The objectives of the proposed research are to develop improved molecular probes for specific cocaine recognition sites in primate brain and to provide fundamental information on the distribution and pharmacological properties of these sites in relation to cocaine abuse. The relatively low affinity and rapid dissociation of [3H]cocaine limited its suitability for these studies and a higher affinity cocaine congener [3H]CFT ([3H]WIN 35,428), which binds to virtually the same sites as [3H]cocaine, was developed. (3H]CFT was suitable for mapping high density cocaine recognition sites in brain, for monitoring dopamine nerve terminal degeneration in Parkinson's diseased brain and as a PET (positron emission tomography) imaging ligand. We propose to continue our ongoing studies with [3H]CFT to clarify the functional relevance of high- and low-affinity binding components for cocaine and to characterize cocaine binding sites in discrete brain regions revealed by autoradiographic mapping of [3H]CFT binding. Although [3H]CFT is an effective probe for cocaine recognition sites, its moderate affinity for the dopamine transporter, a principle target of cocaine in the brain, has prompted a search for higher affinity ligands. We will evaluate the higher affinity ligands [125I]RTI-55 and [3H]Lu 19-005, using techniques similar to those used in our initial studies with [3H]CFT. In addition, novel phenyltropane analogs (3-iodo, 4-chloro, 3,4-dichloro) will be synthesized or acquired, and evaluated in coordinated biochemical and behavioral studies. The relative potencies of these compounds for inhibiting [3H]CFT (dopamine transporter) and [3H]citalopram (serotonin transporter) binding, for producing cocaine-like discriminative stimulus effects and for maintaining i.v. self-administration will be measured. The results will be compared with data from RTI-55 and Lu 19-005. Based on our findings, we will select the highest affinity and most selective for the dopamine transporter for further development. The proposed research will provide needed information for defining the principal neurochemical targets of cocaine in the brain and for developing rational approaches to the pharmacological management of cocaine abuse.
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