Multidrug resistance-associated protein 1 (MRP1), an energy-dependent efflux pump, is expressed widely in various tissues and contributes to many physiological and pathophysiological processes. 6-Bromo-7-[11C]methylpurine ([11C]7m6BP) is expected to be useful for the assessment of MRP1 activity in the human brain and lungs. However, the radiochemical yield (RCY) in the synthesis of [11C]7m6BP was low, limiting its clinical application, because the methylation of the precursor with [11C]CH3I provided primarily the undesired isomer, 6-bromo-9-[11C]methylpurine ([11C]9m6BP). To increase the RCY of [11C]7m6BP, we investigated conditions for improving the [11C]7m6BP/[11C]9m6BP selectivity of the methylation reaction. [11C]7m6BP was manually synthesized via the methylation of 6-bromopurine with [11C]CH3I in various solvents and at different temperatures in the presence of potassium carbonate for 5 min. Several less polar solvents, including tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), and ethyl acetate (AcOEt) improved the [11C]7m6BP/[11C]9m6BP selectivity from 1:1 to 2:1, compared with the conventionally used solvents for the alkylation of 6-halopurines, acetone, acetonitrile, and N,N-dimethylformamide. However, a higher temperature (140 °C or 180 °C) was needed to progress the 11C-methylation in the less polar solvents, and the manual conditions could not be directly translated to an automated synthesis. [11C]Methyl triflate ([11C]CH3OTf) was thus used as a methylating agent to increase the conversion at a lower temperature. The 11C-methylation using [11C]CH3OTf at 100 °C proceeded efficiently in THF, 2-MeTHF, and AcOEt with maintenance of the improved selectivity. Starting from 28 to 34 GBq [11C]CO2, [11C]7m6BP was produced with 2.3–2.6 GBq for THF, 2.7–3.3 GBq for AcOEt, and 2.8–3.9 GBq for 2-MeTHF at approximately 30 min after the end of bombardment (n = 3 per solvent). The isolated RCYs (decay corrected) for THF, 2-MeTHF, and AcOEt were 24–28%, 29–35%, and 22–31% (n = 3), respectively. The use of THF, 2-MeTHF, and AcOEt improved the [11C]7m6BP/[11C]9m6BP selectivity in the methylation reaction, and the improved method provided [11C]7m6BP with sufficient radioactivity for clinical use.

中文翻译：

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临床使用的 6-溴-7-[11C]甲基嘌呤的改进合成

多药耐药相关蛋白 1 (MRP1) 是一种能量依赖性外排泵，广泛表达于多种组织中，参与许多生理和病理生理过程。 6-Bromo-7-[11C]methylpurine ([11C]7m6BP) 预计可用于评估人脑和肺部的 MRP1 活性。然而，[11C]7m6BP 合成中的放射化学产率 (RCY) 较低，限制了其临床应用，因为[11C]CH3I 前体的甲基化主要提供了不需要的异构体 6-bromo-9-[11C]甲基嘌呤 ([11C]9m6BP)。为了提高[11C]7m6BP的RCY，我们研究了提高甲基化反应的[11C]7m6BP/[11C]9m6BP选择性的条件。 [11C]7m6BP 通过 6-溴嘌呤与 [11C]CH3I 在各种溶剂中、在不同温度下、在碳酸钾存在下甲基化 5 分钟来手动合成。与传统溶剂相比，几种极性较小的溶剂，包括四氢呋喃 (THF)、2-甲基四氢呋喃 (2-MeTHF) 和乙酸乙酯 (AcOEt) 将 [11C]7m6BP/[11C]9m6BP 选择性从 1:1 提高到 2:1 6-卤代嘌呤烷基化常用的溶剂有丙酮、乙腈和 N,N-二甲基甲酰胺。然而，在极性较小的溶剂中需要更高的温度（140°C或180°C）来进行11C甲基化，并且手动条件不能直接转化为自动合成。因此，[11C]三氟甲磺酸甲酯([11C]CH3OTf)被用作甲基化剂以提高较低温度下的转化率。使用 [11C]CH3OTf 在 100 °C 下在 THF、2-MeTHF 和 AcOEt 中有效进行 11C-甲基化，同时保持了改进的选择性。从 28 至 34 GBq [11C]CO2 开始，轰击结束后约 30 分钟，THF 产生 2.3–2.6 GBq，AcOEt 产生 2.7–3.3 GBq，2-MeTHF 产生 2.8–3.9 GBq，产生 [11C]7m6BP （每种溶剂 n = 3）。 THF、2-MeTHF 和 AcOEt 的分离 RCY（衰减校正）分别为 24-28%、29-35% 和 22-31% (n = 3)。 THF、2-MeTHF和AcOEt的使用提高了甲基化反应中[11C]7m6BP/[11C]9m6BP的选择性，改进的方法为[11C]7m6BP提供了足够的放射性用于临床。