method according to claim 7, characterized in that, The Al 18 The batch formulation composition (in 22 ml) of the F-labeled PSMA radiopharmaceutical is as follows:

9. The use of the preparation method according to any one of claims 1-8 in the preparation of imaging drugs for diagnosing patients with prostate cancer.

10. The use of the preparation method according to any one of claims 1-8 in the preparation of an imaging drug for diagnosing prostate-specific membrane antigen (PSMA) positive lesions in patients with prostate cancer.

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