Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 45, Issue 25, Pages 5448-5457Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm020921f
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8-Carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (temozolomide, 1) is an anticancer prodrug. As part of investigations to probe its postulated mode of action using PET we have developed two rapid radiosynthetic routes for the preparation of temozolomide labeled with the short-lived positron emitter, carbon-11 (t(1/2) = 20.4 min). Reaction of 5-diazoimidazole-4-carboxamide (7) with the novel labeling agent [C-11-methyllmethyl isocyanate (8) gave [3-N-C-11-methyl]temozolomide (9) in 14-20% radiochemical yield from [C-11-methyl]methyl isocyanate (8) (decay corrected). The position of radiolabeling in the 3-N-methyl group was confirmed by [C-11/13]colabeling and subsequent carbon-13 NMR spectroscopy. Similarly, the reaction of 5-diazoimidazole-4-carboxamide (7) with [C-13-carbonyl]methyl isocyanate (10) gave [4-C-11-carbonyl]temozolomide (11) in 10-15% radiochemical yield from [C-11-carbonyllmethyl isocyanate (10) (decay corrected). Apyrogenic samples of [3-N-C-11-methyl]temozolomide (9) and [4-C-11-carbonyl] temozolomide (11), with good chemical and radiochemical purities, have been prepared and used in human PET studies.
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