PET IMAGING OF SEROTONIN TRANSPORTERS IN THE BRAIN

大脑中血清素转运蛋白的 PET 成像

• 批准号: 6878065
• 负责人: Hank F Kung
• 金额: $ 34.47万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6878065
• 关键词: autoradiography; baboons; bioimaging /biomedical imaging; brain imaging /visualization /scanning; fluorine; intravenous administration; laboratory rat; ligands; method development; neuropsychology; positron emission tomography; radiochemistry; radionuclides; radiotracer; serotonin transporter

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.

描述（由申请人提供）：该资助的目的是使用 F-18 标记的正电子发射断层扫描 (PET) 成像剂评估中枢神经系统 (CNS) 的血清素再摄取位点（又名血清素转运蛋白，SERT）。自 1988 年推出氟西汀 (Prozac) 以来，这一类选择性血清素再摄取抑制剂 (SSRI) 已被广泛用于治疗数百万患有抑郁症、强迫症、社交恐惧症或其他精神障碍的患者。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。血清素信号的大幅增加被认为是症状明显改善的原因。虽然 SSRI 药物已经帮助了许多患者，但很大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靶位点的药物占用（或缺乏）。该项目提出的 PET 成像方法对于研究精神活性药物的结合位点以及监测此类药物治疗在活人大脑中的有效性至关重要。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 标记血清素转运蛋白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，并且现有的用于临床研究的 F-18 FDG 输送基础设施。该项目的假设是测试是否可以利用方便的 PET 成像方法通过 PET 成像快速评估大脑中 SERT 部位的饱和程度。该项目提出了三个具体目标：1) 合成和表征一系列 F-18 联苯硫醇衍生物，作为 PET 成像研究的血清素转运蛋白配体，2) 在非人灵长类动物中静脉注射 F-18 标记配体后，对血清素转运蛋白进行体内 PET 成像，并测量竞争剂量的 SERT 占用率。 SSRI。对几种新报道的用于 SERT PET 成像的 F-18 标记药物的额外比较研究将为在该项目的第三年选择合适的人类研究候选药物提供半定量信息。