6-Bromo-7-[11C]methylpurine ([11C]BMP) is a radiotracer for positron emission tomography (PET) to measure multidrug resistance-associated protein 1 (MRP1) transport activity in different tissues. Previously reported radiosyntheses of [11C]BMP afforded a mixture of 7- and 9-[11C]methyl regioisomers. To prepare for clinical use, we here report an improved regioselective radiosynthesis of [11C]BMP, the results of a non-clinical toxicity study as well as human dosimetry estimates based on mouse PET data. [11C]BMP was synthesised by regioselective N7-methylation of 6-bromo-7H-purine (prepared under good manufacturing practice) with [11C]methyl triflate in presence of 2,2,6,6-tetramethylpiperidine magnesium chloride in a TRACERlab™ FX2 C synthesis module. [11C]BMP was obtained within a total synthesis time of approximately 43 min in a decay-corrected radiochemical yield of 20.5 ± 5.2%, based on starting [11C]methyl iodide, with a radiochemical purity > 99% and a molar activity at end of synthesis of 197 ± 130 GBq/μmol (n = 28). An extended single-dose toxicity study conducted in male and female Wistar rats under good laboratory practice after single intravenous (i.v.) administration of unlabelled BMP (2 mg/kg body weight) revealed no test item related adverse effects. Human dosimetry estimates, based on dynamic whole-body PET data in female C57BL/6J mice, suggested that an i.v. injected activity amount of 400 MBq of [11C]BMP will deliver an effective dose in the typical range of 11C-labelled radiotracers. [11C]BMP can be produced in sufficient amounts and acceptable quality for clinical use. Data from the non-clinical safety evaluation showed no adverse effects and suggested that the administration of [11C]BMP will be safe and well tolerated in humans.

中文翻译：

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将 6-bromo-7-[11C]methylpurine 推向临床应用：改进的区域选择性放射合成、非临床毒性数据和人体剂量测定估计

6-Bromo-7-[11C]methylpurine ([11C]BMP) 是一种用于正电子发射断层扫描 (PET) 的放射性示踪剂，用于测量不同组织中的多药耐药相关蛋白 1 (MRP1) 转运活性。先前报道的[11C]BMP放射合成提供了7-和9-[11C]甲基区域异构体的混合物。为了准备临床使用，我们在此报告了改进的 [11C]BMP 区域选择性放射合成、非临床毒性研究的结果以及基于小鼠 PET 数据的人体剂量测定估计。 [11C]BMP 是在 TRACERlab™ 中，在 2,2,6,6-四甲基哌啶氯化镁存在下，通过 6-溴-7H-嘌呤（在良好生产规范下制备）与[11C]三氟甲磺酸甲酯进行区域选择性 N7-甲基化合成的FX2 C 综合模块。 [11C]BMP 在约 43 分钟的总合成时间内获得，基于起始[11C]甲基碘，衰变校正的放射化学产率为 20.5 ± 5.2%，放射化学纯度 > 99%，最终摩尔活性合成量为 197 ± 130 GBq/μmol (n = 28)。在良好的实验室实践下，在单次静脉 (iv) 施用未标记的 BMP（2 毫克/千克体重）后，对雄性和雌性 Wistar 大鼠进行了一项延长的单剂量毒性研究，结果显示没有与测试项目相关的不良反应。基于雌性 C57BL/6J 小鼠动态全身 PET 数据的人体剂量测定估计表明，静脉注射 400 MBq 的 [11C]BMP 活性量将提供 11C 标记放射性示踪剂典型范围内的有效剂量。 [11C]BMP 可以以足够的量和可接受的质量生产以供临床使用。非临床安全性评估数据显示没有不良反应，表明 [11C]BMP 的给药在人类中是安全且耐受性良好的。