The role of the nigrostriatal and mesolimbic dopamine systems in several neurological and psychiatric disorders, as well as drug abuse, has prompted a flurry of activity in studying dopamine function in vivo with Positron Emission Tomography (PET). Unfortunately, the contradictory results reported to date with PET studies of the D2 receptor have raised serious questions regarding the ability of PET to make accurate estimates of receptor density. It is now clear that a contributing factor in leading to this confusion was the choice of ligands that were not ideal for conducting quantitative PET studies. Over the past three years we have conducted a rigorous structure-activity relationship study as a means of identifying new, high-affinity/high- selectivity ligands that can be used to study dopamine D1 and D2 receptors with PET. This research has resulted in the identification of two benzamide analogs, 2,3-dimethoxy-N-(p-flourobenzyl)piperidin-4-yl benzamide (MBP) and 2,3-dimethoxy-N-(9-p-fluorobenzyl)-9- azabicyclo[3.3.1]nonan-3beta-yl benzamide (MABN), that are promising ligands for studying D2 receptors with PET. Additionally, a benzazepine analog, 4'-methylthio SCH 23390 (MT-SCH), was also synthesized and found to have an equal D1 affinity and higher D1:5-HT2 selectivity than SCH 23390. The goal of the research described in this application is to systematically characterize in vivo and in vitro the binding properties of MBP, MABN and MT-SCH to dopamine receptors. In vitro Scatchard analyses and kinetic studies with the tritiated analogs are proposed in order to determine the dissociation constant (Kd) receptor density (Bmax) and Kon and Koff of the ligands. In vivo Scatchard analyses will also be conduced and the results will be compared with the in vitro results in order to determine the consistency between both methods of analysis. Studies are also designed in order to measure the effect of endogenous dopamine on the binding of radioligand to receptor sites. The selectivity of each ligand for D2/D3/D4 (MBP, MABN) and D1a/D1b (MT-SCH) receptors will be measured. PET imaging studies with [11C]MT-SCH are also proposed in order to determine the uptake and regional distribution of this analog in primate brain. Quantitative autoradiography studies will also be conducted and the results will be compared with the PET data for each ligand.