Brown Adipose Tissue Response Dynamics: In Vivo Insights with the Voltage Sensor 18F-Fluorobenzyl Triphenyl Phosphonium

Abstract

Brown adipose tissue (BAT) thermogenesis is an emerging target for prevention and treatment of obesity. Mitochondria are the heat generators of BAT. Yet, there is no noninvasive means to image the temporal dynamics of the mitochondrial activity in BAT in vivo. Here, we report a technology for quantitative monitoring of principal kinetic components of BAT adaptive thermogenesis in the living animal, using the PET imaging voltage sensor 18F-fluorobenzyltriphenylphosphonium (18F-FBnTP). 18F-FBnTP targets the mitochondrial membrane potential (ΔΨm)—the voltage analog of heat produced by mitochondria. Dynamic 18F-FBnTP PET imaging of rat’s BAT was acquired just before and during localized skin cooling or systemic pharmacologic stimulation, with and without administration of propranolol. At ambient temperature, 18F-FBnTP demonstrated rapid uptake and prolonged steady-state retention in BAT. Conversely, cold-induced mitochondrial uncoupling resulted in an immediate washout of 18F-FBnTP from BAT, which was blocked by propranolol. Specific variables of BAT evoked activity were identified and quantified, including response latency, magnitude and kinetics. Cold stimulation resulted in partial washout of 18F-FBnTP (39.1%±14.4% of basal activity). The bulk of 18F-FBnTP washout response occurred within the first minutes of the cold stimulation, while colonic temperature remained nearly intact. Drop of colonic temperature to shivering zone did not have an additive effect. The ß3-adrenergic agonist CL-316,243 elicited 18F-FBnTP washout from BAT of kinetics similar to those caused by cold stimulation. Thus, monitoring ΔΨm in vivo using 18F-FBnTP PET provides insights into the kinetic physiology of BAT. 18F-FBnTP PET depicts BAT as a highly sensitive and rapidly responsive organ, emitting heat in short burst during the first minutes of stimulation, and preceding change in core temperature. 18F-FBnTP PET provides a novel set of quantitative metrics highly important for identifying novel therapeutic targets at the mitochondrial level, for developing means to maximize BAT mass and activity, and assessing intervention efficacy.

Brown Adipose Reporting Criteria in Imaging STudies (BARCIST 1.0): Recommendations for Standardized FDG-PET/CT Experiments in Humans

“…Subsequent prospective and larger retrospective studies indicate that BAT is likely to be present and activated by chronic cold exposure in most healthy men and women (van der Lans et al, 2013; Lee et al, 2010), but is reduced in underweight (Bredella et al, 2012), overweight, and individuals with metabolic disease (Hanssen et al 2015). BAT accumulates a range of radiotracers beyond FDG, including tracers of other metabolic substrates such as [11C]acetate and [18F]THA (Ouellet et al, 2012), tracers of adrenergic innervation such as [123I]metaiodobenzylguanidine (MIBG), and agents binding to mitochondria such as [99mTc]sestamibi (MIBI) and [99mTc]tetrofosmin (Baba et al, 2007a; Fukuchi et al, 2003), and 18F-Fluorobenzyl Triphenyl Phosphonium (FBnTP)(Madar et al 2015). Although it has several limitations, FDG-PET/CT has become the most popular platform for investigating this unique adipose tissue and its physiological relevance to human metabolism, substrate regulation, and obesity.…”

Radiosynthesis and preliminary biological evaluation of a new 18F‐labeled triethylene glycol derivative of triphenylphosphonium

“…[ 18 F]FBnTP is phosphonium salt DLC that shows promising characteristics as a 18 F‐labeled MPI tracer . Additionally, this tracer has been used for studies on imaging of brown adipose tissue and apoptosis . In a synthetic route for [ 18 F]FBnTP reported in 2004, a corrosive reagent, PPh 3 Br 2 , was used in the step for [ 18 F]FBnBr synthesis.…”

“…Conversely, PET tracers labeled with fluorine-18 ( 18 F) have a suitable half-life (T 1/2 = 109.8 min), which enables their delivery to many PET centers and has contributed to their increased use. Accordingly, drug design involving 18 F for MPI has been undertaken.…”

Multiorgan, Multimodality Imaging in Cardiometabolic Disease

“…Accumulation of radiolabelled tribenzyl phosphonium ( 18 F-FBnTP) in BAT, which targets changes in mitochondrial membrane potential and proton flux, is inversely proportional to tissue activation. Interestingly, dynamic imaging of 18 F-FBnTP has been used to assess changes due to activation in real-time preclinical models 45 . Further investigation is required to establish the consequences of CMD on BAT function and to evaluate the potential of novel PET tracers in humans.…”