抗肿瘤咪唑并四嗪类化合物。40. 用于正电子发射断层扫描（PET）研究的[4-¹¹C-羰基]-和[3-N-¹¹C-甲基]-8-氨基甲酰基-3-甲基咪唑并[5,1-d]-1,2,3,5-四嗪-4(3H)-酮（替莫唑胺）的放射性合成。

Antitumor imidazotetrazines. 40. Radiosyntheses of [4-11C-carbonyl]- and [3-N-11C-methyl]-8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (temozolomide) for positron emission tomography (PET) studies.

作者信息

Brown Gavin D, Luthra Sajinder K, Brock Cathryn S, Stevens Malcolm F G, Price Patricia M, Brady Frank

机构信息

MRC Clinical Sciences Centre, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.

出版信息

J Med Chem. 2002 Dec 5;45(25):5448-57. doi: 10.1021/jm020921f.

DOI:10.1021/jm020921f

PMID:12459013

Abstract

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 [(11)C-methyl]methyl isocyanate (8) gave [3-N-(11)C-methyl]temozolomide (9) in 14-20% radiochemical yield from [(11)C-methyl]methyl isocyanate (8) (decay corrected). The position of radiolabeling in the 3-N-methyl group was confirmed by [(11/13)C]colabeling and subsequent carbon-13 NMR spectroscopy. Similarly, the reaction of 5-diazoimidazole-4-carboxamide (7) with [(11)C-carbonyl]methyl isocyanate (10) gave [4-(11)C-carbonyl]temozolomide (11) in 10-15% radiochemical yield from [(11)C-carbonyl]methyl isocyanate (10) (decay corrected). Apyrogenic samples of [3-N-(11)C-methyl]temozolomide (9) and [4-(11)C-carbonyl]temozolomide (11), with good chemical and radiochemical purities, have been prepared and used in human PET studies.

摘要

8-氨甲酰基-3-甲基咪唑并[5,1-d]-1,2,3,5-四嗪-4(3H)-酮（替莫唑胺，1）是一种抗癌前体药物。作为使用正电子发射断层扫描（PET）探究其假定作用模式的研究的一部分，我们开发了两种快速放射性合成路线来制备用短寿命正电子发射体碳-11（半衰期t(1/2)=20.4分钟）标记的替莫唑胺。5-重氮咪唑-4-甲酰胺（7）与新型标记剂[(11)C-甲基]甲基异氰酸酯（8）反应，从[(11)C-甲基]甲基异氰酸酯（8）（衰变校正）以14 - 20%的放射化学产率得到[3-N-(11)C-甲基]替莫唑胺（9）。通过[(11/13)C]共标记和随后的碳-13核磁共振光谱确定了放射性标记在3-N-甲基基团中的位置。同样，5-重氮咪唑-4-甲酰胺（7）与[(11)C-羰基]甲基异氰酸酯（10）反应，从[(11)C-羰基]甲基异氰酸酯（10）（衰变校正）以10 - 15%的放射化学产率得到[4-(11)C-羰基]替莫唑胺（11）。已制备了具有良好化学和放射化学纯度的[3-N-(11)C-甲基]替莫唑胺（9）和[4-(11)C-羰基]替莫唑胺（11）的无热原样品，并用于人体PET研究。