外周苯二氮卓受体PET显像剂^(11)C-PK 11195的合成

Radiosynthesis of peripheral benzodiazepine receptor radioligand [N-methyl-^(11)C]PK 11195 as an imaging agent for positron emission tomography

目的研究外周苯二氮卓受体PET显像剂N-[11C]甲基-N-(1-甲基丙基)-1-(2-氯苯基)异喹啉-3-氨甲酰(11C-PK11195)在国内现有合成模块上进行自动化合成工艺,并建立11C-PK11195的质量控制方法。方法利用国产11C-CH3I合成模块生产的11C-CH3I与1-(2-氯苯基)-N-(1-甲基丙基)-异喹啉-3-氨甲酰去甲基前体在TracerLabFXF-N自动化合成模块中进行甲基化反应,利用半制备型HPLC系统进行分离纯化制备11C-PK11195,并进行放化纯度、化学纯度、稳定性检测和异常毒性检查。同时探讨了影响11C-PK11195合成的因素。结果从11C-CO2生产到11C-PK11195合成结束,总的合成时间约35min,甲基化反应时间为3～4min,平均放化产率为(33±5)%,11C-PK11195的放化纯度和化学纯度均大于99%,比活度为30～65GBq/μmol(EOS)。11C-PK11195的稳定性高,毒性低。结论利用该方法能够合成出适合临床应用的11C-PK11195,其合成程序也适合于在国内其他模块中应用。

Objective To establish a protocol of automated synthesis of 1-（2-chlorophenyl）-N-[11C]methyl-N-（1-methylpropyl） -3-isoquinoline carboxamide （11C-PK11195） as the positron-emitter-labeled ligand for peripheral benzodiazepine receptor （PBR） using a commercial synthesizer and explore the quality control methods for the resulting product. Methods 11C-methyl iodide （11C-CH3I） was synthesized via liquid-phase distillation approach using a 11C-iodomethane synthesizer. 11C-PK11195 was prepared by 11C-methylation of 1- （2-chlorophenyl）-N- （1-methylpropyl）-3-isoquinoline carboxamide （N-demethyl-PK 11195） as the precursor with 11C-CH3I and purified by semi-preparative reversed phase high performance liquid chromatography （HPLC）. The radiochemical purity, chemical purity and stability of the product were evaluated by HPLC, and the toxicity was assessed in normal mice. The factors that affected 11C-PK11195 synthesis were also studied. Results 11C-PK11195 was successfully synthesized using the TracerLab FXF-N synthesizer. The synthesis time was about 35 min from the end of 11C-carbon dioxide production by cyclotron to the end of 11C-PK11195 synthesis （EOS）, with a 11C-methylation reaction time of 3-4 min. The uncorrected radiochemical yield for 11C-methylation was （33 ±5）% . Analysis with radio-analytical HPLC showed a radiochemical purity and chemical purity of the product both exceeding 99%, with a specific radioactivity of 30-65 GBq/μmol at EOS （from the end of radionuclide production）. The 11C-PK11195 synthesized was radiochemically stable at room temperature and showed low toxicity in normal mice. Conclusion The 11C-PK11195 injection can be conveniently prepared using an automated synthesizer for clinical use in positron emission tomography.