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Synthesis and Quality Control of the PET Radiotracer 11C-Flumazenil

LI Qi-ming;JIN Rong-bing;WANG Fang-yang;TANG Yi;YAO Zhi-peng   

  1. Nuclear Medicine Department of Daping Hospital and Research Institute of Surgery,Third Military Medical University, Chongqing 400042, China
  • Online:2017-02-20 Published:2017-03-06

PET示踪剂11C-氟马西尼的合成及质量控制

李奇明;金榕兵;王方洋;唐毅;姚志鹏   

  1. 第三军医大学 第三附属医院 核医学科,重庆400042

Abstract:

To produce the radioligand 11C-flumazenil at very high quality and specific radioactivity for routinely clinical imaging , the procedures for its synthesis and purification were developed with domestic PET-CM-3H-IT-I synthesis module, and 11C-CH3I was used as methylation agent. 11C-CH3I was first synthesized by liquid phase reaction, the synthesis conditions of radiotracer 11C-flumazenil were studied ,which included the alkali strength, alkali equivalent, solvents, temperature and purification conditions for the product. The optimum conditions were that 11C-CH3I was bubbled through a reactor at room temperature , containing a DMF solution of 1 mg desmethylflumazenic precursor and 1 mg NaH, the reaction was conducted at 55 ℃ for 2 minutes. The reaction solution was first transferred to Semi-HPLC for purification, the mobile phase consisted of acetonitrile-acetic acid-water (30∶4∶66), the flow rate was 5.0 mL/min, then the crude product was purified by C-18 Solid-Extraction Purification(SEP), the product retained on SEP cartridge was eluted with 1 mL alcohol, the eluant was diluted with 6 mL sterile injection water, the dilute solution passed through sterile membrane to end-product. The radiochemical purity and specific radioactivity were measured by High Performance Liquid Chromatograph (HPLC) with the mobile phase of acetonitrile-acetic acid-water (30∶4∶66), and the column was ODS (250 mm×4.6 mm, 5 μm). The results showed that the total synthesis time was (26±2) minutes from 11C-CO2 to obtain 11C-flumazenil injection solution, the synthesis yield of 11C-flumazenil was (45±4)% (decay corrected, n=10), the radiochemical purity was over 99% at specific activity of 4.7 TBq/mmol, the radioactivity concentration was 370~550 MBq/mL. The injection solution was proved to be sterile and pyrogen free. The radiochemical yield was increased greatly by optimizing the reaction conditions ,11C-flumazenil was synthesized from 11C-CH3I with domestic C-11 synthesis module, the quality and quantity of 11C-flumazenil was confirmed to be suitable for clinic use.

Key words: 11C-Flumazenil, synthesis, quality control

摘要:

为制备满足临床应用需要的11C-氟马西尼,以11C-CH3I为甲基化试剂,使用国产PET-CM-3H-IT-I型模块对11C-氟马西尼的制备及纯化方法进行改进。用液相法合成11C-CH3I,研究反应溶剂、碱性强度、碱量、反应温度对合成效率的影响,优化11C-氟马西尼的合成条件。优化后的条件为:先将11C-CH3I在室温下通入含1 mg去甲基氟马西尼前体和1 mg 氢化钠的200 μL DMF溶液中,加热至55 ℃恒温反应2 min。反应物经半制备HPLC分离收集粗产品,再经SEP-PAK C-18柱固相萃取,对产品质量进行分析。结果表明,以捕获11C-CO2计算,11C-氟马西尼合成时间为(26±2) min,经衰减校正后放化产率为(45±4)%(n=10),产品放化纯度大于99%,放射性浓度为370~550 MBq/mL,比活度为4.7 TBq/mmol,产品细菌和热源检测结果符合规定。通过优化反应条件,大幅度提高了标记率,用国产合成模块能够制备高质量、高比活度的11C-氟马西尼,满足临床应用需求。

关键词: 11C-氟马西尼, 合成, 质量控制