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

去甲肾上腺素转运蛋白：棕色脂肪组织成像的新靶点

• 批准号: 8516808
• 负责人: YU-SHIN DING
• 金额: $ 19.56万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516808
• 关键词: Norepinephrine; Transporter; Novel; Target; Imaging

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.

描述（申请人提供）：去甲肾上腺素转运蛋白：棕色脂肪组织成像的新靶点摘要肥胖，更具体地说是胰岛素抵抗的特征在于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，这种组织以前被认为在成年人中完全退化。成年人中活检证实的BAT重新引起了人们对发现BAT的调节和/或活性功能障碍是否有助于肥胖症发病机制的兴趣。需要新的方法来增加我们对人类BAT的了解。本申请的目的是使用人体BAT的正电子发射断层扫描（PET）成像测试一种新的机械驱动方法。BAT受交感神经系统的强烈支配和调节。我们建议使用交感神经系统的结构特征，并将去甲肾上腺素再循环组件（称为去甲肾上腺素转运蛋白（NET））成像。为此，我们将利用最近开发的用于PET成像的高选择性NET配体（（S，S）-[11 C] O-methylreboxylate）（[11 C]MRB）。PET成像NET比目前使用的[18 F]-2-氟-脱氧-D-葡萄糖（[18 F]FDG）更有优势，因为与[18 F]FDG不同，它更具有特异性，并且应该允许检测非刺激的BAT。我们的一般假设是，[11 C]MRB PET成像方法将为BAT提供与BAT质量成比例的非刺激靶点，但也证明了由于环境冷暴露而激活适应性产热的上调。我们的目标分为动物实验和人体实验。动物研究将直接比较室温和轻度寒冷（40 ℃）条件下清醒大鼠中的[11 C]MRB和[18 F]FDG示踪剂与肩胛间BAT尺寸、质量和标记强度的关系。此外，我们将在体内PET成像过程中检查两种环境条件下[11 C]MRB标记动力学的肩胛间BAT。人类工作将使用室温和轻度冷暴露来验证[11 C]MRB PET策略与[18 F]FDG标记的当前金标准，并提供BAT的初步性别比较，还使用室温和轻度冷暴露的[11 C]MRB PET策略。通过靶向BAT，NET的主要调节系统组件，我们正在为肥胖和糖尿病中BAT功能/功能障碍的未来机制研究以及这些疾病的治疗方法奠定基础。 公共卫生关系：本申请的目的是测试一种新的、机械驱动的方法，通过靶向棕色脂肪组织（BAT）的主要调节系统（去甲肾上腺素再循环组分，称为去甲肾上腺素转运蛋白（NET））来对BAT进行成像。NET-PET对FDG-PET的验证研究结果将为肥胖和糖尿病中BAT功能/功能障碍的未来机制研究以及这些疾病的治疗方法奠定基础。