Effect of N-Alkylation on the Affinities of Analogs of Spiperone for Dopamine D₂ and Serotonin 5-HT₂ Receptors

Two series of N-substituted spiperone analogues were prepared and evaluated in vitro to measure their affinities for dopamine D₂ and serotonin 5-HT₂ receptors. Substitution of the amide nitrogen with an alkyl group of five carbon units or less resulted in analogues displaying a low selectivity for D₂ compared to 5-HT₂ receptors. However, a moderate improvement in selectivity for D₂ receptors was observed with N-benzylspiperone. Substitution at either the ortho or para position of the benzyl group resulted in a further reduction in affinity for 5-HT₂ receptors and improvement in the selectivity ratio. Examination of N-substituted analogues of spiperone may provide insights into the topography of the antagonist binding region of the 5-HT₂ receptor. The results also suggest that an 18F-labeled analogue of N-(4-nitrobenzyl)spiperone (4p) may be a suitable tracer for studying D₂ receptors with positron emission tomography since this compound displays a high selectivity for D₂ receptors relative to that of spiperone and N-methylspiperone.