Serotonin 1B Receptor Imaging in PTSD with and without Co-morbid Depression

描述（由申请人提供）：过去几十年的研究一直试图阐明创伤后应激障碍（PTSD）和重度抑郁症（MDD）的神经生物学原因。最近，鉴于共病 PTSD 和 MDD 的高并发率以及在重病患者群体中发现的临床挑战，人们对共病 PTSD 和 MDD 之间的关系越来越感兴趣。基于配体的成像技术虽然更广泛地单独应用于 PTSD 和 MDD，但尚未用于系统地检查它们的共现情况。拟议的转化研究旨在利用最先进的脑成像技术，利用高分辨率研究断层扫描（HRRT）上的正电子发射断层扫描（PET）和血清素（5-HT）1B受体的新型放射性配体，扩展目前对PTSD和MDD同时发生的神经生物学机制的了解。越来越多的证据表明，5-HT1B 受体可能在情绪障碍和焦虑障碍的病因学中发挥重要作用，并且可能在它们的同时发生中发挥重要作用。 5-HT1B 受体在调节血清素 (5-HT) 传输、中皮质边缘回路功能以及情绪和焦虑症的病理生理学中发挥着核心作用。由于 5-HT1B 受体的选择性配体最近才出现，因此有关 5-HT1B 受体参与这些疾病的知识仍然有限。因此，体内 5-HT1B 受体密度和分布的定量可能为了解 PTSD 和 MDD 共病机制提供重要见解。耶鲁大学正电子发射断层扫描 (PET) 中心是开发 5-HT1B 受体选择性 PET 放射性示踪剂的先驱。我们建议应用这种创新配体首次系统地研究 PTSD 和 MDD 的共存。我们建议使用[11C]P943（一种选择性高亲和力5-HT1B受体拮抗剂）来研究患有共病MDD的PTSD受试者和无创伤史的MDD受试者的5-HT1B受体结合电位（BPND）。我们还将他们的数据与没有 MDD 的 PTSD 患者和健康对照受试者队列进行比较，这些受试者是在不同的资助机制下收集的。我们相信这项研究将产生重要的新结果，让我们了解与共病 PTSD 和 MDD 相关的神经生物学机制。此外，这项研究的结果有可能为开发专门针对共病症状的治疗程序提供信息，指导新治疗药物的初始剂量，并且对于预测症状发作、监测疾病进展和评估治疗药物的疗效至关重要。公共健康相关性：神经递质血清素在创伤后应激障碍 (PTSD) 和抑郁症的发展中发挥着重要作用。通过使用正电子发射断层扫描 (PET) 和使用放射性示踪剂，我们能够测量大脑中 1B 型血清素受体的分布。该方法可以确定患有 PTSD 和抑郁症的人与没有 PTSD 和抑郁症的健康人以及仅有抑郁症的人相比，大脑中是否表现出不同数量的 5-羟色胺 1b 受体。

DESCRIPTION (provided by applicant): Research over the past decades has sought to elucidate the neurobiological causes of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). More recently, there is increasing interest into the relationship of co-morbid PTSD and MDD given their high rates of co-occurrence and the clinical challenges found in this severely ill patient population. Ligand-based imaging techniques, while more widely applied to PTSD and MDD alone, have not been utilized to examine systematically their co-occurrence. The proposed translational research study aims to expand current knowledge of the neurobiological mechanisms of the co-occurrence of PTSD and MDD using state-of-the-art brain imaging techniques with positron emission tomography (PET) on a high resolution research tomograph (HRRT) and a novel radioligand for the serotonin (5-HT) 1B receptor. A growing body of evidence suggests that the 5-HT1B receptor might play an important role in the etiology of mood and anxiety disorders, and potentially also in their co-occurrence. The 5-HT1B receptor plays a central role in the regulation of serotonin (5-HT) transmission, mesocorticolimbic circuitry functioning and in the pathophysiology of mood and anxiety disorders. As selective ligands for the 5-HT1B receptor have only recently become available, knowledge for the involvement of 5-HT1B receptors in these disorders is still limited. Thus, in vivo quantitation of the density and distribution of 5-HT1B receptors might provide important insights into mechanisms contributing to the co-morbidity of PTSD and MDD. The Yale Positron Emission Tomography (PET) Center has been a pioneer in the development of a PET radiotracer selective for 5-HT1B receptors. We propose to apply this innovative ligand to study for the first time systematically the co-occurrence of PTSD and MDD. We propose using [11C]P943, a selective, high affinity 5- HT1B receptor antagonist, to investigate 5-HT1B receptor binding potential (BPND) in PTSD subjects with co-morbid MDD and MDD subjects without history of trauma. We will also compare their data to cohorts of patients with PTSD without MDD and healthy control subjects which have been collected under a different grant mechanism. We believe that this study will generate important novel results which will inform us about the neurobiological mechanisms associated with co-morbid PTSD and MDD. In addition, the results derived from this research has the potential to inform the development of treatment procedures that are directed specifically to co-morbid symptoms, 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 post-traumatic stress disorder (PTSD) and depression. With the use of positron emission tomography (PET) and administration of a radiotracer, we are able to measure the distribution of serotonin type 1B receptors in the brain. This method allows to determining whether people with PTSD and depression show a different number of serotonin 1b receptors in the brain as compared to healthy people without PTSD and depression and people with only depression.