Positron emission tomography imaging of (2R,3R)-5-[18F]fluoroethoxybenzovesamicol in rat and monkey brain: a radioligand for the vesicular acetylcholine transporter

Abstract

Introduction The regional brain distribution of (2R,3R)-5-[ [18F]fluoroethoxy-benzovesamicol ((-)-[18F]FEOBV), a radioligand for the vesicular acetylcholine transporter (VAChT), was examined in vivo in mice, rats, and rhesus monkeys. Methods Regional brain distributions of (-)-[18F]FEOBV in mice were determined using ex vivo dissection. MicroPET imaging was used to determine the regional brain pharmacokinetics of the radioligand in rat and rhesus monkey brains. Results In all three species, clear heterogeneous regional brain distributions were obtained, with the rank order of brain tissues (striatum>thalamus>cortex>cerebellum) consistent with the distribution of cholinergic nerve terminals containing the VAChT. Conclusions (-)-[18F]FEOBV remains a viable candidate for further development as an in vivo imaging agent for Positron Emission Tomography (PET) studies of the VAChT in the human brain.

PET imaging of cholinergic deficits in rats using [18F]fluoroethoxybenzovesamicol ([18F]FEOBV)

“…In addition, peripheral [ 18 F]FEOBV metabolism does not generate metabolites capable of crossing the blood-brain barrier (Landry St-Pierre et al, 2008b). [ 18 F]FEOBV is also stable in the brain and plasma, and does not generate significant amounts of free [ 18 F]fluoride in primates, as opposed to other vesamicol derivatives (Giboureau et al, NeuroImage 62 (2012) 555-561 2007; Kilbourn et al, 2009;Soucy et al, 2010). Despite slow in vitro kinetics (Mulholland et al, 1998), reversible kinetics of [ 18 F]FEOBV can be observed during a 60 min dynamic PET scan (Kilbourn et al, 2009;Landry St-Pierre et al, 2008a).…”

“…[ 18 F]FEOBV is also stable in the brain and plasma, and does not generate significant amounts of free [ 18 F]fluoride in primates, as opposed to other vesamicol derivatives (Giboureau et al, NeuroImage 62 (2012) 555-561 2007; Kilbourn et al, 2009;Soucy et al, 2010). Despite slow in vitro kinetics (Mulholland et al, 1998), reversible kinetics of [ 18 F]FEOBV can be observed during a 60 min dynamic PET scan (Kilbourn et al, 2009;Landry St-Pierre et al, 2008a). This discrepancy between in vivo and in vitro kinetic speeds is a relatively common feature of PET radiopharmaceuticals, a notable example being [ 3 H]SCH 23390 (Gifford et al, 2000).…”

New systematically modified vesamicol analogs and their affinity and selectivity for the vesicular acetylcholine transporter – A critical examination of the lead structure

“…Based on the idea of a ring fusion as made with benzovesamicols, structurally related compounds were developed. Two candidates of the class of morpholinovesamicols were 18 F-radiolabeled and studied in vivo in rats and pigs [29e31]. In particular, the 4-fluoro-benzoylated derivative [ 18 F] FBMV showed a typical accumulation in VAChT-containing brain regions and a significant reduction of cortical binding after a specific cholinergic lesion.…”

MicroPET/CT Imaging of [18F]-FEPPA in the Nonhuman Primate: A Potential Biomarker of Pathogenic Processes Associated with Anesthetic-Induced Neurotoxicity

“…The development of microPET imaging applications has provided the ability to collect sensitive and quantitative three-dimensional molecular information from the living brains of a variety of animals including nonhuman primates (NHP) [12][13][14]. In order to obtain sufficient data from living animals and longitudinally assess the neurotoxic effects associated with developmental exposures to anesthesia, we have developed a microPET protocol thought to target neuronal damage in vivo using imaging approaches [15,16].…”