High affinity dopamine D2 receptor radioligands. 3. [ 123I] and [ 125I]epidepride: In vivo studies in rhesus monkey brain and comparison with in vitro pharmacokinetics in rat brain

Abstract

Studies of [ 123I]epidepride uptake in rhesus monkey brain were performed using single photon tomography. Striatal uptake peaked at 0.85% of administered dose/g at 107 min post-injection, then declined slowly to 0.70% of administered dose/g at 6 h. Striatal: posterior brain ratios rose from 2 at 25 min to 6.8 at 105 min, to 15 at 4 h and to 58 at 6.4 h. [ 123I]Epidepride was displaced by haloperidol (0.1 and 1 mg/kg) with a half-life of washout of 55 min. Little displacement of [ 123I]epidepride was observed following administration of 1 or 2 mg/kg d-amphetamine, respectively, indicating [ 123I]epidepride is not easily displaced by endogenous dopamine. In vitro equilibrium binding studies using rat striatum revealed a K D of 46 pM and B max of 33 pmol/g tissue at 37°C, while at 25°C the K D was 25 pM and the B max 32 pmol/g tissue. In vitro kinetic analysis of association and dissociation curves revealed a half-life for receptor dissociation at 37°C of 15 min and 79–90 min at 25°C. Allowing for the temperature difference, there is good correspondence between in vivo and in vitro dissociation kinetics at 25°C. Increasing in vitro incubation temperature from 25 to 37°C caused a 6-fold increase in the dissociation rate, suggesting that there is a change in binding kinetics at the dopamine D2 receptor at 37°C compared to in vivo binding. The results of this study indicate that [ 123I]epidepride is an excellent radioligand for SPECT studies of the dopamine D2 receptor in man.