Effect of Lipophilicity on the in vivo localization of radiolabelled spiperone analogues

A series of N-alkylated and para-brominated analogues of spiperone were synthesized to ascertain the effect of lipophilicity on the in vivo localization of neuroleptics. While the IC₅₀ for D₂ receptor binding was within the same order of magnitude for these compounds, the calculated octanol-water partition coefficients varied 300-fold. When the in vivo distribution data for ⁷⁷Br-labelled compounds were compared with previous data for ¹⁸F- and ¹¹C-labelled analogues it was seen that the highest cerebral uptake was for bromospiperone, but the optimum striatum-to-cerebellum and brain-to-blood concentrations were achieved by N-methyl spiperone. The implications of these results for radiopharmaceutical design or medicinal chemistry are discussed.