Radioligands for PET Imaging of GABA Transporters

描述（由申请人提供）：本授权申请提出设计、合成和评价（体外和体内）新的PET（正电子发射断层扫描）放射性配体，用于定位于突触前神经元膜的γ-氨基丁酸（GABA）转运蛋白的体内成像。虽然GABA是哺乳动物脑中主要的抑制性神经递质之一，并且GABA系统的功能障碍在诸如癫痫、精神分裂症和自闭症等重要的人类疾病中是明显的，但是目前没有用于研究人脑中突触前GABA能神经支配的体内成像剂。该项目的具体目标是合成临床使用的药物噻加宾（Gabatril®）的一系列二芳基烯基醚哌啶甲酸类似物，并评估其体外结合亲和力和亲脂性。具有低纳摩尔亲和力和适当亲脂性的候选化合物将用碳-11或氟-18进行放射性标记，并在啮齿动物体内进行测试，以确定 血脑屏障通透性、代谢、脑药代动力学和GABA转运蛋白1型（GAT-1）的药理学特异性。最有前途的放射性示踪剂，然后将在恒河猴脑中进行评估，以确定GABA能神经元神经支配的定量测量的药代动力学和潜力。该项目的目标是确定具有合适脑摄取和药代动力学的候选放射性配体，以进一步开发成PET放射性药物，用于人类神经和精神疾病中GABA神经元系统的非侵入性研究。

DESCRIPTION (provided by applicant): This grant application proposes the design, synthesis, and evaluation (in vitro and in vivo) of new PET (positron Emission Tomography) radioligands for in vivo imaging of the γ-aminobutyric acid (GABA) transporter localized in the presynaptic neuronal membrane. Although GABA is one of the predominant inhibitory neurotransmitters in the mammalian brain, and dysfunctioning of the GABA system is evident in such important human diseases as epilepsy, schizophrenia and autism, there are currently no in vivo imaging agents for studies of the presynaptic GABA-ergic innervation in the human brain. The specific aims of this project are the synthesis of a series of diarylalkenyl ether nipecotic acid analogs of the clinically used drug tiagabine (Gabatril®) and evaluation of their in vitro binding affinitie and lipophilicity. Candidate compounds with low nanomolar affinities, and appropriate lipophilicity, will be radiolabeled with carbon-11 or fluorine-18 and tested in vivo in rodentsto determine blood-brain-barrier permeability, metabolism, brain pharmacokinetics, and pharmacological specificity for the GABA transporter type 1 (GAT-1). The most promising radiotracers will then be evaluated in the rhesus monkey brain, to determine pharmacokinetics and potential for quantitative measures of GABA-ergic neuron innervation. The goal of the project is to identify candidate radioligands with suitable brain uptake and pharmacokinetics for further development into PET radiopharmaceuticals for non-invasive studies of the GABA neuronal system in human neurological and psychiatric diseases.