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

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，更具体地说是胰岛素抵抗，其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，这种组织以前被认为在成人中完全退化。活组织检查证实的成人BAT重新激起了人们对发现BAT调节和/或活性障碍是否与肥胖发病机制有关的兴趣。需要新的方法来增加我们对人类BAT的认识。本应用程序的目的是测试一种新的，机械驱动的方法，使用正电子发射断层扫描（PET）成像人类BAT。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，并成像去甲肾上腺素循环成分，指定的去甲肾上腺素转运体（NET）。为此，我们将利用最近开发的高选择性NET配体（(S， S)-[11C] o -甲基瑞波西汀）（[11C]MRB）进行PET成像。PET成像NET比目前使用的[18F]-2-氟脱氧-d -葡萄糖（[18F]FDG）有优势，因为与[18F]FDG不同，它更具特异性，应该可以检测到未受刺激的BAT。我们对啮齿动物和人类受试者进行的初步离体和体内成像研究表明，[11C]MRB在室温和轻度寒冷条件下都能有效地标记BAT；相比之下[18F]， BAT的FDG标记仅发生在温和的寒冷条件下。我们对未标记MRB的初步阻断研究结果也证明了[11C]MRB成像BAT的特异性和饱和性。这些数据支持了我们的一般假设，即[11C]MRB PET成像方法将为BAT提供与BAT质量成正比的非受刺激靶标。数据还表明，由于环境冷暴露，NET随着适应性产热的激活而上调。我们的目的分为动物实验和人体实验。动物实验将直接比较室温和低温（40℃）条件下清醒大鼠的[11C]MRB和[18F]FDG示踪剂与肩胛骨间BAT尺寸、质量和标记强度的关系。此外，我们将在两种环境条件下的体内PET成像中检查肩胛间BAT [11C]MRB标记动力学。人类工作将验证[11C]MRB PET策略与当前的[18F]FDG标签金标准（使用室温和轻度冷暴露），并提供BAT的初步性别比较，也使用室温和轻度冷暴露的[11C]MRB PET策略。通过靶向BAT的主要调控系统组件，NET，我们正在为未来研究肥胖和糖尿病中BAT功能/功能障碍的机制以及这些疾病的治疗方法奠定基础。