The Norepinephrine Transporter: A Novel Target for Imaging Brown Adipose Tissue

描述(申请人提供)：去甲肾上腺素转运蛋白：一种新的棕色脂肪组织成像靶标摘要肥胖，更具体地说，胰岛素抵抗的特征是与适应性产热相关的能量消耗受损。动物的适应性产热涉及棕色脂肪组织(BAT)的激活，这是一种以前被认为在成年人类中完全退化的组织。经活组织检查证实的成人BAT重新燃起了人们对发现BAT调节和/或活动障碍是否与肥胖发病有关的兴趣。需要新的方法来增加我们对人类BAT的了解。这项应用的目的是测试一种新的机械驱动方法，使用人体BAT的正电子发射断层扫描(PET)成像。蝙蝠强烈地受到交感神经系统的支配和调节。我们建议使用交感神经系统的结构特征，并想象去甲肾上腺素循环组件，称为去甲肾上腺素转运体(NET)。为此，我们将利用最近开发的一种用于PET成像的高选择性网络配体((S，S)-[11C]O-甲基瑞波西汀)([11C]MRB)。与目前使用的[18F]-2-氟-脱氧-D-葡萄糖([18F]FDG)相比，PET成像网络具有优势，因为它与[18F]FDG不同，它更具特异性，应该可以检测到非刺激性BAT。我们的一般假设是，[11C]MRB PET成像方法将为BAT提供一个与BAT质量成正比的非刺激靶，但也证明了由于环境寒冷暴露而激活的适应性产热上调。我们的目标分为动物实验和人体实验。这项动物研究将在室温和轻度寒冷(40摄氏度)条件下，直接比较清醒大鼠的[11C]MRB和[18F]FDG示踪剂，以确定它们与肩胛间蝙蝠的尺寸、质量和标记强度的关系。此外，在这两种环境条件下，我们将在活体PET成像过程中检查肩胛间BAT的[11C]MRB标记动力学。人工工作将根据当前的黄金标准[18F]FDG标记，使用室温和轻度冷暴露来验证[11C]MRB PET策略，并提供BAT的初步性别比较，还将使用室温和轻度冷暴露的[11C]MRB PET策略。通过瞄准BAT的主要调节系统组件Net，我们正在为未来BAT功能/功能障碍在肥胖和糖尿病中的机械性研究以及这些疾病的治疗方法奠定基础。 与公共健康相关：此应用程序的目的是测试一种新的、机械驱动的方法来成像棕色脂肪组织(BAT)，目标是其主要调节系统，即去甲肾上腺素回收组件，被称为去甲肾上腺素转运体(NET)。NET-PET和FDG-PET的验证研究结果将为未来肥胖和糖尿病中BAT功能/功能障碍的机制研究以及这些疾病的治疗方法奠定基础。

DESCRIPTION (provided by applicant): The Norepinephrine Transporter: A Novel Target for Imaging Brown Adipose tissue Abstract Obesity, and more specifically insulin resistance is characterized by impaired energy expenditure associated adaptive thermogenesis. Adaptive thermogenesis in animals involves activation of brown adipose tissue (BAT), a tissue previously thought to completely regress in adult humans. Biopsy-confirmed BAT in adult humans has revived interest in discovering whether dysfunction in regulation and/or activity of BAT contributes to the pathogenesis of obesity. New methodologies are needed to increase our knowledge of BAT in humans. The purpose of this application is to test a new, mechanistically driven approach using positron emission tomography (PET) imaging of BAT in humans. BAT is strongly innervated and regulated by the sympathetic nervous system. We propose to use a structural feature of the sympathetic nervous system, and image the norepinephrine recycling component, designated the norepinephrine transporter (NET). For this purpose, we will utilize a recently developed, highly selective NET ligand for PET imaging, ((S,S)-[11C]O-methylreboxetine) ([11C]MRB). PET imaging NET has the advantage over [18F]-2-fluoro-deoxy-D-glucose ([18F]FDG) currently in use, because unlike [18F]FDG, it is more specific, and should allow detection of non-stimulated BAT. Our general hypothesis is that the [11C]MRB PET imaging approach will provide a non-stimulated target for BAT that is proportional to BAT mass, but also demonstrates up-regulation with activation of adaptive thermogenesis due to environmental cold exposure. Our aims are divided into both animal, and human experiments. The animal work will directly compare the [11C]MRB and [18F]FDG tracers in awake rats under room temperature and mild cold (40C) conditions for their relationship to interscapular BAT dimensions, mass, and intensity of label. Moreover, we will examine interscapular BAT during in vivo PET imaging after both environmental conditions for [11C]MRB labeling kinetics. Human work will both validate the [11C]MRB PET strategy against the current gold standard of [18F]FDG labeling, using both room temperature and mild cold exposure, as well as provide a preliminary gender comparison of BAT, also using the [11C]MRB PET strategy with room temperature and mild cold exposures. By targeting a primary regulatory system component of BAT, NET, we are establishing a basis for future mechanistic studies of BAT function/dysfunction in obesity and diabetes, as well as for therapeutic approaches for these disorders. PUBLIC HEALTH RELEVANCE: The purpose of this application is to test a new, mechanistically driven approach to image brown adipose tissue (BAT) by targeting its primary regulatory system, the norepinephrine recycling component, designated the norepinephrine transporter (NET). The results from the validation study of NET-PET against FDG-PET will establish a basis for future mechanistic studies of BAT function/dysfunction in obesity and diabetes, as well as for therapeutic approaches for these disorders.