PET IMAGING OF SEROTONIN TRANSPORTERS IN THE BRAIN

描述（由申请人提供）：本拨款的目的是使用F-18标记的正电子发射断层扫描（PET）显像剂评估中枢神经系统（CNS）的血清素再摄取位点（又称血清素转运体，SERT）。自1988年氟西汀（百忧解）问世以来，选择性5 -羟色胺再摄取抑制剂（SSRIs）已被广泛用于治疗数百万抑郁症、强迫强迫症、社交恐惧症或其他精神障碍患者。通过阻断再摄取位点，突触中神经化学物质血清素的浓度大大增加。血清素信号的大量增加被认为是症状明显改善的原因。虽然SSRI类药物帮助了许多患者，但仍有相当一部分患者对治疗没有反应。迫切需要找到一种简单的方法来测量无反应者大脑中目标部位的药物占用（或缺乏）。本项目提出的PET成像方法对于研究精神活性药物的结合位点和监测此类药物在活体人脑中的治疗效果至关重要。该项目的最终目标是测试PET成像技术用于研究行为和情绪障碍及其治疗的可行性。用于PET成像的F-18标记的5 -羟色胺转运体配体将比目前的配体有更好的机会广泛应用，因为它的半衰期更长，并且现有的基础设施可以为临床研究提供F-18 FDG。本项目的假设是测试是否可以利用一种方便的PET成像方法，通过PET成像快速评估脑内SERT位点的饱和程度。本项目提出了三个具体目标：1)合成并表征一系列F-18联苯硫醇衍生物作为5 -羟色胺转运体的PET成像研究，2)在非人类灵长类动物中静脉注射F-18标记的配体后对5 -羟色胺转运体进行体内PET成像，并测量在竞争剂量的SSRI后SERT的占用。另外，对几种新报道的用于SERT PET成像的F-18标记剂进行比较研究，将为本项目第三年选择合适的人体研究候选人提供半定量信息。

DESCRIPTION (provided by applicant): The objective of this grant is to evaluate serotonin reuptake sites (a.k.a. serotonin transporters, SERT) of the central nervous system (CNS) using F-18 labeled positron emission tomography (PET) imaging agents. Since the introduction of fluoxetine (Prozac) in 1988, the class of selective serotonin reuptake inhibitors (SSRIs), have been extensively prescribed for millions of patients with depressive, compulsive-obsessive, social phobic or other mental disorders. By blocking the reuptake sites the concentration of a neural chemical, serotonin, in the synapse is greatly increased. A substantial increase in serotonin signaling is credited for apparent symptomatic improvements. While the SSRI drugs have helped many patients, a significant segment of patients does not respond to the treatment. There is a compelling need to find a simple method to measure the drug occupancy (or the lack thereof) of the target sites in the brain of non-responders. The PET imaging methods proposed in this project are critically important for studying binding sites of psychoactive drugs and monitoring the effectiveness of such drug treatment in the living human brain. The ultimate goal of this project is to test the feasibility of the PET imaging technique for studying behavioral and emotional disorders and their treatment. A F-18 labeled serotonin transporter ligand for PET imaging will have a better chance than current ligands for widespread application due to its longer half-life and the existing infrastructure for delivering F-18 FDG for clinical studies. The hypothesis of this project is to test if a convenient PET imaging method could be utilized to quickly assess the degree of saturation of SERT sites in the brain by PET imaging. Three specific aims are proposed for this project: 1) to synthesize and to characterize of a series of F-18 biphenylthiol derivatives as serotonin transporter ligands for PET imaging studies, 2) to perform in vivo PET imaging of serotonin transporters after an iv injection of F- 18 labeled ligand in non-human primates and to measure the occupancy of SERT after a competing dose of SSRI. Additional comparison studies on several newly reported F-18 labeled agents for PET imaging of SERT will provide semi-quantitative information for selecting a suitable candidate for human study in year 3 of this project.