Medications Development Division, The National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA.
Section of High Resolution Brain Positron Emission Tomography Imaging, Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan Department of Radiology and Radiological Science, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
CNS Neurosci Ther. 2019 Jan;25(1):136-146. doi: 10.1111/cns.12994. Epub 2018 Jun 20.
RPR 102681, 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 of RPR 102681 and cocaine, and to confirm the DA release mechanism of RPR 102681.
Sixteen cocaine-dependent participants were randomized to either placebo or RPR102681 at 3 ascending doses; cocaine was co-administered at steady state of RPR 102681. [ C]raclopride positron emission tomography scans were conducted at baseline and at each RPR102681 dose.
RPR 102681 was well tolerated, and safe to co-administer with cocaine. RPR 102681 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, RPR 102681 significantly increased the binding potential of [ C]raclopride in the ventral striatum (t test, P < .001) and caudate nucleus (t test, P < .0001) in a small subset of patients, suggesting that it may reduce intrasynaptic striatal DA.
Overall, this pilot study suggests that RPR 102681 would be unlikely candidate, as an agonist medication for the treatment for cocaine addiction but worth investigating further for possible role in reducing craving.
胆囊收缩素 B 拮抗剂 RPR 102681 可增加动物的多巴胺（DA）释放并减少可卡因的自我给药。这项初步研究旨在评估 RPR 102681 与可卡因共同给药的安全性和药代动力学（PK），并确认 RPR 102681 的 DA 释放机制。
16 名可卡因依赖者被随机分为安慰剂或 RPR102681 的 3 个递增剂量组；在 RPR 102681 稳定状态下共同给予可卡因。在基线和每个 RPR102681 剂量时进行 [ C]raclopride 正电子发射断层扫描。
RPR 102681 耐受良好，与可卡因共同给药安全。RPR 102681 不改变可卡因或其代谢物苯甲酰古柯碱的 PK，也没有显示出内在的滥用倾向。可卡因渴望评分有降低的趋势。与动物研究相反，RPR 102681 显著增加了 [ C]raclopride 在腹侧纹状体（t 检验，P < 0.001）和尾状核（t 检验，P < 0.0001）中的结合潜能，这表明它可能降低了突触内纹状体 DA。
总体而言，这项初步研究表明，RPR 102681 不太可能成为可卡因成瘾治疗的激动剂药物候选物，但值得进一步研究以确定其在减少渴望方面的可能作用。
