PET imaging of serotonin transporters in the brain

描述（由申请人提供）：本拨款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）的血清素转运体（SERT）。中枢神经系统中血清素能神经元功能的改变发生在重度抑郁症患者中。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）的传递。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对抑郁症的治疗，现在它们被广泛用于治疗各种其他精神障碍，如强迫性强迫症和社交恐惧症。在本项目中测试的PET显像剂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。在过去的资助期内，我们制备了许多氟化联苯硫醇衍生物，但成效有限。然而，最近我们发现，改变联苯硫醇在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摄取和保留）的关键，更重要的是减少非特异性结合（在小脑）。在这个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PET成像研究的SERT配体。2)对SERT在大鼠脑内的选择性和结合动力学进行体内生物学评价。3)比较本项目提出的PET显像剂与其他非人类灵长类动物中标记有18F的SERT配体，最终确定一到两个适合人类研究的候选药物。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点- SERT结合位点的药物占用。因此，SERT结合位点的成像可能打开一个小窗口，允许直接测量药物在大脑靶点的作用。为了研究这一调节大脑血清素功能的重要靶点，迫切需要开发改进的PET显像剂。18F标记的SERT显像示踪剂很可能可以由区域性放射性药厂制备，并分布在任何主要大都市地区。因此，成像工具将被广泛使用，使大量患者受益。公共卫生相关性：重度抑郁症患者大脑中血清素能神经元功能的变化。在这个项目中测试的血清素转运显像剂对于研究抗抑郁药在活人大脑中的结合至关重要。建议的用于SERT成像的示踪剂可以由区域性放射性药厂制备，并分布在任何主要大都市地区，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.