Improved synthesis of 6-bromo-7-[11C]methylpurine for clinical use
Abstract 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-[11C]methylpurine ([11C]7m6BP) is expected to be useful for the assessment o...
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| Format: | Article |
| Language: | English |
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SpringerOpen
2024-02-01
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| Series: | EJNMMI Radiopharmacy and Chemistry |
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| Online Access: | https://doi.org/10.1186/s41181-024-00240-8 |
| _version_ | 1827325666799910912 |
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| author | Toshimitsu Okamura Tatsuya Kikuchi Masanao Ogawa Ming-Rong Zhang |
| author_facet | Toshimitsu Okamura Tatsuya Kikuchi Masanao Ogawa Ming-Rong Zhang |
| author_sort | Toshimitsu Okamura |
| collection | DOAJ |
| description | Abstract 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-[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. Results [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. Conclusions 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. |
| first_indexed | 2024-03-07T14:33:34Z |
| format | Article |
| id | doaj.art-078955d33f6f4a46bad4dbf66c7b38e3 |
| institution | Directory Open Access Journal |
| issn | 2365-421X |
| language | English |
| last_indexed | 2024-03-07T14:33:34Z |
| publishDate | 2024-02-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | EJNMMI Radiopharmacy and Chemistry |
| spelling | doaj.art-078955d33f6f4a46bad4dbf66c7b38e32024-03-05T20:46:16ZengSpringerOpenEJNMMI Radiopharmacy and Chemistry2365-421X2024-02-019111210.1186/s41181-024-00240-8Improved synthesis of 6-bromo-7-[11C]methylpurine for clinical useToshimitsu Okamura0Tatsuya Kikuchi1Masanao Ogawa2Ming-Rong Zhang3Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and TechnologyDepartment of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and TechnologyDepartment of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and TechnologyDepartment of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, National Institutes for Quantum Science and TechnologyAbstract 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-[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. Results [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. Conclusions 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.https://doi.org/10.1186/s41181-024-00240-86-BromopurineCarbon-11MethylationMRP1Regioselectivity |
| spellingShingle | Toshimitsu Okamura Tatsuya Kikuchi Masanao Ogawa Ming-Rong Zhang Improved synthesis of 6-bromo-7-[11C]methylpurine for clinical use EJNMMI Radiopharmacy and Chemistry 6-Bromopurine Carbon-11 Methylation MRP1 Regioselectivity |
| title | Improved synthesis of 6-bromo-7-[11C]methylpurine for clinical use |
| title_full | Improved synthesis of 6-bromo-7-[11C]methylpurine for clinical use |
| title_fullStr | Improved synthesis of 6-bromo-7-[11C]methylpurine for clinical use |
| title_full_unstemmed | Improved synthesis of 6-bromo-7-[11C]methylpurine for clinical use |
| title_short | Improved synthesis of 6-bromo-7-[11C]methylpurine for clinical use |
| title_sort | improved synthesis of 6 bromo 7 11c methylpurine for clinical use |
| topic | 6-Bromopurine Carbon-11 Methylation MRP1 Regioselectivity |
| url | https://doi.org/10.1186/s41181-024-00240-8 |
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