18F-FDG PET imaging of brown adipose tissue to evaluate {beta}3-adrenoreceptor agonist efficacy in vivo

1216 Objectives The β3-adrenoreceptor (β3-A) on brown adipose tissue (BAT) is known as a regulator of glucose metabolism. Here, we report the evaluation of two β3-A agonists, CL316, 243 (CL; affinity 3 nM) and Mirabegron (YM178, 40 nM), and compared with norepinephrine (NE, 475 nM) using NE transporter inhibitor, Atomoxetine (ATX), in activating BAT using 18F-FDG dynamic PET. Methods Male Sprague-Dawley rats were fasted for 17 hrs prior to experiments. Rats were administered iv with either normal saline or 0.5 mg/kg of either CL or YM178 or ATX. The rats were then imaged for upper-body Inveon MicroPET/CT for 120 minutes 18F-FDG uptake in BAT, white adipose tissue (WAT), myocardium, skeletal muscle, brain, and liver. The magnitude of 18F-FDG uptake was expressed as standard uptake value (SUV). Separate 30 min static 18F-FDG scans were also used to evaluate dose-dependence (0.03, 0.3, 3 mg/kg) of YM178. Results IBAT and other areas of BAT were visualized with all three treatments. SUV curves of IBAT in drug-treated were compared with those in untreated rats (Fig. 1). The average 18F-FDG SUV of IBAT was increased to 2.27±0.40 (6.5-fold increase) in CL-treated; to 0.76±0.2 (2.2-fold increase) in Mirabegron-treated; and to 0.67±0.1 (1.85-fold increase) in ATX-treated rats as compared to control (0.35±0.1). This enhancement was due to upregulation of both 18F-FDG delivery into the tissue (glucose transporter) and its restriction to intracellular metabolism (hexokinase activity). A dose-dependent effect on 18F-FDG uptake was observed with YM178. Conclusions Affinity of CL, Mirabegron and norepinephrine for β3-A are each an order of magnitude apart but activation by YM178 and ATX was similar, while CL was 3-fold higher compared to YM178 and ATX. This suggests that although β3-A receptor activation increases 18F-FDG uptake and retention, additional factors such as drug bioavailability, drug kinetics at the receptor and other cellular mechanisms may be involved. Further evaluation of drug development for diabetes and obesity is in progress. Research Support NIH DK092917, EB006110