In Vivo Differences between Two Optical Isomers of Radioiodinated o-iodo-trans-decalinvesamicol for Use as a Radioligand for the Vesicular Acetylcholine Transporter

Abstract

PurposeTo develop a superior VAChT imaging probe for SPECT, radiolabeled (-)-OIDV and (+)-OIDV were isolated and investigated for differences in their binding affinity and selectivity to VAChT, as well as their in vivo activities.ProceduresRadioiodinated o-iodo-trans-decalinvesamicol ([125I]OIDV) has a high binding affinity for vesicular acetylcholine transporter (VAChT) both in vitro and in vivo. Racemic [125I]OIDV was separated into its two optical isomers (-)-[125I]OIDV and (+)-[125I]OIDV by HPLC. To investigate VAChT binding affinity (Ki) of two OIDV isomers, in vitro binding assays were performed. In vivo biodistribution study of each [125I]OIDV isomer in blood, brain regions and major organs of rats was performed at 2,30 and 60 min post-injection. In vivo blocking study were performed to reveal the binding selectivity of two [125I]OIDV isomers to VAChT in vivo. Ex vivo autoradiography were performed to reveal the regional brain distribution of two [125I]OIDV isomers and (-)-[123I]OIDV for SPECT at 60 min postinjection.ResultsVAChT binding affinity (Ki) of (-)-[125I]OIDV and (+)-[125I]OIDV was 22.1 nM and 79.0 nM, respectively. At 2 min post-injection, accumulation of (-)-[125I]OIDV was the same as that of (+)-[125I]OIDV. However, (+)-[125I]OIDV clearance from the brain was faster than (-)-[125I]OIDV. At 30 min post-injection, accumulation of (-)-[125I]OIDV (0.62 ± 0.10%ID/g) was higher than (+)-[125I]OIDV (0.46 ± 0.07%ID/g) in the cortex. Inhibition of OIDV binding showed that (-)-[125I]OIDV was selectively accumulated in regions known to express VAChT in the rat brain, and ex vivo autoradiography further confirmed these results showing similar accumulation of (-)-[125I]OIDV in these regions. Furthermore, (-)-[123I]OIDV for SPECT showed the same regional brain distribution as (-)-[125I]OIDV.ConclusionThese results suggest that radioiodinated (-)-OIDV may be a potentially useful tool for studying presynaptic cholinergic neurons in the brain.

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

“…D , c = 2.08, chloroform), respectively. These results showed that optical separation of OMDV was performed successfully, which is similar to the previously reported optical separation of o-iodo-trans-decalinvesamicol (OIDV) (Uno et al, 2016). (−)-OMDV showed five times higher binding affinity for VAChT than (+)-OMDV.…”

“…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.…”

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

“…The rat brain uptake of (−)-[ 123 I]OIDV ( 13 ) was decreased by 71–73% by coadministration of (−)-[ 123 I]OIDV ( 13 ) with vesamicol (0.25 μ mol). (−)-[ 123 I]OIDV ( 13 ) was distributed in characteristically VAChT-rich regions, such as the cortex, striatum, diagonal band, amygdaloid nucleus, and trigeminal and facial nucleus [ 65 , 66 , 77 ].…”

“…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.…”