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

Autor: Okamura T; 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. okamura.toshimitsu@qst.go.jp., Kikuchi T; 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., Ogawa M; 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., Zhang MR; 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.
Jazyk: angličtina
Zdroj: EJNMMI radiopharmacy and chemistry [EJNMMI Radiopharm Chem] 2024 Feb 09; Vol. 9 (1), pp. 10. Date of Electronic Publication: 2024 Feb 09.
DOI: 10.1186/s41181-024-00240-8
Abstrakt: Background: 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-[ 11 C]methylpurine ([ 11 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 [ 11 C]7m6BP was low, limiting its clinical application, because the methylation of the precursor with [ 11 C]CH 3 I provided primarily the undesired isomer, 6-bromo-9-[ 11 C]methylpurine ([ 11 C]9m6BP). To increase the RCY of [ 11 C]7m6BP, we investigated conditions for improving the [ 11 C]7m6BP/[ 11 C]9m6BP selectivity of the methylation reaction.
Results: [ 11 C]7m6BP was manually synthesized via the methylation of 6-bromopurine with [ 11 C]CH 3 I 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 [ 11 C]7m6BP/[ 11 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 11 C-methylation in the less polar solvents, and the manual conditions could not be directly translated to an automated synthesis. [ 11 C]Methyl triflate ([ 11 C]CH 3 OTf) was thus used as a methylating agent to increase the conversion at a lower temperature. The 11 C-methylation using [ 11 C]CH 3 OTf at 100 °C proceeded efficiently in THF, 2-MeTHF, and AcOEt with maintenance of the improved selectivity. Starting from 28 to 34 GBq [ 11 C]CO 2 , [ 11 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.
Conclusions: The use of THF, 2-MeTHF, and AcOEt improved the [ 11 C]7m6BP/[ 11 C]9m6BP selectivity in the methylation reaction, and the improved method provided [ 11 C]7m6BP with sufficient radioactivity for clinical use.
(© 2024. The Author(s).)
Databáze: MEDLINE
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