SEROTONIN 5-HT1A RADIOLIGANDS FOR PET

拟议的研究涉及放射性药物的开发。 它们定位于大脑的离散区域，基于它们的选择性 与5-羟色胺5-HT1a受体结合。5-HT1a受体被认为是 在5-羟色胺系统的调节中起关键作用。试图 在体内直接评估该系统功能障碍的性质 到目前为止，患有抑郁症和焦虑症的人一直受到 缺乏合适的放射性药物。这项工作的目标是 正电子发射标记多种选择性5-HT1a配体 放射性核素11C，正电子定量5-HT1a受体部位 非人灵长类动物的发射断层扫描(PET)成像，以及 展示它们在试验性人体研究中的适用性。我们的计划是 开发选择性强的拮抗剂和激动剂5-HT1a放射性配体 为了这些目的。拮抗剂放射性配基将在 测定高、低亲和力5-HT1A的结合密度 受体和激动剂将被用来确定区域 高亲和力5-HT1a受体的浓度及测定 体内局部内源性5-羟色胺浓度。这是意料之中的 建议的5-HT1a放射性配基的应用，以及 同时使用5-HT2拮抗剂放射性配体(目前正在进行中 匹兹堡大学PET设施)，将使第一个 直接评估这些5-羟色胺能受体系统的变化 接受抗抑郁药物治疗的人体受试者。5-HT1a和5-HT2 受体系统一直是抗抑郁药物治疗的靶点 多年来，尽管对适应性缺乏明确的了解 与它们在人类身上的成功(或失败)相关的变化。建议数 研究将提供直接研究中枢神经系统的方法 5-羟色胺能受体在抗抑郁治疗中的变化 这是人类第一次。 我们的具体目标包括：1)彻底评估精选和 有效的5-HT1a拮抗剂[11C]标记Way 100635作为正电子发射计算机断层扫描的放射性配体 2)高效性[11C]标记的5-羟基异丁基苯的合成与鉴定 HT1a激动剂用于活体测量血管局部密度 这些受体的高亲和力激动剂状态；3)合成和 低效价[11C]标记5-HT1a激动剂的体内评价 区域内源性5-羟色胺浓度的估计。

The proposed research involves the development of radiopharmaceuticals which localize in discrete regions of the brain based upon their selective binding to serotonin 5-HT1A receptors. 5-HT1A receptors are believed to play a key role in the regulation of the serotonin system. Attempts to directly assess the nature of dysfunctions in this system in vivo in humans with depression and anxiety disorders have been limited to date by the lack of suitable radiopharmaceuticals. The goals of this work are to label various selective 5-HT1A ligands with the positron-emitting radionuclide 11C, to quantitate 5-HT1A receptor sites using positron emission tomography (PET) imaging in non-human primates, and to demonstrate their applicability in pilot human studies. Our plan is to develop selective and potent antagonist and agonist 5-HT1A radioligands for these purposes. The antagonist radioligand will be useful in quantitating the combined densities of both high and low affinity 5-HT1A receptors, and the agonist will be used to determine the regional concentrations of high affinity 5-HT1A receptors as well as to estimate regional endogenous serotonin concentrations in vivo. It is anticipated that the application of the proposed 5-HT1A radioligands, along with the concurrent use of a 5-HT2 antagonist radioligand (presently underway at the University of Pittsburgh PET Facility), will make possible the first direct assessments of changes in these serotonergic receptor systems in human subjects with antidepressant drug treatments. The 5-HT1A and 5-HT2 receptor systems have been the targets of antidepressant therapies for many years despite the lack of a definitive understanding of the adaptive changes associated with their success (or failure) in humans. The proposed studies will make available methods to directly investigate CNS serotonergic receptor changes as a result of antidepressant therapies in humans for the first time. Our specific aims include: 1) a thorough evaluation of the selective and potent 5-HT1A antagonist [11C]labeled WAY 100635 as a radioligand for PET imaging; 2) synthesis and evaluation of a high potency [11C]-labeled 5- HT1A agonist for in vivo measurements of the regional densities of the high affinity agonist state of these receptors; and 3) synthesis and evaluation of a lower potency [11C]-labeled 5-HT1A agonist for in vivo estimates of regional endogenous serotonin concentrations.