Search

CN-122010860-A - Al (aluminum) alloy18F-labeled PSMA radioactive drug, preparation method and application thereof

CN122010860ACN 122010860 ACN122010860 ACN 122010860ACN-122010860-A

Abstract

The invention provides a fluorination method of PSMA radioactive drug intermediate, and further provides a preparation method of an Al 18 F marked PSMA radioactive drug preparation based on the fluorination method, the fluorination method and the preparation method effectively reduce the requirement on the fluorination reaction temperature in the marking process while ensuring the marking aging, the radiochemical purity of the final product, the radiochemical conversion rate and the product yield through the adjustment of a reaction system, the preparation method of the PSMA radioactive pharmaceutical preparation marked by Al 18 F provided by the invention has good applicability and thorough reaction, the final product does not introduce new impurities due to the reduction of reaction temperature or the adjustment of a reaction system, and the preparation method can further reduce and control the types and the contents of the impurities in the final product, so that the medication safety of patients is further ensured. In addition, the fluorination method or the preparation method provided by the invention is used for obtaining the end product preparation product which has good batch-to-batch uniformity and good stability under the storage conditions of 30 ℃ plus or minus 2 ℃ and 40 ℃ plus or minus 2 ℃.

Inventors

  • WU XIAOMING
  • LI YAJING
  • MA WEIWEI
  • HE TIAN
  • WEN XUEJUN

Assignees

  • 烟台蓝纳成生物技术股份有限公司

Dates

Publication Date
20260512
Application Date
20250326

Claims (10)

  1. 1. A preparation method of an Al 18 F marked PSMA radioactive drug, which is characterized in that the radioactive drug is an injection containing an Al 18 F marked PSMA radioactive drug intermediate, the structure of the PSMA radioactive drug intermediate is shown as a formula (I), and the preparation method comprises the following fluorination process: (I) Adding a potassium hydrogen phthalate solution containing aluminum chloride hexahydrate, a dimethyl sulfoxide solution containing PSMA radioactive drug intermediates and a potassium hydrogen phthalate solution into a reaction container containing fluorine [ 18 F ] ion solution for reaction, wherein the reaction temperature is about 75-85 ℃, the reaction time is 15 minutes, the molar ratio of the aluminum chloride hexahydrate to the PSMA radioactive drug intermediates is 0.7-0.8:1, and the specification of the injection is 37-1850MBq/ml.
  2. 2. The method of claim 1, wherein the concentration of aluminum chloride hexahydrate in the potassium hydrogen phthalate solution containing aluminum chloride hexahydrate is between about 0.6 and about 0.9mg/ml.
  3. 3. The method of claim 1, wherein the concentration of PSMA radiopharmaceutical intermediate in the dimethyl sulfoxide solution containing PSMA radiopharmaceutical intermediate is about 0.4-0.6 mg/ml.
  4. 4. The method of claim 1, wherein the concentration of the potassium hydrogen phthalate solution is about 0.1 to about 1M.
  5. 5. The method of claim 1, wherein the volume ratio of potassium hydrogen phthalate solution containing aluminum chloride hexahydrate to dimethyl sulfoxide solution containing PSMA radiopharmaceutical intermediate is 1:5-10.
  6. 6. The method of claim 1, wherein the volume ratio of dimethyl sulfoxide solution to potassium hydrogen phthalate solution of the PSMA-containing radiopharmaceutical intermediate is about 5-10:1.
  7. 7. The method of claim 1, wherein the Al 18 F-labeled PSMA radiopharmaceutical further comprises sterile injectable water, absolute ethanol.
  8. 8. The method of claim 7, wherein the batch formulation (in 22 ml) of the Al 18 F-labeled PSMA radiopharmaceutical is as follows: Composition of the components Content of Al 18 F labeled PSMA radiopharmaceuticals 37-1850MBq/ml Sodium chloride injection 20ml Sterilized water for injection 0.4ml Absolute ethyl alcohol 1.6ml
  9. 9. Use of the method of any one of claims 1-8 for the preparation of an imaging medicament for diagnosing a patient with prostate cancer.
  10. 10. Use of the method of any one of claims 1-8 for the preparation of an imaging drug for diagnosing Prostate Specific Membrane Antigen (PSMA) positive lesions in a prostate cancer patient.

Description

PSMA radioactive drug marked by Al 18 F, preparation method and application thereof Technical Field The invention relates to the field of radiopharmaceuticals, in particular to an Al 18 F-marked PSMA radiopharmaceuticals, and a preparation method and application thereof. Background With the progress of aging of the population, the incidence of prostate cancer is the sixth of the incidence of male malignant tumor in China, and how to accurately detect the prostate cancer in early stage has become a clinical urgent problem. Nuclear medicine imaging can be used for noninvasive, visual, qualitative/quantitative monitoring at molecular and cellular level and involved in physiological and pathological processes in tumorigenesis and development processes, and has become an important means for clinical tumor detection. PSMA (Prostate Specific Membrane Antigen ) is used as a specific target to be highly expressed in prostate cancer cells, is highly expressed in advanced prostate cancer, is also specifically highly expressed in cells of prostate cancer metastasis, and has the expression degree obviously related to the tumor differentiation degree, the metastasis tendency, the hormone therapy sensitivity and the like, and the specific prostate cancer molecular probe targeting PSMA at the present stage has become a big hot spot for research. PSMA-BCH is a compound with PSMA targeting function composed of glutamic acid, lysine and naphthylalanine, which has a good application prospect in diagnosis and treatment of prostate cancer [ document 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 Al18F-PSMA-BCH for Prostate Cancer PET Imaging. J Nucl Med. 2019 Sep;60(9):1284-1292.]. currently labeled mainly with 68 Ga and 18 F for diagnostic probes of PSMA-like targeting compounds, 18 F (half-life of 109.8 minutes) has a longer half-life and higher positron energy than 68 Ga (half-life of 68 minutes), and 18 F can show a higher maximum standardized uptake value (SUVmax) and detection rate than 68 Ga [ document 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 [68Ga]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 clinically more preferable to select a 18 F-labeled molecular probe. According to the decay characteristic of 18 F nuclides, in order to ensure normal administration of the patient, the nuclear pharmacy needs to be produced immediately on the day of administration, and in order to ensure timeliness of the drug, the whole probe production preparation to delivery process is generally controlled within 4 hours, and the production and delivery of the probe also have a range radius limit of 3-4 hours, which has a strict limit on the time of the whole production process of the molecular probe. In addition, the conventional 18 F labeling method has the defects of long labeling time, high reaction temperature, low labeling rate and the like, and limits the application of the 18 F molecular probe. Document 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 Al18F-PSMA-BCH for Prostate Cancer PET Imaging. J Nucl Med. 2019 Sep;60(9):1284-1292.] discloses a manual method of labeling PSMA-BCH with Al 18 F by mixing 18F2 saline solution without carrier addition, sodium acetate buffer and AlCl 3 in sodium acetate buffer to form an Al 18 F complex, adding PSMA-BCH and heating at 110 ℃ for 15 minutes to perform fluorination. This method is a manual labeling method which will inevitably increase the chance of the operator coming into contact with the radionuclide, resulting in radiation damage to the operator due to unnecessary overexposure. Patent application publication No. CN110938041A discloses an automatic marking method of Al 18 F-PSMA-BCH in [0066] - [0080] of specification, which is to mix PSMA-BCH, alCl 3 and pH buffer, then add the captured 18 F into a fluorination reaction bottle loaded with aqueous solution of PSMA-BCH, alCl 3 and pH buffer for fluorination reaction at 110 ℃ for 15min. Although the method can effectively reduce the contact probability of operators and radionuclides, the fluorination reaction temperature is higher, so that the actual production process needs to be carried out in a high-temperature environment, and the high-temperature reaction environment theoretically generates more impurities, thereby bringing trouble to subsequent purification. In summary, how to provide a labeling method with low exposure, mild reaction conditions, good labeling rate and low impurity rate remains a challenge to be solved in the art. Disclosure of Invention In view of the above, the present invention provides a method for fluorinating a PSMA radi