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.

该项目的目标是针对 GABAA 受体印防己毒素结合位点的新放射性标记配体的设计、合成和初步体外和体内评估。特别是，我们寻求对体内 GABAA 受体功能状态敏感的配体的鉴定和表征。 GABAA 受体存在于大脑突触中的比例非常高，并且该受体的功能障碍与多种神经、精神和药物滥用病症有关。待制备的新放射性配体将基于最近报道的高亲和力picotoxin位点配体的二噻烷和二噻烷氧化物结构类。对 11C 和 18F 标记的二噻烷氧化物进行的初步体内研究表明，给予 GABA 激动剂后，血脑屏障的通透性、血液中的代谢稳定性以及大脑体内摄取的一些依赖性改变。将检查新化合物的体外结合亲和力（抑制 [35S]TBPS 与啮齿动物皮质膜的结合）。然后将以碳 11 或氟 18 形式制备高亲和力化合物（Ki<20 nM），并确定啮齿动物的区域脑药代动力学。还将在已知会改变 GABAA 功能的药物存在的情况下检查这些分布。 受体，例如 GABA 激动剂、苯二氮卓类药物和 β-咔啉类药物。然后使用 PET 成像和猴脑中放射性示踪剂药代动力学的定量来检查最佳化合物的重现性和对 GABA 能扰动的敏感性。目标是开发具有适当药代动力学和药理学特异性的放射性配体，以适合体内研究 使用正电子发射断层扫描 (PET) 检测印防己毒素位点作为人脑 GABAA 受体的功能标记。与现有的用于测量苯二氮卓位点数量的放射性配体相结合，这些新的功能性放射性配体将能够更完整地表征正常和患病人脑中的 GABA 能神经传递。