This proposal is aimed at the development of radiotracer that map the density of cholinergic neurons in mammalian brain. The specific objective is to develop an iodine-123 or technetium-99m labeled tracer that will allow external detection of regional cholinergic neuron density of the human brain by single photon emission tomography (SPECT). Such an agent would have potential widespread use in Nuclear Medicine for assessing the extent of cholinergic neuron involvement in Alzheimer's disease, Parkinson's disease with dementia, olivopontocerebellar atrophy, and progressive supranuclear palsy. We have adopted benzovesamicol and vesamicol, potent inhibitors of the vesicular acetylcholine transporter, as the design bases for development of a presynaptic cholinergic nerve marker. Work in our laboratory under the current grant produced (-)-5- [123I]iodobenzovesamicol which underwent successful preclinical testing and is presently under evaluation in humans. This tracer would be greatly improved if the brain uptake was enhanced by lowering the lipophilicity (log P=3.43) of the tracer to the optimum range of log P=1- 2. This has been difficult to accomplish in the benzovesamicol series because of low synthetic yields and isomeric mixtures. Hence, a new structural class of benzovesamicols, the benzovesamicols, the benzo(a) series, will be synthesized, which favors regiospecific incorporation of radioiodine ortho to log P-lowering substituents such as hydroxy and amino groups. Two additional radioiodine-based approaches, quinoline analogs of benzovesamicol and 4-iodo-vinylvesamicol, should possess improved lipophilicitities while maintaining high affinity for the vesamicol receptor. Three types of [99mTc]-N2S2 derivatives of vesamicol will be synthesized which should possess log P values, molecular volumes, and molecular weights that make them likely choices to cross the blood-brain barrier and map the cholinergic nerve terminals. A thiosemicarbazone vesamicol analogue will also be prepared for both Tc-99m and Cu-62 labeling. Evaluation of promising tracers will include gross regional brain distribution, quantitative autoradiography, in vivo pharmacological blocking/receptor saturation studies, in vitro competitive binding to the vesamicol receptor in rat cortical homogenates, tracer kinetic analysis in rat and monkey, the latter by SPECT, and correlation with other cholinergic markers such as choline acetyltransferase.
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