Serotonin 1B Receptor Imaging in Major Depressive Disorder

描述（由申请人提供）：1B型5-羟色胺（5-HT 1B）受体与重度抑郁症（MDD）的发病机制有关。5-HT 1B受体的最高浓度在人类苍白球中发现。由于苍白球与被认为参与MDD病理生理学的中脑边缘回路的功能和解剖学联系，最近受到关注。神经递质释放的异常调节作为神经元回路中5-HT 1B受体功能障碍的结果，其已被证明在MDD的病理生理学中起作用，这至少可以部分解释潜在的神经生理功能障碍。5-HT 1B受体也可能是药物开发的候选靶点。尽管动物研究和人体研究表明5-HT 1B受体在MDD发病机制中的重要作用，但这些模型是否构成人类MDD的相关模型尚不清楚。选择性5-HT 1B受体放射性配体[11 C] CE-142，943首次允许使用正电子发射断层扫描（PET）在体内评估中心5-HT 1B受体结合。该提案是一项为期2年的研究，涉及10名根据DSM-IV标准患有当前MDD的无药物治疗、有症状的受试者和10名单独匹配的健康对照受试者。所有受试者将在静息状态下接受一次磁共振成像（MRI）扫描和一次[11 C] CE-142，943 PET扫描。这项研究将提供重要的5-HT 1B受体在MDD的病理生理作用的新信息。此外，我们相信这项研究将产生重要的新结果，我们计划将其用作后续研究的基础，这些研究旨在确定情绪障碍的异常过程，指导新治疗药物的初始给药，以及预测症状发作，监测疾病进展和评估治疗药物的疗效。公共卫生相关性：神经递质血清素在抑郁症的发展中起着重要作用。血清素是大脑的天然化学物质之一。5-羟色胺与脑细胞上的1B型5-羟色胺受体（结合位点）结合，以调节情绪、焦虑、睡眠和压力激素。通过使用正电子发射断层扫描（PET）和放射性示踪剂，我们能够测量大脑中5-羟色胺1b受体的数量。在注射放射性示踪剂之后，PET扫描仪将检测存在于脑区域中的放射性示踪剂。这些信息将用于创建大脑的图片，显示大脑中血清素1B型受体的分布。这种方法可以确定抑郁症患者与没有抑郁症或其他精神疾病的健康人相比，大脑中5-羟色胺1b受体的数量是否不同。这项研究不仅有助于更多地了解抑郁症的生物学，而且可能最终有助于为抑郁症患者找到更好的治疗方法。

DESCRIPTION (provided by applicant): The serotonin type 1B (5-HT1B) receptor has been implicated in the pathogenesis of major depressive disorder (MDD). Highest concentrations of 5-HT1B receptors are found in the globus pallidus in humans. The globus pallidus has received attention recently given its functional and anatomical connection to the mesolimbic circuit which is believed to be involved in the pathophysiology of MDD. Abnormal modulation of neurotransmitter release as a consequence of dysfunctional 5-HT1B receptors in the neuronal circuits which have been shown to play a role in the pathophysiology of MDD may at least partially explain the potential neurophysiologic dysfunction underlying depression. The 5- HT1B receptor may also be a candidate target for drug development. Even though animal studies and studies in human suggest an important role for the 5-HT1B receptor in the pathogenesis of MDD it is not clear at all whether such models constitute relevant models for MDD in humans. The selective 5-HT1B receptor radioligand, [11C] CE-142,943, permits for the first time in vivo assessment of central 5-HT1B receptor binding using positron emission tomography (PET). This proposal is a 2-year study involving 10 medication-free, symptomatic subjects with current MDD according to DSM-IV criteria, and 10 individually matched healthy control subjects. All subjects will undergo one magnetic resonance imaging (MRI) scan, and one [11C] CE-142,943 PET scan under resting conditions. This study will provide important new information about the role of 5- HT1B receptors in the pathophysiology of MDD. Moreover, we believe that this study will generate important novel results which we plan to use as basis for subsequent studies that aim to determine the abnormal processes which underlie mood disorders, guide initial dosing of new therapeutic agents and that are central to predict symptom onset, monitor disease progression and assess the efficacy of therapeutic agents. PUBLIC HEALTH RELEVANCE: The neurotransmitter serotonin plays an important role in the development of depression. Serotonin is one of the brain's natural chemicals. Serotonin binds to serotonin receptors (binding sites) type 1B on brain cells to regulate emotion, anxiety, sleep, and stress hormones. With the use of positron emission tomography (PET) and administration of a radiotracer, we are able to measure the number of serotonin 1b receptors in the brain. Following the injection of the radiotracer, the PET scanner will detect the radiotracer present in brain areas. This information will be used to create pictures of the brain showing the distribution of serotonin type 1B receptors in the brain. This method allows to determining whether people with depression show a different number of serotonin 1b receptors in the brain as compared to healthy people without depression or other psychiatric illnesses. This study will help not only to learning more about the biology of depression, but may ultimately help to find better treatments for people with depression.