Antitumor Imidazotetrazines. 40. Radiosyntheses of [4-11C-C arbonyl]- and [3-N-11C-M ethyl]-8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (Temozolomide) for Positron Emission Tomography (PET) Studies

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 posi...

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Published in:Journal of medicinal chemistry 2002-12, Vol.45 (25), p.5448-5457
Main Authors: Brown, Gavin D, Luthra, Sajinder K, Brock, Cathryn S, Stevens, Malcolm F. G, Price, Patricia M, Brady, Frank
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Brain Diseases - diagnostic imaging
Carbon Radioisotopes
Cyclization
Dacarbazine - analogs & derivatives
Dacarbazine - chemical synthesis
Dacarbazine - chemistry
Dacarbazine - pharmacology
Gas Chromatography-Mass Spectrometry
Humans
Isotope Labeling
Magnetic Resonance Spectroscopy
Parietal Lobe - diagnostic imaging
Prodrugs - chemical synthesis
Prodrugs - chemistry
Prodrugs - pharmacology
Structure-Activity Relationship
Temozolomide
Tomography, Emission-Computed
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Summary: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 [11C-methyl]methyl isocyanate (8) gave [3-N-11C-methyl]temozolomide (9) in 14−20% radiochemical yield from [11C-methyl]methyl isocyanate (8) (decay corrected). The position of radiolabeling in the 3-N-methyl group was confirmed by [11/13C]colabeling and subsequent carbon-13 NMR spectroscopy. Similarly, the reaction of 5-diazoimidazole-4-carboxamide (7) with [11C-carbonyl]methyl isocyanate (10) gave [4-11C-carbonyl]temozolomide (11) in 10−15% radiochemical yield from [11C-carbonyl]methyl isocyanate (10) (decay corrected). Apyrogenic samples of [3-N-11C-methyl]temozolomide (9) and [4-11C-carbonyl]temozolomide (11), with good chemical and radiochemical purities, have been prepared and used in human PET studies.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm020921f