基于α-羰基杂环骨架的脂肪酸酰胺水解酶靶向型F-18正电子示踪剂研究

Fatty acid amide hydrolase (FAAH) functions as a serine hydrolase in the endocannabinoid system, whose abnormity has been found to be associated with Alzheimer’s and Huntington’s disease. In addition, inhibition of FAAH results in anti-tumor, antidepressant and analgesic effects in preclinical models. Therefore, many efforts have been devoted to the development of potent inhibitors due to the exciting therapeutic potential by targeting FAAH. A positron emission tomography (PET) tracer for FAAH would enable investigations of the FAAH system under normal and disease conditions, and is desirable to allow quantitative enzyme mapping and dose selection for validation of promising drug candidates. A number of FAAH PET tracers have been disclosed with a feature of irreversible binding mechanism, which only provides the measurement of FAAH activity, as opposed to FAAH availability. A FAAH tracer with reversibility would allow us to access key information from PET quantifications, including volumes of distribution, binding potentials, and monitor neurological response to therapeutics. To date, however, only two reversible ligands have been radiolabeled with C-11, including OUR reported tracer [11C]MPPO. Due to the short half-life (20.4 min), their use is confined to sites that have an on-site cyclotron for the production of C-11. Our previous research revealed that [11C]MPPO, with an intrinsic α-ketoheterocyclic structure, could realize a reversible PET imaging of FAAH, but demonstrated moderate brain uptake and specificity. Based on our previous work, in this project we would like to use our developed “Spirocyclic Iodonium Ylide (SCIDY)” method to label several 18F-aryl α-ketoheterocyclic compounds with high affinity to FAAH, evaluate the in vivo behavior for targeting FAAH by means of PET imaging study with animal models. This work would offer a new roadmap for further FAAH PET tracer development.

脂肪酸酰胺水解酶（FAAH）的异常与抑郁、肿瘤、阿尔兹海默症等疾病密切相关，其作为潜在药物作用靶点受到了制药公司广泛关注。FAAH正电子示踪剂可探知生理病理状态下FAAH的生物学信息，对相关疾病早期诊断及新药研发等具有重要作用。目前靶向FAAH的正电子示踪剂多为非可逆型，增加了定量化研究和临床转化难度；可逆型示踪剂仅有两例报道，均为11C标记，短半衰期（20.4分钟）限制了其应用。我们前期的研究表明，基于α-羰基杂环的示踪剂[11C]MPPO可以实现FAAH可逆型显像，但透脑效率和专一性不高，不利于后续转化。本项目基于前期研究结果，拟采用螺环高价碘叶立德方法标记一系列新型18F杂环化合物，通过小动物PET研究评价示踪剂的体内成像行为，为开发透脑效率高、专一性好的可逆型FAAH示踪剂提供科学支持。

FAAH是内源性大麻素系统中一种重要的丝氨酸水解酶，在中枢成瘾性疾病中发挥着重要作用，但是目前缺乏靶向FAAH 的可逆型PET探针用于相关疾病的显像及靶点信息的研究。申请人前期基于α-羰基杂环骨架开发了一类新型FAAH靶向型PET探针，虽实现了靶点的可逆结合，但过脑量不足，限制了进一步的转化研究。在本项目的支持下，团队成员继续围绕α-羰基杂环骨架核心，通过药物化学设计筛选，开发了一种新型FAAH小分子抑制剂，其半数抑制浓度（IC50）低至11 nM，并呈现可逆性结合特性；标记前体、抑制剂均可通过有机反应高产率制备得到，便于转化；利用回旋加速器及自动化合成模块，实现了目标分子的11C标记，成功制备了一种新型可逆性靶向FAAH的探针11C-FAAH1906，放射标记产率高达17%，探针具有高放射化学纯度（>99%）和高比活度（>2Ci/μmol）；具有适宜的脂水分配系数；通过啮齿类动物实验，对探针进行了生物分布学研究和特异性验证，结果显示，注射示踪剂5min后脑内的摄取量为9.2 %ID/g，随后逐渐降低，符合可逆型探针的结合特征，在体内各个器官的分布情况与FAAH的表达一致；使用URB597进行阻断研究显示，周围组织放射性摄取有明显下降，脑内放射性摄取下降了约35%。. 本项目研究工作达到了预期的目标，成功开发了新型FAAH靶向型正电子成像探针，动物实验结果显示，新型探针具有高的脑摄取量，并且与靶点可逆性地结合。该结论为进一步实现探索脑内FAAH的定量分析及相关疾病的分子影像机制奠定了基础。该探针在非人类灵长类动物中的显像研究正在进行当中。

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