PET imaging of serotonin transporters in the brain

项目描述（申请人提供）：本基金的目的是开发显像剂，用于使用正电子发射断层扫描（PET）研究中枢神经系统（CNS）的5-羟色胺转运蛋白（SERT）。抑郁症患者中枢神经系统中肾上腺素能神经元功能发生变化。一系列新的抗抑郁药通过抑制5-羟色胺再摄取优先增加5-HT（5-羟色胺）传输。这些选择性5-羟色胺再摄取抑制剂（SSRIs）已经彻底改变了数百万患者的抑郁症管理，现在它们被广泛用于治疗各种其他精神障碍，如强迫症和社交恐惧症。在这个项目中测试的PET成像剂对于研究精神活性药物的结合位点和监测这种药物治疗在活体人脑中的有效性至关重要。在过去的资助期间，我们已经制备了许多氟化联苯硫醇衍生物，但成功有限。然而，最近我们发现，改变联苯硫醇不同位置的取代似乎是改善特异性SERT结合（在SERT结合位点高度集中的下丘脑中的摄取和保留）的关键，更重要的是减少非特异性结合（在小脑中）。在本更新申请中，提出了三个具体目标：1）合成和测试一系列18F标记的联苯硫醇衍生物作为用于PET成像研究的SERT配体。2)对大鼠脑中与SERT结合的选择性和动力学进行体内生物学评价。3)在非人灵长类动物中比较本项目中提出的PET显像剂和其他18F标记的SERT配体，最终目的是确定一个或两个适合人类研究的最终候选物。体内PET或SPECT成像研究可以提供一种有效的方法来估计用于治疗的抗抑郁药对靶位点- SERT结合位点的药物占用率。因此，SERT结合位点的成像可以打开一个小窗口，允许直接测量大脑中靶位点处的药物作用。迫切需要开发改进的PET显像剂来研究这一重要的调节脑中5-羟色胺功能的靶点。用于SERT成像的18F标记示踪剂可能可以由区域放射性药物学制备并分布在任何主要的大都市区域内。因此，该成像工具将被广泛使用，以使大量患者受益。公共卫生相关性：重度抑郁症患者大脑中肾上腺素能神经元功能发生变化。在这个项目中测试的5-羟色胺转运体显像剂对于研究抗抑郁药在活体人脑中的结合至关重要。所提出的用于成像SERT的示踪剂可以由区域放射性药物制剂制备，并分布在任何主要的大都市区域内，使大量接受抗抑郁治疗的患者受益。

DESCRIPTION (provided by applicant): The objective of this grant is to develop imaging agents for studying serotonin transporters (SERT) of the central nervous system (CNS) using positron emission tomography (PET). Changes in serotonergic neuronal function in the CNS occur in patients with major depression. A series of new antidepressants preferentially increase 5-HT (serotonin) transmission by inhibiting serotonin reuptake. These selective serotonin reuptake inhibitors (SSRIs) have revolutionized the management of depression for millions of patients, and they are now widely prescribed for treating various other mental disorders such as compulsive obsessive and social phobic disorders. The PET imaging agents to be tested 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. In the past funding period we have prepared many fluorinated biphenylthiol derivatives with limited success. However, recently we found that changing the substitution at a different position of biphenylthiol appears to hold the key for improving the specific SERT binding (uptake and retention in the hypothalamus where SERT binding sites are highly concentrated) and more importantly for reducing the non-specific binding (in the cerebellum). In this renewal application three specific aims are proposed: 1) to synthesize and test a series of 18F labeled biphenylthiol derivatives as SERT ligands for PET imaging studies. 2) to perform in vivo biological evaluation of selectivity and kinetics of binding to SERT in the brain of rats. 3) to compare PET imaging agents proposed in this project and other SERT ligands labeled with 18F in non-human primates with the ultimate objective of identifying one or two final candidates suitable for human study. In vivo PET or SPECT imaging studies may provide an effective approach in estimating the drug occupancy of the target sites - SERT binding sites by the antidepressants used for treatment. Thus, imaging of SERT binding sites may open a small window allowing a direct measurement of drug action at the target sites in the brain. There is a compelling need to develop improved the PET imaging agents for studying this important target modulating the serotonin function in the brain. It is likely that 18F labeled tracers for imaging SERT can be prepared by regional radiopharmacies and distributed within any major metropolitan area. Thus, the imaging tool would be widely available to benefit a large number of patients. PUBLIC HEALTH RELEVANCE: Changes in serotonergic neuronal function in the brain occur in patients with major depression. The serotonin transporter imaging agents to be tested in this project are critically important for studying binding of antidepressants in the living human brain. The proposed tracers for imaging SERT can be prepared by regional radiopharmacies and distributed within any major metropolitan area benefiting a large number of patients undergoing antidepressant treatment.