Two series of (N-benzylpiperidin-4-yl)- and (9-azabicyclo[3.3.1]nonan- 3 beta-yl)benzamides were prepared, and in vitro binding assays were used to measure the affinity of these compounds for dopamine D2, dopamine D3, serotonin 5-HT2, and alpha 2-adrenergic receptors. The results of these studies indicated compounds 23, 26b, and 34 have the selectivity needed for in vivo studies of the D2 (and possibly D3) receptors. 18F-Labeled analogues of 23, 26b and 34 were prepared by N-alkylation of the corresponding desbenzyl precursors with [18F]-4-fluorobenzyl iodide. Preliminary in vivo studies demonstrated that [18F]-23 and [18F]-26b are suitable candidates for further evaluation in positron emission tomography imaging studies. The slow rate of washout of [18F]-34 from nondopaminergic regions and its comparatively high lipophilicity indicates that this compound may not be suitable for imaging studies because of a high level of nonspecific binding.
A series of positron emission tomography (PET) imaging studies was conducted in a baboon with the benzamide derivatives [18F]2,3-dimethoxy-N-[9-(4-fluorobenzyl)-9-azabicyclo[3.3.1]non an-3 beta-yl]benzamide ([18F]MABN) and [18F]2,3-dimethoxy-N-[1-(4-fluorobenzyl)piperidin-4-yl]be nza mide ([18F]MBP). Studies were also conducted with the butyrophenone [18F]N-methylspiperone (NMSP) for comparison. Tissue-time activity curves of [18F]MABN are similar to those of [18F]NMSP since both compounds displayed approximately the same uptake in the basal ganglia and displayed irreversible binding kinetics in vivo. However, the rapid rate of clearance from the cerebellum and high basal ganglia:cerebellum ratio of [18F]MABN indicate that this compound has a much lower amount of nonspecific binding than [18F]NMSP. [18F]MBP displayed a higher uptake in the basal ganglia relative to [18F]NMSP and [18F]MABN and exhibited reversible binding kinetics in vivo. This property of [18F]MBP is desirable since the uptake of radioactivity in D2-rich ligands is less likely to be influenced by changes in cerebral blood flow. The current data suggest that both [18F]MABN and [18F]MBP are promising ligands for studying dopamine D2 receptors with PET.
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