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：
8813260
负责人：
MICHAEL R KILBOURN
金额：
$ 19.43万
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 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8813260
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 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 in vivo in vivo imaging inhibitor/antagonist lipophilicity meetings metabolic abnormality assessment nerve supply nervous system disorder nonhuman primate novel pharmacokinetic model presynaptic public health relevance 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 ?---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.

描述（由申请人提供）：该赠款申请提出了新PET的设计，合成和评估（体外和体内）的新PET（正电子发射断层扫描）放射性物体，用于在体内成像？----氨基酸酸（GABA）在临时性神经元中局部的转运蛋白。 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.该项目的具体目的是合成一系列二透氨基甲基乙醚nipecitic Acity的类似物临床使用的药物tiagabine（Gabatril（r））及其体外结合伴侣和亲脂性的评估。具有低纳米尔亲和力且适当的亲脂性的候选化合物将用碳放射性标记--- 11或氟-18- 18，并在啮齿动物中进行体内测试，确定血液----脑---屏障的渗透性，代谢，代谢，脑部药物动力学和药理学特异性的Gaba Transporter typers类型1（GAT）1（GAT）。然后，将在恒河猴大脑中评估最有希望的放射性示踪剂，以确定GABA定量测量的药代动力学和潜力。该项目的目的是鉴定具有合适脑部吸收和药代动力学的候选放射性体系，以进一步发展为人类神经和精神病学中GABA神经元系统的非 - 侵入性研究。