Imaging Adrenergic Stimulation of Brown Adipose Tissue

描述（由申请人提供）：本提案的总体目标是开发和评估用于测量棕色脂肪组织（BAT）活性和分布（质量）的PET成像方法。这与当前申请有关：“人类棕色脂肪组织：质量和活性测量方法”，RFA-DK-10-002。2型糖尿病（T2DM），以前被称为“非胰岛素依赖型糖尿病”（NIDDM）或“成人发病型糖尿病”，是最常见的糖尿病形式。大约90%到95%的糖尿病患者患有2型糖尿病。美国有2360万人患有糖尿病，占总人口的8%。根据美国糖尿病协会的数据，从2005年到2007年，糖尿病的总患病率增加了13.5%。BAT已被证明具有产热特性，可以减少白色脂肪组织。它可能是预防或治疗肥胖的重要药物靶点。我们的目标是开发新的成像方法，以测量BAT的活性和质量。我们建议使用肾上腺素能系统来测量BAT的活性和分布（质量）。肾上腺素能系统（肾上腺素/去甲肾上腺素和3肾上腺素能受体）通过解偶联蛋白（UCP）直接参与BAT产热。因此，肾上腺素能受体一直被视为BAT激活疗法开发的靶标。我们建议在啮齿类动物模型中研究两种激活BAT的方法，分别是使用¿3-肾上腺素受体激动剂CL 316243和去甲肾上腺素转运蛋白（NET）阻滞剂托莫西汀。这两种方法都有望刺激肾上腺素能系统并增加MicroPET/CT成像中的BAT 18F-FDG。为了测量BAT质量，我们将开发11C-CL 316243作为一种选择性的¿3-肾上腺素能激动剂放射性示踪剂，用于成像BAT分布和质量，并评估NET放射性示踪剂18F-MFP3作为测量BAT分布和质量的潜在放射性示踪剂。我们的目标之一是利用18F-FDG和11C-CL 316243在饮食性肥胖啮齿动物模型中评估BAT的活性和质量。11C-CL 316243将在啮齿类动物身上进行辐射剂量学研究，以进行探索性的研究性新药（eIND）申请，以便转化为人类研究。肾上腺素能神经递质受体成像方法的发展将有力地补充正在进行的肥胖和糖尿病成像方法。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop and evaluate PET imaging methods for measuring activity and distribution (mass) of brown adipose tissue (BAT). This is relevant to the current request for applications: "Human brown adipose tissue: Methods for measurement of mass and activity", RFA-DK-10-002. Type-2 diabetes mellitus, T2DM, previously known as "noninsulin-dependent diabetes mellitus" (NIDDM) or "adult- onset diabetes", is the most common form of diabetes. About 90 to 95 percent of people who have diabetes have T2DM. There are 23.6 million people in the United States, or 8% of the population, who have diabetes. The total prevalence of diabetes increased 13.5% from 2005-2007 according to the American Diabetes Association. BAT has been shown to have thermogenic properties and can reduce white adipose tissue. It may be an important drug target for preventing or treating obesity. Our goal is to develop new imaging methods that will allow measurement of BAT activity and mass. We propose to use the adrenergic system for measuring both activity and distribution (mass) of BAT. The direct involvement of adrenergic system (epinephrine/norepinephrine and ¿3 adrenergic receptor) via the uncoupling protein (UCP) in BAT thermogenesis has been reported. The ¿3 adrenergic receptor has therefore been pursued as a target for therapeutics development for BAT activation. We propose to investigate two approaches towards activation of BAT using the rodent model by using a ¿3-adrenoreceptor agonist, CL 316243 and the norepinephrine transporter (NET) blocker, tomoxetine. Both approaches are expected to stimulate the adrenergic system and increase BAT 18F-FDG in MicroPET/CT imaging. For measuring BAT mass we will develop 11C-CL 316243 as a selective ¿3-adrenergic agonist radiotracer for imaging BAT distribution and mass, and also evaluate the NET radiotracer 18F-MFP3 as a potential radiotracer for measuring BAT distribution and mass. One of our goals is to evaluate BAT activity and mass using 18F-FDG and 11C-CL 316243 in the diet-induced obesity rodent model. Radiation dosimetry studies of 11C-CL 316243 will be carried out on rodents for an exploratory Investigational New Drug (eIND) application for translation to human studies. Development of the adrenergic neurotransmitter receptor imaging methods will strongly complement ongoing imaging approaches for obesity and diabetes.