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: 8325011
• 负责人: YU-SHIN DING
• 金额: $ 26.91万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8325011
• 关键词: Adult; Animals; Attention deficit hyperactivity disorder; Biopsy; Body Weight decreased; Brain region; Brown Fat; Cardiac; Characteristics; Childhood; Cocaine Dependence; Data; Detection; Development; Diabetes Mellitus; Diet; Dimensions; Disease; Drug or chemical Tissue Distribution; Energy Metabolism; Functional disorder; Future; Gender; Glucose; Gold; Human; Image; Individual; Insulin Resistance; Intervention; Kinetics; Knowledge; Label; Ligands; Metabolic; Methodology; Neurons; Norepinephrine; Obesity; Pathogenesis; Peripheral; Play; Positron-Emission Tomography; Rattus; Recycling; Regulation; Resistance; Rodent; Role; Sex Characteristics; Specificity; Sympathetic Nervous System; System; Technology; Temperature; Testing; Therapeutic; Thermogenesis; Tissues; Tracer; Up-Regulation; Weight; Woman; Work; awake; base; cold temperature; energy balance; glucose uptake; human subject; imaging probe; in vivo; inhibitor/antagonist; interest; nonhuman primate; noradrenaline transporter; norepinephrine system; novel; reboxetine; research study; tool; validation studies; Adult; Animals; Attention deficit hyperactivity disorder; Biopsy; Body Weight decreased; Brain region; Brown Fat; Cardiac; Characteristics; Childhood; Cocaine Dependence; Data; Detection; Development; Diabetes Mellitus; Diet; Dimensions; Disease; Drug or chemical Tissue Distribution; Energy Metabolism; Functional disorder; Future; Gender; Glucose; Gold; Human; Image; Individual; Insulin Resistance; Intervention; Kinetics; Knowledge; Label; Ligands; Metabolic; Methodology; Neurons; Norepinephrine; Obesity; Pathogenesis; Peripheral; Play; Positron-Emission Tomography; Rattus; Recycling; Regulation; Resistance; Rodent; Role; Sex Characteristics; Specificity; Sympathetic Nervous System; System; Technology; Temperature; Testing; Therapeutic; Thermogenesis; Tissues; Tracer; Up-Regulation; Weight; Woman; Work; awake; base; cold temperature; energy balance; glucose uptake; human subject; imaging probe; in vivo; inhibitor/antagonist; interest; nonhuman primate; noradrenaline transporter; norepinephrine system; novel; reboxetine; research study; tool; validation studies

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.

描述（由申请人提供）：肥胖症和更具体的胰岛素抵抗的特征是能量消耗受损相关的自适应生热。动物的自适应热发生涉及激活棕色脂肪组织（BAT），这是一种以前认为在成年人中完全消退的组织。成人人类的活检确认的蝙蝠恢复了兴趣发现蝙蝠调节和/或活动中功能障碍是否有助于肥胖的发病机理。需要新的方法来增加我们对人类蝙蝠的了解。该应用的目的是使用人类蝙蝠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。蝙蝠受到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，并图像去甲肾上腺素的回收成分，指定为去甲肾上腺素转运蛋白（NET）。为此，我们将利用最近开发的高度选择性的净配体进行宠物成像，（（S，S） - [11C] O-甲基瑞碱）（[[11C] MRB）。 PET成像网比当前正在使用的[18F] -2 -2-氟-deoxy-d-葡萄糖（[18F] FDG）的优势是，因为与[18F] FDG不同，它更具体，并且应该允许检测非刺激的蝙蝠。我们在啮齿动物和人类受试者中的初步体内和体内成像研究表明，[11C] MRB可以在室温和轻度冷条件下有效地标记蝙蝠。相比之下，[18F]蝙蝠的FDG标记仅在轻度寒冷条件下发生。我们对未标记的MRB的初步阻止研究的结果也证明了[11C] MRB对蝙蝠的特异性和饱和性。这些数据支持我们的总体假设，即[11C] MRB PET成像方法将为BAT提供与BAT质量成正比的蝙蝠的非刺激靶标。数据还表明，由于环境冷暴露，自适应生热发生，净上调。我们的目标分为动物和人类实验。该动物的工作将直接比较室温下的[11C] MRB和[18F] FDG示踪剂在清醒的大鼠中，并且在轻度寒冷（40c）条件下（40c）条件，以使其与capular bat bat尺寸，质量和标签的强度进行比较。此外，在[11C] MRB标记动力学的两个环境条件下，我们将在体内宠物成像期间检查capular蝙蝠。人类的工作将使用室温和轻度的冷暴露，以及对BAT的初步性别比较，以验证[11C] MRB PET策略，以针对[18F] FDG标记的当前黄金标准进行验证，并使用[11C] MRB PET策略进行了室温和轻度冷暴露。通过针对BAT，NET的主要调节系统组成部分，我们为肥胖和糖尿病的BAT功能/功能障碍以及这些疾病的治疗方法建立了基础。