The long-term objective of this research is to relate the action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NMPTP) to the cause of Parkinson's disease. The recently reported finding that primates injected with relatively small doses of this drug developed symptoms and a histological picture closely resembling this disease raises the possibility that the effects produced by this drug might be the same as those causing Parkinsonism. In order to investigate the action of NMPTP, procedures are outlined for the organic synthesis of highly radioactive NMPTP and related derivatives based on the syntheses described in the literature. The radiolabeled compounds, will be administered to animals to determine the uptake and disposal of the drug. Experiments will be conducted to see if there is a cellular localization of the radioactive drug that corresponds to the tissues known to be affected in Parkinsonism. The subcellular distribution of the drug will also be determined. Although NMPTP produces parkinson-like effects there is no information as to whether it is actually the causitive agent or these effects are due to a metabolite of this compound. For this reason the metabolism of NMPTP will be studied using classical biochemical techniques in which the radioactive compound is incubated with tissue slices, homogenates, and subcellular fractions and the reaction products are isolated and characterized. Reaction products can then be synthesized and tested for the physiological effects. Once the overall metabolism of NMPTP has been elucidated, we should be aware of one or more compounds that may accumulate and are potentially toxic. These compounds will by synthesized using radioactive precursors and their interaction with cellular components derived from the central nervous system will be determined. A knowledge of the chemical structures will aid in predicting possible mechanisms of action. The use of synthetic radiolabeled compounds should provide an approach to uncovering the mechanism by which these compounds exert their toxic action.
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