SPECIES-DIFFERENCES IN [H-3] LINOPIRDINE (DUP-996) BINDING TO BRAIN MEMBRANES

Binding of [H-3]linopirdine was evaluated in membranes prepared from r at, mouse, calf, pig, and human brain tissue. Saturation and homologou s competition experiments with freshly prepared and subsequently froze n brain membranes of young adult rats yielded biphasic binding curves. Analysing binding data with two-site models confirmed the existence o f specific, high-affinity binding sites for [H-3]linopirdine with a K- d value of 7.8 +/- 3.5 nM and revealed that another site with micromol ar affinity for the radioligand may exist. Almost identical data were obtained with mouse brain membranes. However, high-affinity binding of [H-3]linopirdine could not be detected in cerebral cortical membranes from calf, pig or an aged human subject, respectively. In these tissu es [H-3]linopirdine bound only with moderate affinity (K-d about 200 n M). In subsequent experiments using brain membranes either freshly pre pared from aged (25-month-old) rats or prepared from young adult (3-mo nth-old) rats after a post-mortem delay of up to 15 h, it could be exc luded that the factors age or post-mortem delay were responsible for t he lack of high-affinity [3H]linopirdine binding sites in calf pig or human brain. It is concluded that [H-3]linopirdine binding data obtain ed from rodent studies, and consequently physiological drug effects me diated by this drug target, cannot be readily extrapolated to other sp ecies including man.