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，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，以前认为这种组织在成年人体内会完全退化。活检证实的成年人体内 BAT 重新引起了人们对发现 BAT 调节和/或活性功能障碍是否导致肥胖发病机制的兴趣。需要新的方法来增加我们对人类最佳可行技术的了解。此应用的目的是使用人体 BAT 的正电子发射断层扫描 (PET) 成像来测试一种新的机械驱动方法。 BAT 受到交感神经系统的强烈支配和调节。我们建议利用交感神经系统的结构特征，并对去甲肾上腺素回收成分进行成像，称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选择性 NET 配体进行 PET 成像，((S, S)-[11C]O-甲基瑞波西汀) ([11C]MRB)。 PET 成像 NET 比目前使用的 [18F]-2-氟脱氧-D-葡萄糖 ([18F]FDG) 具有优势，因为与 [18F]FDG 不同，它更具特异性，并且应该允许检测非刺激物蝙蝠。我们对啮齿动物和人类受试者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可以有效标记 BAT；相反，BAT 的 [18F]FDG 标记仅在轻度寒冷条件下发生。我们使用未标记的 MRB 进行的初步阻断研究的结果也证明了 [11C]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 [11C]MRB PET 成像方法将为 BAT 提供与 BAT 质量成比例的非刺激目标。数据还表明，由于环境寒冷暴露，NET 上调，并激活适应性生热作用。我们的目标分为动物实验和人体实验。动物工作将直接比较室温和微冷 (40C) 条件下清醒大鼠的 [11C]MRB 和 [18F]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 [11C]MRB 标记动力学的两种环境条件后，在体内 PET 成像过程中检查肩胛间 BAT。人类工作将使用室温和轻度冷暴露，根据当前 [18F]FDG 标记的黄金标准验证 [11C]MRB PET 策略，并提供 BAT 的初步性别比较，也使用 [11C] MRB PET 策略采用室温和轻度冷暴露。通过针对 BAT 的主要调节系统组成部分 NET，我们正在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。