The objectives of Phase II of this proposal are to continue the development and evaluation of molecular probes for D1 and D2 dopamine receptors. Dysfunctions of brain dopamine systems have been implicated in neurological, psychiatric and endocrine disorders and dopaminergic agents are widely prescribed to alleviate their symptoms. Brain dopamine receptors are the molecular targets of the most effective drugs used in the treatment of schizophrenia and Parkinson's disease. The cellular and subcellular distribution and mobility of these receptors remain poorly understood because the available receptor probes do not provide the resolution or detection capabilities required for this vital research. We propose to synthesize fluorescent and biotin probes for dopamine receptors using antagonist drugs as precursors. We will evaluate the affinity and receptor selectivity at D1 and D2 dopamine receptors, brain distribution and cellular distribution in progressive stages. Receptor- selective molecular probes will permit detection of the receptors by fluorescence, light, and electron microscopy and will be useful for mapping cellular and subcellular distribution of dopamine receptors, prior to and after drug treatment, for monitoring receptor mobility, and cell-sorting of dopamine receptor-containing cells. These novel compounds may expedite a clearer understanding of dopamine receptor function in the diseased state and drug-induced adaptive processes. They may furthermore create novel methodologies in psycho- and neuropharmacology research.
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