Endocannabinoid Metabolism in Cannabis Users: PET Studies with the Novel Probe [1

说明（由申请人提供）：大麻是美国人使用的最普遍的非法药物，滥用大麻会对社会和个人健康造成严重后果，包括成瘾。在这方面，三分之一尝试大麻的人逐渐滥用大麻，而在那些试图戒烟的人中，70%的人失败了。目前还没有批准的药物治疗大麻使用障碍（CUD）。来自临床前和人类遗传学研究的证据表明，脂肪酸酰胺水解酶（FAAH）参与了CUD，这种酶代谢主要的内源性大麻素anandamide。特别是，对FAAH功能多态性的研究表明，较高的酶活性与CUD的风险增加以及戒断的严重程度增加、大麻诱导的欣快感和线索诱导的神经反应有关。同样，啮齿类动物CUD模型的药理学研究表明，FAAH抑制剂可以缓解大麻戒断。总之，这些发现表明，FAAH抑制剂可能为治疗这种疾病提供一种可能的治疗途径。FAAH抑制剂已被制药公司大力开发，目前正在CUD中进行测试。尽管有证据表明FAAH参与了CUD，并且在开发FAAH靶向药物方面进行了投资，但没有关于这种酶在CUD中的直接数据。我们是世界上唯一开发出（PET）放射性配体[11C]-CURB的团队，它可以直接测量FAAH。我们非常适合研究FAAH在CUD中的作用，因为我们拥有CUD领域的临床和科学专业知识（Huestis, Le Foll, George）和成像（Boileau），并且拥有唯一可用的神经成像工具（Wilson, Houle）来研究这个问题。迫切需要通过提供神经影像学信息来促进我们对内源性大麻素在CUD中的代谢的理解，从而加快已在开发的CUD药物治疗的临床转化。在我们发展了[11C]-CURB之后，我们主要的具体目标和假设是通过PET成像确定CUD中FAAH活性是否升高以及差异是否与成瘾严重程度有关。在一项为期2年的概念验证研究中，对这一假设的确认可以帮助确定治疗（可能预防）CUD的药物靶点，并可以指导已经开发的治疗方法（使用FAAH抑制剂）的临床应用。这个项目的潜在影响是巨大的，因为它提供了CUD中内源性大麻素代谢的第一个影像学研究。该项目产生的知识将为进一步开发针对FAAH的循证治疗方法提供基础。主要制药公司正在开发的靶向FAAH的化合物的可用性允许我们将人类大脑的发现快速转化为临床。

DESCRIPTION (provided by applicant): Cannabis is the most prevalent illicit drug consumed by Americans and its abuse is associated with significant consequences to social and personal health, including addiction. In this regard, a third of individuals experimenting with cannabis progress to develop abuse, and of those who try to quit, 70% fail. There are currently no approved pharmacotherapies for cannabis use disorder (CUD). Evidence from preclinical and human genetic studies suggests the involvement of Fatty Acid Amide Hydrolase (FAAH), the enzyme metabolizing the major endocannabinoid anandamide in CUD. In particular, studies of FAAH functional polymorphisms suggest that higher enzyme activity is linked to greater risk for CUD as well as increased severity of withdrawal, cannabis-induced euphoria, and cue- induced neural response. As well, pharmacological studies in rodent models of CUD suggest that FAAH inhibitors alleviate cannabis withdrawal. Together these findings suggest that FAAH inhibitors, which have been avidly developed by pharmaceutical companies and are currently being tested in CUD, might offer a possible therapeutic avenue for the treatment of this disorder. Despite evidence suggesting the involvement of FAAH in CUD and the investment in developing FAAH-targeting drugs, there are no direct data on this enzyme in CUD. We are the only group world-wide to have developed a (PET) radioligand, [11C]-CURB, which allows direct measurement of FAAH. We are uniquely suited to investigate the role of FAAH in CUD as we have the clinical and scientific expertise in the field of CUD (Huestis, Le Foll, George) and imaging (Boileau) and have the only available neuroimaging tool (Wilson, Houle) to investigate this question. There is an urgent need to accelerate the translation, into clinic, of pharmacotherapies already in development for CUD, by providing neuroimaging information which could advance our understanding of endocannabinoid metabolism in CUD. Following upon our development of [11C]-CURB, our major specific aim and hypothesis is to establish by PET imaging whether FAAH activity is elevated in CUD and whether differences are related to addiction severity. Confirmation of this hypothesis, in a 2 year proof-of-concept study, can help identify a drug target to treat (perhaps prevent) CUD and can guide clinical application of treatment approaches (using FAAH inhibitors) already in development. The potential impact of this project is immense, as it provides the first imaging investigation of endocannabinoid metabolism in CUD. The knowledge generated by this project will provide the basis for the further development of evidence-based therapeutic approaches targeting FAAH. The availability of compounds targeting FAAH that are in development by major pharmaceutical companies allows for a quick translation of our human brain findings into the clinic.