EMISSION TOMOGRAPHY OF NEUROPHARMACOLOGIC MARKERS

本项目将采用既定的平衡约束方法， 局部脑苯二氮卓类结合位点（“苯二氮卓类”）的估计 正常人受试者和患有 焦虑症它将采用正电子发射断层扫描（PET）， 放射性示踪剂[11 C]氟马西尼成像和定量脑BZR vivo.该项目有三个主要部分：第一部分致力于 计算特异性放射性配体结合图谱，并对其求和 以产生人口平均数据;第二个 关于苯二氮卓类结合位点占有率估计的评价 给予药理学剂量的未标记药物后; 第三个将探索改变苯二氮卓受体的可能性， 在焦虑症患者中。这些研究将产生新的 关于苯二氮卓类药物对中枢神经系统作用的信息， 人类，并将允许直接测试假设的精神病学 疾病机制。 实验提出了进一步研究量化的高- 亲和配体结合BZR通过应用微创 程序.实验设计将利用静脉血 采样和连续示踪剂注入，以实现真正的平衡 血液和大脑之间。成功的实施可能会带来更多 该方法的广泛应用，特别是在 动脉取样可能不可行。 将开发分析方法来量化和显示BZR的变化 药理学剂量给药导致的可用性 未标记的苯二氮卓类药物 血浆中的 咪达唑仑、脑BZR占用率以及行为和生理指标 将在亚急性给药后的正常受试者中研究药物作用 静脉输液 剂量-反应关系的证据 血浆药物水平和PET BZR占用率，功率谱变化， 将寻求EEG和神经心理测量测试的改变表现。 我们的总体目标是推动公正的，定量的，但相对 研究人脑神经感受器的简单程序， 发射断层扫描本项目开发的方法将具有 广泛适用于各种配体和结合位点。

This project will apply an established equilibrium binding method for estimation of regional brain benzodiazepine binding site ("benzOdiazepine receptor"; BZR) numbers to normal human subjects and to patients with anxiety disorders. It will employ positron emission tomography (PET) and the radiotracer [11C]flumazenil to image and quantify cerebral BZR in vivo. The project has three major divisions: the first is devoted to calculation of specific radioligand binding maps, and for their summation across individuals to produce population-average data; the second concerns evaluation of benzodiazepine binding site occupancy estimation following administration of pharmacologic doses of unlabeled drugs; the third will explore the possibility of altered benzodiazepine receptors in patients with anxiety disorders. These studies will yield new information on the central nervous system actions of benzodiazepines in humans, and will permit the direct testing of hypothesized psychiatric disease mechanisms. Experiments are proposed to further investigate quantification of high- affinity ligand binding to the BZR by application of less-invasive procedures. The experimental design will make use of venous blood sampling and continuous tracer infusion to achieve a true equilibrium between blood and brain. Successful implementation may lead to more widespread application of the method, particularly in populations where arterial sampling may not be feasible. Analytic methods will be developed to quantify and display changes in BZR availability resulting from administration of pharmacologic doses of unlabeled benzodiazepines. The relationships between plasma levels of midazolam, brain BZR occupancy, and behavioral and physiologic measures of drug action will be investigated in normal subjects following subacute intravenous infusion. Evidence for dose-response relationships between plasma drug levels and PET BZR occupancy, power spectral changes in the EEG, and altered performance on neuropsychometric testing will be sought. Our overall goal is to advance unbiased, quantitative, yet relatively simple procedures for the study of neuroreceptors in human brain with emission tomography. The methodology developed in this project will have widespread applicability to a variety of ligands and binding sites.