Radioligands for PET Imaging of GABA Transporters

描述（由申请人提供）：本拨款申请提出了用于体内成像的新型PET（正电子发射断层扫描）放射配体的设计，合成和评估（体外和体内）？-氨基丁酸（GABA）转运体定位于突触前神经元膜。虽然GABA是哺乳动物大脑中主要的抑制性神经递质之一，而且GABA系统的功能障碍在癫痫、精神分裂症和自闭症等重要的人类疾病中是明显的，但目前还没有用于研究人脑突触前GABA-能神经支配的体内显像剂。本项目的具体目的是合成一系列的二芳基烯基醚苯乙烯酸类似物

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 ?---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(R)) 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.