New PET ligands for brain serotonin transporter in neuropsychiatric disorders

描述（由申请人提供）：活体人脑5-羟色胺转运蛋白（SERT）的正电子发射断层扫描（PET）成像取决于对SERT位点显示高亲和力和选择性以及低非特异性结合的高比活度放射性示踪剂的开发。拟议的研究集中在氟-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，用于神经精神和药物成瘾疾病患者SERT的潜在体内成像。该研究包括三个阶段：（1）开发了制备新型18F标记的N，N-二甲基-2-（2-（2-甲基-1，2-二氧杂环己基）-1，3-二氧杂环己基）-1，3-二氧杂环己基的类似物的合成方法。（2 ′-氨基-4 ′-羟甲基苯硫基）苄胺（HOMADAM），（2）体外测定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的转染细胞中含氟-19候选物的相对亲和力，和（3）定义食蟹猴脑感兴趣区域（ROI）中特异性和非特异性结合的时间-活性曲线（TAC）的microPET研究。 公共卫生相关性：吸毒成瘾和神经精神疾病已经袭击了数百万美国人。K 01提案的结果将帮助我们了解这些疾病的机制，并开发更有效的治疗方法，以改善公众健康和生活质量。

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.