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.