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Radioligands for PET Imaging of GABA Transporters

用于 GABA 转运蛋白 PET 成像的放射性配体

基本信息

批准号：
8934198
负责人：
MICHAEL R KILBOURN
金额：
$ 23.25万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-30 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8934198
关键词：
Adverse effects Affinity Aminobutyric Acids Anxiety Disorders Applications Grants Autistic Disorder Binding Binding Sites Blood Blood - brain barrier anatomy Brain Carbon Cerebrum Chemicals Development Discipline of Nuclear Medicine Disease Dissection Drug Kinetics Drug usage Epilepsy Ethers Evaluation Fluoride Ion Fluorine Functional disorder GABA transporter Goals Grant Health Human Image In Vitro Label Macaca mulatta Measures Membrane Membrane Transport Proteins Mental Depression Mental disorders Metabolism Methods Modeling Neuraxis Neurodegenerative Disorders Neurologic Neurons Neurotransmitters Nipecotic Acids Permeability Pharmaceutical Preparations Positron-Emission Tomography Propionates Radiolabeled Radiopharmaceuticals Rattus Regulation Schizophrenia Series Side Specificity Structure Synapses System Techniques Testing Time analog autism spectrum disorder base brain metabolism brain tissue design dihydrotetrabenazine experience fluoroethoxy-benzovesamicol gamma-Aminobutyric Acid human disease imaging agent in vivo in vivo imaging inhibitor/antagonist lipophilicity meetings metabolic abnormality assessment microPET nerve supply nervous system disorder nonhuman primate novel pharmacokinetic model presynaptic radiochemical radioligand radiotracer single photon emission computed tomography tiagabine tool uptake

项目摘要

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.

描述（由申请人提供）：本拨款申请提出了新型 PET（正电子发射断层扫描）放射性配体的设计、合成和评估（体外和体内），用于对位于突触前神经元膜的 γ-氨基丁酸 (GABA) 转运蛋白进行体内成像。尽管GABA是哺乳动物大脑中主要的抑制性神经递质之一，并且GABA系统的功能障碍在癫痫、精神分裂症和自闭症等重要的人类疾病中很明显，但目前还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药物噻加宾（Gabatril®）的一系列二芳基烯基醚哌啶酸类似物，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 1 型 GABA 转运蛋白 (GAT-1) 的药理学特异性。然后将在恒河猴大脑中评估最有前途的放射性示踪剂，以确定药代动力学和定量测量 GABA 能神经元神经支配的潜力。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。