title: 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.
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.
authors.affiliation: MRC Clinical Sciences Centre, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. gavin.brown@ic.ac.uk
authors.forename: Gavin D
authors.initials: GD
authors.lastname: Brown
authors.forename: Sajinder K
authors.initials: SK
authors.lastname: Luthra
authors.forename: Cathryn S
authors.initials: CS
authors.lastname: Brock
authors.forename: Malcolm F G
authors.initials: MF
authors.lastname: Stevens
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Price
authors.forename: Frank
authors.initials: F
authors.lastname: Brady
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001927:Brain Diseases / Q000000981:diagnostic imaging; D002250:Carbon Radioisotopes; D003500:Cyclization; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007553:Isotope Labeling; D009682:Magnetic Resonance Spectroscopy; D010296:Parietal Lobe / Q000000981:diagnostic imaging; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000077204:Temozolomide; D014055:Tomography, Emission-Computed
chemical_list: D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D011355:Prodrugs; D003606:Dacarbazine; D000077204:Temozolomide