Ex Vivo and In Vivo Evaluation of the Norepinephrine Transporter Ligand [11C]MRB for Brown Adipose Tissue Imaging

Abstract

Introduction It has been suggested that brown adipose tissue (BAT) in humans may play a role in energy balance and obesity. We conducted ex vivo and in vivo evaluation using [11C]MRB, a highly selective NET (norepinephrine transporter) ligand for BAT imaging at room temperature which is not achievable with [18F]FDG. Methods PET images of male Sprague-Dawley rats with [18F]FDG and [11C]MRB were compared. Relative [18F]FDG or [11C]MRB retention at 20, 40 and 60 min post-injection was quantified on awake rats after exposing to cold (4°C for 4h) or remaining at room temperature. Rats pretreated with unlabeled MRB or nisoxetine 30 min before [11C]MRB injection were also assessed. The [11C]MRB metabolite profile in BAT was evaluated. Results PET imaging demonstrated intense [11C]MRB uptake (SUV of 2.9 to 3.3) in the interscapular BAT of both room temperature and cold-exposed rats and this uptake was significantly diminished by pretreatment with unlabeled MRB; in contrast, [18F]FDG in BAT was only detected in rats treated with cold. Ex vivo results were concordant with the imaging findings; i.e. the uptake of [11C]MRB in BAT was 3 times higher than that of [18F]FDG at room temperature (P=0.009), and the significant cold-stimulated uptake in BAT with [18F]FDG (10-fold, P=0.001) was not observed with [11C]MRB (P=0.082). HPLC analysis revealed 94-99% of total radioactivity in BAT represented unchanged [11C]MRB. Conclusions Our study demonstrates that BAT could be specifically labeled with [11C]MRB at room temperature and under cold conditions, supporting a NET-PET strategy for imaging BAT in humans under basal conditions.

The Cannabinoid Receptor-1 Is an Imaging Biomarker of Brown Adipose Tissue

“…White to brown fat conversion (browning) is a key step for exploring the potential use of BAT activation in obesity treatment. Only few reports on detection of browning in vivo have been reported, including the use of the norepinephrine transporter as a surrogate imaging biomarker due to the extensive sympathetic innervation of BAT (14)(15)(16). However, the activity and up-and downregulation of norepinephrine transporter and other components of the noradrenergic system are tightly connected to the activation of BAT.…”

Imaging of Brown Adipose Tissue: State of the Art

“…This is also true for (S,S)-O-[ 11 C] methylreboxetine, a PET tracer that labels sites of sympathetic innervation by binding to the norepinephrine transporter. Although no published data are yet available regarding 11 C-methylreboxetine use in humans, preclinical data suggest that accumulation of this tracer is relatively high in inactive BAT (higher uptake relative to heart than for FDG); however, little increase is seen upon BAT activation (68).…”

Synthesis and in Silico Evaluation of Novel Compounds for PET-Based Investigations of the Norepinephrine Transporter

“…Thus, the NET, responsible for NE equilibrium in the synaptic cleft, is representing the reuptake site and considered to be involved in a variety of neurological/psychiatric disorders [1,2], but also plays a pivotal role in cardiovascular [1][2][3] and metabolic diseases [3][4][5]. Reduced NET levels go along with neurological disorders like major depression [6,7], Parkinson's disease (PD), Alzheimer's disease (AD) [8][9][10][11][12][13][14][15][16][17][18], and cardiovascular diseases such as hypertension, cardiomyopathy, and heart failure [5,13]. Furthermore, a dysfunction of the NE system was reported in Attention Deficit Hyperactivity Disorder (ADHD) [9,17,19], suicide [1,12,20], substance abuse (cocaine dependence) [16], and schizophrenia [10].…”

“…Furthermore, a dysfunction of the NE system was reported in Attention Deficit Hyperactivity Disorder (ADHD) [9,17,19], suicide [1,12,20], substance abuse (cocaine dependence) [16], and schizophrenia [10]. A more recent discovery is the involvement of the NET in diseases like diabetes and obesity, due to its presence in brown adipose tissue (BAT) and the proposed activation thereof via NE [4,5,21].…”