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。

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.