Improved synthesis of 6-bromo-7-[¹¹C]methylpurine for clinical use

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.