13N-ammonia: A novel biomarker for blood flow-dependent imaging of brown adipose tissue in rodents and humans

Objectives Brown adipose tissue proposes an attractive mechanism for weight loss by increasing energy expenditure. Currently, imaging modalities for detecting BAT and monitoring its physiological activity in humans are rare. BAT is a highly vascularized organ. Cold and pharmacological activation of BAT are associated with an immediate, marked increase of blood flow, which may play a role in nutrient and energy substrates supply. Yet, the mechanism(s) underlying the hyperemic response are far from clear. Here, we tested the hypothesis that the established perfusion agent 13N-ammonia (NH3) is an appropriate probe to detect BAT and measure BAT activation by monitoring blood flow.

Methods In Brown Norway rats, a 20-min dynamic 13N-NH3 (1 mCi, bolus injection) PET was acquired at ambient temperature and after 20 and 60 min of localized skin cooling. Human studies were carried out in 7 healthy volunteers. 20-min dynamic 13N-NH3 (10 mCi IV)-PET was carried out at ambient temperature and after 40 min of mild cold stimulation. At the completion of the 2ed 13N-NH3 scan, FDG (10 mCi) was administered and after 60-min uptake period, under cold condition, 40-min dynamic scan was acquired.

Results In rodents, 20-min cold stimulation was sufficient to elevate blood flow and obtain clear visualization of interscapular BAT depots on 13N-NH3 image, co-localized with 18F-FDG BAT. Compartmental modeling (1-tissue, de Grado), using LV cavity activity as input function, revealed cold duration-dependent increase of blood flow (mL/min/g). This finding provides the first clue, in vivo, that BAT activation is not all-or-none event, but mediated by an ongoing mechanism. In humans, 13N-NH3 detected BAT depots in the upper shoulder area in 6/7 volunteers, co-localized with 18F-FDG-BAT uptake.

Conclusions This study demonstrates the feasibility of detecting stimulated BAT, and quantifying the hyperemic response using 13N-NH3 and dynamic PET. 13N-NH3 affords a potent means for investigating the role of blood flow in BAT thermogenesis, by voxel-based comparison with glycolysis, measured by 18F-FDG PET, and mitochondrial oxidative metabolism, measured by 18F-FBnTP PET.