NON-CATECHOLIC L-DOPA ANALOGS

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The main objective of this research is the development of novel non- catecholic compounds which would be useful as tracers for the estimation of dopaminergic activity in the central nervous system. Brominated and fluorinated analogs of o-L-tyrosine and m-L-tyrosine and non-catecholic L-dihydroxyphenylalanines, 2,4-L-dopa, 2,5-L-dopa, 2,6-L-dopa and 3,5-L-dopa, will be prepared and characterized chemically, biochemically an pharmacologically using conventional methods. These compounds would not be substrates of the enzyme catechol-o-methyl-transferase (COMT) since each la k the essential enediol moiety. However, these compounds are expected to reta n important dopamine properties related to (1) cerebral uptake via carrier mediated transport through the blood brain barrier, (2) regionally selective on consistent with dopamine innervation, (3) vesicular storage in dopamine neurons, (4) regulated release and (5) metabolism by oxidation and excretion. Since the COMT metabolic pathway is blocked, less metabolites would be formed compared to dopamine. This would be an advantage since it may simplify the assessment of dopamine turnover in the living brain. Non-invasive estimation of CNS dopamine turnover may be possible by quantitative radionuclide imaging such as PET or SPECT. Assessment of dopamine activity may be useful in (1) the routine diagnosis of preclinical Parkinson's disease (PD) and other dopamine-related disorders, (2) monitoring therapy of these dopamine-related disorders, (3) gaining insights into the underlying causes of the incomplete success of L-dopa therapy in PD including dyskinesias and end-of-dose failures, and (4) in monitoring novel PD therapies such as neural tissue autotransplantation. In evaluating the suitability of these non-catecholic compounds as dopamine tracers, significant information on the structural requirements of the enzymes involved in CNS dopamine synthesis and metabolism will be obtained. Further, insights into the structural requirements of the transport system through the blood brain barrier, and also requirements for vesicular storage in dopamine neurons would result. This in turn may lead to a better understanding of structure activity relationships which may aid in the development of therapeutic agents for disorders involving central dopamine such as PD.