Species differences in [3H]linopirdine (DuP 996) binding to brain membranes

Binding of [3H]linopirdine was evaluated in membranes prepared from rat, mouse, calf, pig, and human brain tissue. Saturation and homologous competition experiments with freshly prepared and subsequently frozen brain membranes of young adult rats yielded biphasic binding curves. Analysing binding data with two-site models confirmed the existence of specific, high-affinity binding sites for [3H]linopirdine with a Kd value of 7.8 +/- 3.5 nM and revealed that another site with micromolar affinity for the radioligand may exist. Almost identical data were obtained with mouse brain membranes. However, high-affinity binding of [3H]linopirdine could not be detected in cerebral cortical membranes from calf, pig or an aged human subject, respectively. In these tissues [3H]linopirdine bound only with moderate affinity (Kd about 200 nM). In subsequent experiments using brain membranes either freshly prepared from aged (25-month-old) rats or prepared from young adult (3-month-old) rats after a post-mortem delay of up to 15 h, it could be excluded that the factors age or post-mortem delay were responsible for the lack of high-affinity [3H]linopirdine binding sites in calf, pig or human brain. It is concluded that [3H]linopirdine binding data obtained from rodent studies, and consequently physiological drug effects mediated by this drug target, cannot be readily extrapolated to other species including man.