Imaging of cholinergic terminals using the radiotracer [18F](+)-4-fluorobenzyltrozamicol: In vitro binding studies and positron emission tomography studies in nonhuman primates

Abstract

The goal of the present set of studies was to characterize the in vitro binding properties and in vivo tissue kinetics for the vesicular acetylcholine transporter (VAcChT) radiotracer, [18F](+)-4-fluorobenzyltrozamicol ([18F](+)-FBT). In vitro binding studies were conducted in order to determine the affinity of the (+)- and (-)-stereoisomers of FBT for the VAcChT as well as sigma (sigma 1 and sigma 2) receptors. (+)-FBT was found to have a high affinity (Ki = 0.22 nM) for the VAcChT and lower affinities for sigma 1 (21.6 nM) and sigma 2 (35.9 nM) receptors, whereas (-)-FBT had similar affinities for the VAcChT and sigma 1 receptors (approximately 20 nM) and a lower affinity for sigma 2 (110 nM) receptors. PET imaging studies were conducted in rhesus monkeys (n = 3) with [18F](+)-FBT. [18F](+)-FBT was found to have a high accumulation and slow rate of washout from the basal ganglia, which is consistent with the labeling of cholinergic interneurons in this brain region. [18F](+)-FBT also displayed reversible binding kinetics during the 3 h time course of PET and produced radiolabeled metabolites that did not cross the blood-brain barrier. The results from the current in vitro and in vivo studies indicate that [18F](+)-FBT is a promising ligand for studying cholinergic terminal density, with PET, via the VAcChT.

Cholinergic activity of aged rhesus monkeys revealed by positron emission tomography

“…In our initial studies, we demonstrated that (ϩ)-[ 18 F]FBT has an appropriate binding profile for use in PET studies of the VAChT in primates (Mach et al, 1997) and has a low test-retest variability profile (Gage et al, 1998). In those studies, the highest accumulations of (ϩ)-[ 18 F]FBT were found in the basal ganglia, which is consistent with, and represents, the labeling of cholinergic interneurons in this region.…”

“…The synthesis of FBT was accomplished via N-alkylation of the corresponding des-benzyl precursor with [ 18 F]4-fluorobenzyliodide ([ 18 F]FBI) (Mach et al, 1993(Mach et al, , 1997. Synthesis time was approximately 115 min and the overall yield was 25.9 Ϯ 6.5% from [ 18 F]FBI (18 Ϯ 3% from [ 18 F]cesium fluoride).…”

“…Vesamicol (and its analogs) noncompetitively inhibits the transport of ACh into synaptic vesicles from a variety of sources (reviewed in Parsons et al, 1993). Accordingly, a number of studies have revealed that the in vitro distribution of (Ϫ)-[ 3 H]vesamicol (Altar and Marien, 1988;Marien et al, 1987) and the in vivo distribution of many radiolabeled vesamicol analogs (Efange et al, 1994(Efange et al, , 1995Ingvar et al, 1993;Kuhl et al, 1994;Mach et al, 1997) is consistent with patterns of cholinergic innervation delineated by choline acetyltransferase (Kuczenski et al, 1975;Levey et al, 1983;Satoh et al, 1983;Stavinoha et al, 1974) and [ 3 H]hemicholinium-3 (Quirion, 1987). Moreover, the inhibitory action of vesamicol appears to be selective for recycling vesicles (Melega and Howard, 1984;Ricny and Whittaker, 1993;Toll and Howard, 1980).…”

Dual Radiotracer Analysis of Cholinergic Neuronal Changes in Prediabetic Mouse Pancreas

“…[4][5][6][7][8][9] However, few have applied neurofunctional radiotracers to the study of the peripheral nervous system, which includes autonomic control of the richly innervated pancreas. [10][11][12][13] The goal of this project is to adapt the use of tracers used primarily in the central nervous system to develop a strategy that will ultimately allow an in vivo, radiotracer-based method of imaging cholinergic function by PET to identify type 1 diabetes mellitus in its earliest stages, when therapeutic interventions may be most effective.…”

“…The PET radiotracer (ϩ)- 5,8,9 The VAChT is responsible for loading presynaptic vesicles with the neurotransmitter ACh and has been shown to be a reliable marker of acetylcholine activity in vivo. 16 We have previously reported that [ 18 F]FBT localizes in the pancreas.…”