PET imaging of Naltrexone Occupancy of Kappa Receptors in Heavy Drinkers

描述（由申请人提供）：该转化项目的长期目标是优化阿片类拮抗剂纳曲酮（NTX）治疗酒精依赖的使用，并为酒精饮酒的新药物疗法确定新的受体靶点——NIAAA的优先事项。具体目标是汇集专家，以确定Kappa阿片受体（KOR）是否受到大量饮酒的影响，以及它们是否在介导NTX疗效的变异性中发挥作用。知识缺口：我们需要更多地了解酒精中毒、KOR以及NTX如何减少酒精摄入量。有趣的证据从我们的小组与饮酒范式（ADP）表明酗酒家族史（FH）和性别可能介导NTX的反应。在FHP阳性的酗酒者中，NTX减少了饮酒量，但在FHN阴性的酗酒者中，NTX似乎增加了饮酒量——这种差异在男性饮酒者中观察到，而在女性饮酒者中没有观察到。NTX不同程度地与Mu， Delta和Kappa受体结合。先前的PET研究测量了NTX对Mu和Delta位点的占用（OCC），但没有检查KOR，也没有与NTX疗效相关。另一项研究比较了酗酒者（HD）和健康对照组（HC）的基线Mu和Delta位点。由于缺乏特异性的KOR示踪剂，PET成像一直是不可能的。创新：我们开发了一种选择性KOR示踪剂。目前的提案将首次使用该示踪剂(1)在基线时以高清图像显示可用的KOR，(2)将基线时的高清与HC进行比较，以及(3)通过NTX比较男性和女性、FHP和FHN HD的KOR OCC。我们的初步PET证据表明，HC患者的基线KOR水平存在性别差异。研究还表明，FHP和FHN饮酒者在KOR的NTX OCC上存在差异，这可能与NTX引起的饮酒变化有关。我们的新数据表明，HD患者的KOR高于HC患者。这与最近关于穆遗址的发现是相反的。我们的项目将是第一个在FHP或FHN的男性和女性重度饮酒者中，研究NTX引起的KOR OCC与NTX诱导的ADP饮酒变化之间的关系。主要假设是，在FHP和FHN HD中，NTX OCC是不同的，这种差异可以预测NTX的疗效。我们将使用一种新的示踪剂来阐明可能的影响

DESCRIPTION (provided by applicant): The long-term objectives of this translational project is to optimize the use of the opioid antagonist naltrexone (NTX) for treating alcohol dependence and to identify novel receptor targets for new pharmacotherapies for alcohol drinking - a priority of NIAAA. The specific objective is to bring together experts to determine if Kappa opioid receptors (KOR) are affected by heavy drinking and if they have a role in mediating variability in efficacy of NTX. Knowledge gap: We need to know more about alcoholism, KOR, and how NTX decreases alcohol intake. Intriguing evidence from our group with an alcohol drinking paradigm (ADP) suggests that family history (FH) of alcoholism and gender may mediate responses to NTX. NTX decreased drinking in those with a positive FH (FHP) of alcoholism but appeared to increase drinking in negative FH (FHN) - a difference observed in male but not female drinkers. NTX binds with varying degrees to Mu, Delta and Kappa receptors. A prior PET study measured occupancy (OCC) of Mu and Delta sites by NTX but did not examine KOR, nor correlate with NTX efficacy. Another study compared baseline Mu and Delta sites in heavy drinkers (HD) to healthy controls (HC). PET imaging of KOR has been impossible due to the lack of a specific KOR tracer. Innovation: We have developed a selective KOR tracer. The current proposal will be the first to use this tracer to (1) image available KOR in HD at baseline, (2) to compare HD at baseline to HC, and (3) to compare OCC of KOR by NTX, in male and female, FHP and FHN HD. Our preliminary PET evidence suggests gender differences in baseline KOR levels in HC. It also suggests that FHP and FHN drinkers differ in NTX OCC of KOR and this may be associated with NTX-induced changes in drinking. Our new data suggest that KOR are higher in HD than HC. This would be counter to the recent findings regarding the Mu site. Our project will be the first to examine the association of KOR OCC by NTX with NTX- induced changes in drinking in the ADP, in male and female heavy drinkers who are either FHP or FHN. The primary hypothesis is that NTX OCC will be different in FHP vs. FHN HD and that such differences will predict NTX efficacy. We will use a novel tracer to shed light on possible effects of heavy drinking, the actions of NTX, and FH and gender-related differences. The work will inform future studies into the KOR/dynorphin system and the search for pharmacotherapies for alcoholism.