NEW RADIOTRACERS FOR NEUROLOGICAL PET

用于神经宠物的新型放射示踪剂

• 批准号: 6647810
• 负责人: MICHAEL R KILBOURN
• 金额: $ 10.35万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6647810
• 关键词: GABA receptor; Macaca mulatta; benzodiazepines; binding sites; bioimaging /biomedical imaging; biomaterial development /preparation; biotechnology; brain; carbon; drug metabolism; fluorine; gamma aminobutyrate; laboratory mouse; laboratory rat; neural transmission; neurochemistry; neuroimaging; neurotransmitter agonist; pharmacokinetics; picrotoxin; positron emission tomography; pyridoindole; radionuclides; radiopharmacology; radiotracer; receptor binding; tissue /cell preparation

The goals of this project are the design, synthesis and preliminary in vitro and in vivo evaluation of new radiolabeled ligands for the picrotoxin binding site of the GABAA receptor. In particular, we seek the identification and characterization of ligands that display sensitivity to the functional state of the GABAA receptor in vivo. The GABAA receptor is present at a very high proportion of synapses in the brain, and dysfunction of this receptor has been implicated in a wide variety of neurological, psychiatric and drug abuse conditions. The new radioligands to be prepared will be based on the recently reported dithiane and dithiane oxide structural class of high affinity picotoxin site ligands. Preliminary in vivo studies with 11C- and 18F- labeled dithiane oxides have demonstrated blood-brain-barrier permeability, metabolic stability in the blood, and some-dependent alterations of in vivo uptake in brain after administration of a GABA agonist. New compounds will be examined for in vitro binding affinities (inhibition of binding of [35S]TBPS to rodent cortical membranes. High affinity compounds (Ki<20 nM) will then be prepared in carbon-11 or fluorine-18 form, and the regional brain pharmacokinetics in rodents determined. These distributions will also be examined in the presence of drugs known to alter the functioning of the GABAA receptor, such as GABA agonists, benzodiazepines, and beta-carbolines. The optimal compounds will then be examined for reproducibility and sensitivity to GABAergic perturbations using PET imaging and quantification of radiotracer pharmacokinetics in the monkey brain. The goal will be the development of radioligands with appropriate pharmacokinetics and pharmacological specificity to be suitable for in vivo studies of the picrotoxin site as a functional marker of the human brain GABAA receptor using Positron Emission Tomography (PET). In combination with existing radioligands for measurement of the numbers of benzodiazepine sites, these new functional radioligands will allow more complete characterization of GABAergic neurotransmission in the normal and diseased human brain.

该项目的目标是对GABAA受体的Picrototoxin结合位点的新放射性标记配体的设计，合成和初步的体外和体内评估。特别是，我们寻求对体内GABAA受体功能状态敏感的配体的识别和表征。 GABAA受体的大脑中存在很大比例，该受体的功能障碍与多种神经，精神病和药物滥用条件有关。要制备的新的放射性配体将基于最近报道的高亲和力皮毒素位点配体的二硫代和氧化二硫氧化物结构类别。对11C和18F标记的二硫代氧化物进行的体内研究表明，在给药GABA激动剂后，脑部体内摄取体内摄取的体内摄取的某种依赖性改变了血脑屏障的渗透性，代谢稳定性以及某种依赖性改变。将检查新化合物的体外结合亲和力（抑制[35s] TBP与啮齿动物皮质膜的结合。高亲和力化合物（KI <20 nm），然后将以碳-11或氟-18形式进行制备，并将在这些分布中所确定的啮齿动物的区域性药物进行。受体，例如GABA激动剂，苯二氮卓类药物和β-碳纤维蛋白。使用正毒素发射断层扫描（PET）与现有的放射性物体结合使用，这些新功能放射性物体将允许对GABAEGIC神经释放的正常人脑中的正常人脑中的更多完整表征。