Synthesis and evaluation of a new vesamicol analog o-[11C]methyl-trans-decalinvesamicol as a PET ligand for the vesicular acetylcholine transporter

Abstract

[(11)C]OMDV selectively binds to VAChT with high affinity in the rat brain in vivo, and that [(11)C]OMDV may be utilized in the future as a specific VAChT ligand for PET imaging.

(−)‐o‐[11C]methyl‐trans‐decalinvesamicol ((−)‐[11C]OMDV) as a PET ligand for the vesicular acetylcholine transporter

“…(−)-[ 11 C]OMDV showed high accumulation in the cortex and striatum (0.57 and 0.72%ID/g at 60 min post-injection) and a high striatum to cortex ratio (1.26 at 60 min postinjection). These results support that (−)-[ 11 C]OMDV is a superior VAChT imaging agent compared with racemic [ 11 C]OMDV that was reported previously (Kitamura et al, 2016).…”

“…PET scan was performed for 40 min postinjection, and these images were acquired for 5 min, starting at 28 min post-injection ligand, hardly inhibited the brain accumulation of (−)-[ 11 C]OMDV (Table 3). These results demonstrated that (−)-[ 11 C]OMDV bound more selectively to VAChT in the rat brain in vivo than the previously reported racemic [ 11 C]OMDV (Kitamura et al, 2016). The selective accumulation of (−)-[ 11 C]OMDV to VAChT was also confirmed by PET-CT imaging, which showed the decrease in brain accumulation of (−)-[ 11 C]OMDV by coadministration of vesamicol.…”

“…imaging probe, PET, VAChT, vesamicol analog (Bar & Parsons 1986;Marshall & Parsons 1987), many vesamicol analogs have been developed as potential VAChT imaging agents for PET or SPECT (Azim et al, 2014;Bando et al, 2001;Barthel et al, 2015;Custers, Leysen, Stoof, & Herscheid, 1997;Efange, Michelson, Khare, & Thomas, 1993;Efange et al, 1994, Efange et al, 2000Kitamura et al, 2016;Kozaka et al, 2014;Mulholland et al, 1998;Shiba, Mori, & Tonami, 2003;Sorger et al, 2000Sorger et al, , 2008Sorger et al, , 2009. Furthermore, several reported vesamicol analogs were separated into optical isomers to improve in vitro and in vivo characteristics as VAChT imaging agents (Efange et al, 1994;Jung, Van Dort, Gildersleeve, & Wieland, 1990;Kovac et al, 2010;Li et al, 2013;Mulholland et al, 1998;Shiba et al, 2003Shiba et al, , 2009Tu et al, 2009Tu et al, , 2015Uno et al, 2016).…”

“…However, many of the reported vesamicol analogs were shown to be insufficient for use as VAChT imaging probes because of binding to sigma receptors (σ1 and σ2) or low accumulation in the brain in vivo. We reported that o-[ 11 C]methyl-trans-decalinvesamicol ([ 11 C]OMDV), which showed high binding affinity and moderate selectivity for VAChT and high accumulation in VAChT-rich regions of the rat brain in vivo, was one of the leading VAChT imaging probes in comparison with many reported VAChT imaging probes (Kitamura et al, 2016). The identical behavior of enantiomers can be expected only in achiral environment, however, all living systems are chiral systems due to the chirality of amino acids.…”

In Vivo and In Vitro Characteristics of Radiolabeled Vesamicol Analogs as the Vesicular Acetylcholine Transporter Imaging Agents

“…OMDV is a vesamicol analog having a decalin skeleton (as A ring) and a 4-(2-methylphenyl)piperidine moiety [ 68 ]. The binding affinity (Ki) of OMDV ( 15 ) to VAChT, σ 1 , and σ 2 was 11.9 nM (rat brain), 70.3 nM (rat brain), and 43.6 nM (rat liver), respectively, and the binding affinity (Ki) of vesamicol to VAChT, σ 1 , and σ 2 was 21.1 nM (rat brain), 20.8 nM (rat brain), and 139 nM (rat liver), respectively.…”