Imaging Adrenergic Stimulation of Brown Adipose Tissue

University Of California-Irvine, Irvine CA

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Abstract

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 [unreadable]3 adrenergic receptor) via the uncoupling protein (UCP) in BAT thermogenesis has been reported. The [unreadable]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 [unreadable]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 [unreadable]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.