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（由应用程序提供）：本赠款应用提出了新PET的设计，合成和评估（体外和体内）的设计（正电子发射断层扫描）放射性物体，用于在体内成像γ-氨基丁酸（GABA）转运蛋白的体内成像。 Although GABA is one of the predominant inhibitory neurotransmitters in the mammalian brain, and dysfunctioning of the GABA system is evidenced 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临床使用的药物tiabine（Gabatril®）的一系列二维拉烯基乙醚nipecotic Atalogs，并评估其体外结合伴侣和亲脂性。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的放射性标记，并在rodentsto中进行体内测试 GABA转运蛋白1型（GAT-1）的血脑屏障渗透性，代谢，脑药代动力学和药物特异性。然后，将在恒河猴大脑中评估最有希望的放射性示踪剂，以确定药代动力学和潜在的GABA - 凝胶神经元神经支配的潜力。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物质，以进一步发展为PET放射性药物，以对人类神经和精神病学中GABA神经元系统进行非侵入性研究。