NEW RADIOTRACERS FOR NEUROLOGICAL PET

本项目的目的是设计、合成GABAA受体微毒素结合位点的新型放射性标记配体，并进行初步的体内体外评价。特别是，我们寻求在体内对GABAA受体功能状态敏感的配体的鉴定和表征。GABAA受体在大脑突触中占有很高的比例，这种受体的功能障碍与各种神经、精神和药物滥用状况有关。新的放射性配体的制备将基于最近报道的高亲和皮毒素位点配体的二硫烷和二硫烷氧化物结构类。11C-和18F-标记的二硫烷氧化物的初步体内研究表明，在给予GABA激动剂后，血脑屏障通透性、血液代谢稳定性和脑内摄取的一些依赖性改变。将检测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）。然后以碳-11或氟-18的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。这些分布也将在已知改变GABAA受体功能的药物（如GABA激动剂、苯二氮卓类药物和-碳水化合物）存在的情况下进行检查。然后将使用PET成像和猴子大脑放射性示踪剂药代动力学量化来检查最佳化合物对gaba能扰动的再现性和敏感性。目标将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，以适用于使用正电子发射断层扫描（PET）作为人脑GABAA受体功能标记的微毒素部位的体内研究。结合现有的用于测量苯二氮卓类药物位点数量的放射配体，这些新的功能性放射配体将允许更完整地表征正常和患病人脑中的gaba能神经传递。

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.