New PET ligands for brain serotonin transporter in neuropsychiatric disorders

描述(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)成像依赖于高比活度放射性示踪剂的开发，这些示踪剂对SERT位点具有高亲和力和选择性，非特异性结合低。这项拟议的研究集中在18F标记配体的设计、合成、体外药理学表征和在非人类灵长类动物中的体内成像，以期在神经精神和药物成瘾障碍患者中进行SERT的体内成像。这项研究包括三个阶段：(1)开发制备新型18F标记的N，N-二甲基-2-(2‘-氨基-4’-羟甲基苯硫基)苯甲胺类似物(HOMADAM)的合成方法；(2)在体外测定稳定表达人多巴胺转运体(DAT)、去甲肾上腺素转运体(NET)或SERT的细胞中氟-19候选化合物的相对亲和力；(3)MicroPET研究定义了食蟹猴大脑感兴趣区(ROI)特异性和非特异性结合的时间-活性曲线(TAC)。 与公共健康相关：吸毒成瘾和神经精神疾病打击了数百万美国人。K01提案的结果将有助于我们了解导致这些疾病的机制，以及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.