Application of PET to the further understanding of the causes and development of neurological diseases will require more radiopharmaceuticals designed for specific aspects of neuronal biochemistry which might be involved. In this Project, new radiopharmaceuticals are proposed for in vivo studies of biochemical processes which may be important in numerous neurological disease, including Parkinson's, Huntington's, and Alzheimer's disease, among others. These new radiopharmaceuticals include markers of the mitochondrial electron transport chain, specifically at complex I, and radiotracers to study the formation of, concentration of or effects of reactive oxygen species such as free radicals. For study of complex I, it is proposed to prepare positron-emitter labeled derivatives of rotenone and related rotenoids. To study free radicals, appropriately labeled spin trapping agents based on the nitrone structure such as alpha-phenyl-t- butyl-nitrone (PBN) are proposed. This Project will undertake the radiochemical synthesis of these proposed new in vivo radiochemicals and their initial animal evaluation to determine distribution, kinetics and metabolism. Such new radiopharmaceuticals, when available for PET applications, could be used to examine numerous recent hypotheses of the underlying biochemical changes occurring in a large number of neurological disorders.
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