The potential ofo-bromo-trans-decalinvesamicol as a new PET ligand for vesicular acetylcholine transporter imaging

Abstract

We investigated the characteristics of the regional rat brain distribution of radio-brominated o-bromo-decalinvesamicol (OBDV) in vivo to evaluate its potential as a PET ligand for vesicular acetylcholine transporter (VAChT). In in vivo biodistribution study, the specific brain regional accumulation of [(77) Br]OBDV was revealed 30 min after intravenous injection. The specific brain regional accumulation of [(77) Br]OBDV was significantly inhibited by co-injection of (+/-)-vesamicol. In contrast, no significant inhibition of the uptake of [(77) Br]OBDV in all brain regions was observed with co-injection of (+)-pentazocine (selective σ-1 receptor agonist) and (+)-3-(3-hydroxyphenyl)-N-propylpiperidine, [(+)-3-PPP] (σ-1 and σ-2 receptor agonist) with [(77) Br]OBDV. [(77) Br]OBDV accumulation in VAChT-rich brain regions was observed in ex vivo autoradiography. These results showed that [(77) Br]OBDV selectively bound to VAChT with high affinity in rat brain in vivo. Hence, OVBDV radiolabelled with more suitable (76) Br was suggested to be a potent VAChT ligand for PET.

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

“…The influence of enantioselectivity of the vesamicol analogs FEOBV ( 2 ) [ 45 ], MIBT ( 8 ) [ 55 ], FBT ( 9 ) [ 60 ], oIV ( 10 ) [ 62 ], OMV ( 11 ) [ 63 ], OIDV ( 13 ) [ 67 ], FBBV ( 18 ) [ 78 ], 19 [ 81 ], TZ659 ( 20 ) [ 82 ], VAT ( 21 ) [ 83 ], and 22 [ 84 ] on the binding affinity for VAChT, σ 1 , and σ 2 receptors was reported. The investigated vesmicol analogs except for MIBT ( 8 ) and FBT ( 9 ) showed that (−)-enantiomers had about 3- to 29-fold higher binding affinity for VAChT than (+)-enantiomers.…”

“…OBDV is a vesamicol analog having a decalin skeleton (as A ring) and a 4-(2-bromophenyl)piperidine moiety [ 67 ]. The binding affinity (Ki) of OBDV ( 14 ) to VAChT, σ 1 , and σ 2 was 13.8 nM (rat brain), 150.7 nM (rat brain), and 137.5 nM (rat liver), respectively, and the binding affinity (Ki) of vesamicol to VAChT, σ 1 , and σ 2 was 33.9 nM (rat brain), 22.1 nM (rat brain), and 86.7 nM (rat liver), respectively.…”

“…Decalinvesamicol ((−)-OIDV ( 13 ) [ 66 ], OBDV ( 14 ) [ 67 ], and OMDV ( 15 )) [ 68 ] showed a higher affinity to VAChT than morpholinovesamicol analogs (FAMV ( 16 ) and FBMV ( 17 )). On the contrary, morpholinovesamicol analogs showed a higher selectivity to VAChT affinity than decalinvesamicol.…”

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

“…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).…”