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

描述（由申请人提供）：肥胖，更具体地说，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。我们在啮齿动物和人类受试者中的初步离体和体内成像研究表明，[11 C]MRB可以在室温和轻度寒冷条件下有效标记BAT;相反，[18 F]FDG标记BAT仅在轻度寒冷条件下发生。我们用未标记的MRB进行的初步阻断研究的结果也证明了[11 C]MRB对BAT成像的特异性和饱和性。这些数据支持我们的一般假设，即[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。数据还表明NET上调与激活的适应性产热由于环境冷暴露。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。

DESCRIPTION (provided by applicant): 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 preliminary ex vivo and in vivo imaging studies in rodents and a human subject have shown that [11C]MRB can efficiently label BAT at both room temperature and mild cold conditions; in contrast, [18F]FDG labeling of BAT occurs only under mild cold conditions. The results from our preliminary blocking study with unlabeled MRB also demonstrated the specificity and saturability of [11C]MRB for imaging BAT. These data support our general hypothesis that the [11C]MRB PET imaging approach will provide a non-stimulated target for BAT that is proportional to BAT mass. Data also suggest NET 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.