New PET ligands for brain serotonin transporter in neuropsychiatric disorders

描述（由申请人提供）：活体人脑5 -羟色胺转运体（SERT）的正电子发射断层扫描（PET）成像依赖于高比活性放射性示踪剂的开发，该示踪剂对SERT位点具有高亲和力和选择性，并且具有低非特异性结合。本研究的重点是氟-18 （18F）标记配体的设计、合成、体外药理学表征和非人灵长类动物体内成像，以期在神经精神和药物成瘾障碍患者中进行SERT的潜在体内成像。研究包括三个阶段：(1)开发了制备新型18F标记的N，N-二甲基-2-（2'-氨基-4'-羟甲基苯基硫代）苄基胺（HOMADAM）类似物的合成方法；(2)在体外测定含氟-19候选物在稳定表达人多巴胺转运蛋白（DAT）、去甲肾上腺素转运蛋白（NET）或SERT的转染细胞中的相对亲和力；(3)微pet研究定义了食蟹猴大脑兴趣区（ROI）特异性和非特异性结合的时间-活性曲线（TAC）。

DESCRIPTION (provided by applicant): Positron emission tomographic (PET) imaging of the living human brain serotonin transporter (SERT) depends upon the development of high specific activity radiotracers that display high affinity and selectivity for the SERT sites and low nonspecific binding. The proposed research is focused on the design, synthesis, in vitro pharmacological characterization, and in vivo imaging in nonhuman primates of fluorine-18 (18F) labeled ligands, for the potential in vivo imaging of the SERT in patients with neuropsychiatric and drug addiction disorders. The research involves three phases: (1) the development of synthetic methods for the preparation of novel 18F labeled analogues of N,N-dimethyl-2-(2'-amino-4'- hydroxymethylphenylthio)benzylamine (HOMADAM), (2) the in vitro determination of relative affinities of fluorine-19 containing candidates in transfected cells stably expressing the human dopamine transporter (DAT), norepinephrine transporter (NET), or SERT, and (3) microPET studies defining time-activity curves (TAC) for specific and nonspecific binding in brain regions of interest (ROI) in cynomolgus monkeys. PUBLIC HEALTH RELEVANCE: Drug addiction and neuropsychiatric diseases have hit millions of Americans. The outcome of the K01 proposal will help us understand the mechanisms responsible for those diseases as well as develop more effective treatments to improve public health and quality of life.