Occupancy of Brain Dopamine D 3 Receptors and Drug Craving: A Translational Approach

Selective dopamine D 3 receptor (D 3 R) antagonists prevent reinstatement of drug-seeking behavior and decrease the rewarding effects of contextual cues associated with drug intake preclinically, suggesting that they may reduce drug craving in humans. GSK598809 is a selective D 3 R antagonist recently progressed in Phase I trials. The aim of this study was to establish a model, based on the determination of the occupancy of brain across species, to predict the ability of GSK598809 to reduce nicotine-seeking behavior in humans, here assessed as cigarette craving in smokers. Using ex vivo [ 125 I]( R )- trans -7-hydroxy-2-[ N -propyl- N -(3′-iodo-2′-propenyl)amino] tetralin ([ 125 I]7OH-PIPAT) autoradiography and [ 11 C]PHNO positron emission tomography, we demonstrated a dose-dependent occupancy of the D 3 Rs by GSK598809 in rat, baboon, and human brains. We also showed a direct relationship between and pharmacokinetic exposure, and potencies in line with the in vitro binding affinity. Likewise, GSK598809 dose dependently reduced the expression of nicotine-induced conditioned place preference (CPP) in rats, with an effect proportional to the exposure and at every time point, and 100% effect at values ⩾72%. In humans, a single dose of GSK598809, giving submaximal levels (72–89%) of , transiently alleviated craving in smokers after overnight abstinence. These data suggest that either higher is required for a full effect in humans or that nicotine-seeking behavior in CPP rats only partially translates into craving for cigarettes in short-term abstinent smokers. In addition, they provide the first clinical evidence of potential efficacy of a selective D 3 R antagonist for the treatment of substance-use disorders.