SummaryAimsRPR102681, a cholecystokinin‐B antagonist, increased dopamine (DA) release and reduced cocaine self‐administration in animals. This pilot study sought to assess the safety and pharmacokinetics (PK) of co‐administration ofRPR102681 and cocaine, and to confirm the DA release mechanism ofRPR102681.MethodsSixteen cocaine‐dependent participants were randomized to either placebo orRPR102681 at 3 ascending doses; cocaine was co‐administered at steady state ofRPR102681. [11C]raclopride positron emission tomography scans were conducted at baseline and at eachRPR102681 dose.ResultsRPR102681 was well tolerated, and safe to co‐administer with cocaine.RPR102681 did not alter the PK of either cocaine or its metabolite benzoylecgonine and showed no intrinsic abuse liability. There was a trend toward reduction of cocaine craving scores. In contrast to animal studies,RPR102681 significantly increased the binding potential of [11C]raclopride in the ventral striatum (ttest,P < .001) and caudate nucleus (ttest,P < .0001) in a small subset of patients, suggesting that it may reduce intrasynaptic striatal DA.ConclusionOverall, this pilot study suggests thatRPR102681 would be unlikely candidate, as an agonist medication for the treatment for cocaine addiction but worth investigating further for possible role in reducing craving.