he Slow and Long-Lasting Blockade of Dopamine ransporters in Human Brain Induced by the New ntidepressant Drug Radafaxine Predict Poor einforcing Effects

ackground: (2S,3S)-2-(3-Chlorophenyl)-3,5,5,-trimethyl-2-morpholinol hydrochloride (radafaxine) is a new antidepressant that locks dopamine transporters (DAT). A concern with drugs that block (DAT) is their potential reinforcing effects and abuse liability. sing positron emission tomography (PET) we have shown that for DAT-blocking drugs to produce reinforcing effects they must induce 50% DAT blockade and the blockade has to be fast (within 15 minutes). This study measures the potency and kinetics for DAT lockade by radafaxine in human brain. ethods: PET and [ C]cocaine were used to estimate DAT blockade at 1, 4, 8, and 24 hours after radafaxine (40 mg p.o) in 8 ontrols. Plasma pharmacokinetics and behavioral and cardiovascular effects were measured in parallel. esults: DAT blockade by radafaxine was slow, and at 1 hour, it was 11%. Peak blockade occurred at about 4 hours and was 22%. lockade was long lasting: at 8 hours 17%, and at 24 hours 15%. Peak plasma concentration occurred about 4 to 8 hours. No ehavioral or cardiovascular effects were observed. onclusions: The relatively low potency of radafaxine in blocking DAT and its slow blockade suggests that it is unlikely to have einforcing effects. This is consistent with preclinical studies showing no self-administration. This is the first utilization of PET to predict buse liability of a new antidepressant in humans based on DAT occupancy and pharmacokinetics.