PET示踪剂11C-氟马西尼的合成及质量控制

摘要

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 endproduct.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.%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200μL 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.