SEROTONIN 5-HT1A RADIOLIGANDS FOR PET

拟议的研究涉及放射性药物的开发 它们基于选择性地定位在大脑的离散区域， 与5-羟色胺5-HT 1A受体结合。5-HT 1A受体被认为是 在调节血清素系统中起着关键作用。试图 直接评估该系统在体内的功能障碍的性质， 迄今为止，患有抑郁症和焦虑症的人 缺乏合适的放射性药物。这项工作的目标是 用正电子发射标记各种选择性5-HT 1A配体， 放射性核素11 C，以使用正电子探针定量5-HT 1A受体位点 发射断层扫描（PET）成像在非人类灵长类动物， 证明其在试点人体研究中的适用性。我们的计划是 开发选择性和有效的拮抗剂和激动剂5-HT 1A放射性配体 为了这些目的。拮抗剂放射性配体将用于 定量高和低亲和力5-HT 1A的组合密度 受体，激动剂将用于确定区域 高亲和力5-HT 1A受体的浓度以及估计 体内局部内源性5-羟色胺浓度。预计 所提出的5-HT 1A放射性配体的应用，沿着 同时使用5-HT 2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 直接评估这些多巴胺能受体系统的变化， 抗抑郁药物治疗的人类受试者。5-HT 1A和5-HT 2 受体系统一直是抗抑郁治疗的目标， 多年来，尽管缺乏对适应性的明确理解， 与人类成功（或失败）相关的变化。拟议 研究将提供直接研究CNS的方法 抗抑郁药治疗引起的肾上腺素能受体的变化 人类首次。 我们的具体目标包括：1）对选择性和 作为PET放射性配体的强效5-HT 1A拮抗剂[11 C]标记WAY 100635 成像; 2）合成和评价高效[11 C]-标记的5- HT 1A激动剂，用于体内测量 这些受体的高亲和力激动剂状态;和3）合成和 评价较低效力的[11 C]-标记的5-HT 1A激动剂用于体内 局部内源性5-羟色胺浓度的估计值。

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.