SYNTHESES OF 14C LABELED NITRONE SPIN TRAPS

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Some commonly used nitrone spin traps, including alpha-phenyl-N-t- butylnitrone (PBN), 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), and alpha-(4- pyridyl-1-oxide)-N-t-butylnitrone (4-POBN), possess many potentially useful therapeutic and prophylactic activities such as lowering septic shock fatality, reversing the effects of aging, cardioprotection and vasodilation in ischemia/reperfusion models of myocardial infarction. Their 14C-labeled analogs are needed to facilitate disposition and metabolism studies in further pharmacological evaluation of the nitrones. Using unlabeled materials and reagents in cold runs, Phase I has demonstrated all the synthetic steps leading to a commercially viable preparation of . and 4-POBN-alpha-14C. Efforts in Phase I have also introduced two new alternate steps in th existing route to DMPO to provide a much more convenient and productive approach without the hazards of explosion and acute toxicity of acrolein. This Phase II application proposes to complete the synthetic development, including: (a) the actual "hot" synthesis of the 14C-labeled spin traps named above; (b) cold runs and then hot synthesis of MeO3-PBN-alpha14C; (c) determination of the stability of these radiolabeled nitrones to recommend appropriate storage and handling methods: and (d) repurification procedures for the aged nitrones to regain greater than or equal to 98% purity.