Okamura Toshimitsu, Kikuchi Tatsuya, Ogawa Masanao, Zhang Ming-Rong
Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan.
SHI Accelerator Service, Ltd., 7-1-1 Nishigotanda, Shinagawa-ku, Tokyo, 141-0031, Japan.
EJNMMI Radiopharm Chem. 2024 Feb 9;9(1):10. doi: 10.1186/s41181-024-00240-8.
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-[C]methylpurine ([C]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 [C]7m6BP was low, limiting its clinical application, because the methylation of the precursor with [C]CHI provided primarily the undesired isomer, 6-bromo-9-[C]methylpurine ([C]9m6BP). To increase the RCY of [C]7m6BP, we investigated conditions for improving the [C]7m6BP/[C]9m6BP selectivity of the methylation reaction.
[C]7m6BP was manually synthesized via the methylation of 6-bromopurine with [C]CHI 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 [C]7m6BP/[C]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 C-methylation in the less polar solvents, and the manual conditions could not be directly translated to an automated synthesis. [C]Methyl triflate ([C]CHOTf) was thus used as a methylating agent to increase the conversion at a lower temperature. The C-methylation using [C]CHOTf at 100 °C proceeded efficiently in THF, 2-MeTHF, and AcOEt with maintenance of the improved selectivity. Starting from 28 to 34 GBq [C]CO, [C]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 [C]7m6BP/[C]9m6BP selectivity in the methylation reaction, and the improved method provided [C]7m6BP with sufficient radioactivity for clinical use.
多药耐药相关蛋白1（MRP1）是一种能量依赖性外排泵，在各种组织中广泛表达，并参与许多生理和病理生理过程。6-溴-7-[碳-11]甲基嘌呤（[碳-11]7m6BP）有望用于评估人脑中的MRP1活性和肺部情况。然而，[碳-11]7m6BP合成中的放射化学产率（RCY）较低，限制了其临床应用，因为用[碳-11]碘甲烷对前体进行甲基化主要得到不需要的异构体6-溴-9-[碳-11]甲基嘌呤（[碳-11]9m6BP）。为了提高[碳-11]7m6BP的RCY，我们研究了改善甲基化反应中[碳-11]7m6BP/[碳-11]9m6BP选择性的条件。
[碳-11]7m6BP通过在碳酸钾存在下，于不同溶剂和不同温度下用[碳-11]碘甲烷对6-溴嘌呤进行甲基化反应手动合成5分钟。与传统用于6-卤嘌呤烷基化的溶剂丙酮、乙腈和N,N-二甲基甲酰胺相比，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[碳-11]7m6BP/[碳-11]9m6BP的选择性从1:1提高到了2:1。然而，在极性较小的溶剂中进行碳甲基化需要更高的温度（140°C或180°C），并且手动条件无法直接转化为自动化合成。因此，使用[碳-11]三氟甲磺酸甲酯（[碳-11]CHOTf）作为甲基化剂以在较低温度下提高转化率。在100°C下使用[碳-11]CHOTf进行的碳甲基化反应在THF、2-MeTHF和AcOEt中高效进行，并保持了提高后的选择性。从28至34GBq的[碳-11]CO开始，在轰击结束后约30分钟，用THF制备出2.3 - 2.6GBq的[碳-11]7m6BP，用AcOEt制备出2.7 - 3.3GBq，用2-MeTHF制备出2.8 - 3.9GBq（每种溶剂n = 3）。THF、2-MeTHF和AcOEt的分离RCY（衰变校正后）分别为24 - 28%、29 - 35%和22 - 31%（n = 3）。
使用THF、2-MeTHF和AcOEt提高了甲基化反应中[碳-11]7m6BP/[碳-11]9m6BP的选择性，改进后的方法为临床应用提供了具有足够放射性的[碳-11]7m6BP。
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