Radioligands for PET Imaging of GABA Transporters

描述(由申请人提供)：这项拨款申请建议设计、合成和评估(体外和体内)新的正电子发射断层扫描(PET)放射配基，用于对定位于突触前神经细胞膜的氨基丁酸(GABA)转运体进行体内成像。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人类重要疾病中都很明显，但目前还没有体内显像剂来研究突触前GABA-人脑的能神经支配。本项目的具体目标是合成一系列二芳基烯基醚-硝杂环酸类似物。 临床用药替加他滨(Gabtril(R))及其体外结合亲和力和亲脂性的评价。具有低纳摩尔亲和力和适当亲脂性的候选化合物将被碳-11或氟-18放射性标记，并在体内进行机器人测试，以确定血-脑屏障通透性、代谢、脑药代动力学和GABA转运体1(GAT-1)的药理学特异性。然后，最有希望的放射性示踪剂将在恒河猴的大脑中进行评估，以确定药物动力学和定量测量GABA-能神经元神经支配的可能性。该项目的目标是确定具有合适的脑摄取和药代动力学的候选放射性配基，以便进一步开发成PET放射性药物，用于对人类神经和精神疾病中的GABA神经系统进行非侵入性研究。

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 ?---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.