Regional brain imaging of vesicular acetylcholine transporter using o‐[¹²⁵I]iodo‐trans‐decalinvesamicol as a new potential imaging probe

Abstract

In this study, the regional rat brain distribution of radioiodinated o-iodo-trans-decalinvesamicol ([(125) I]OIDV) was determined in vivo to evaluate its potential as a single-photon emission computed tomography (SPECT) imaging probe for vesicular acetylcholine transporter (VAChT). Following intravenous injection, [(125) I]OIDV passed freely across the blood-brain barrier and accumulated in rat brain. The accumulation of [(125) I]OIDV in rat brain was significantly reduced by coadministration of (+/-)-vesamicol (0.125 µmol). In contrast, the coadministration of σ-receptor ligands, such as (+)-pentazocine (0.125 µmol) as a σ-1 receptor ligand and (+)-3-(3-hydroxyphenyl)-N-propylpiperidine (0.125 µmol) as a σ-1 and σ-2 receptor ligands, barely affected the accumulation of [(125) I]OIDV in rat brain. These findings in vivo were corroborated by autoradiographic analysis ex vivo. The authors found that the tracer binds with pharmacological selectivity to VAChT in rat brain and predicted that it may likewise serve in translational SPECT imaging studies of this marker in the integrity of cholinergic innervations.

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

“…BV had a high binding affinity for both VAChT (11.8 nM) and the r-1 receptor (16.7 nM), indicating BV had a lower selectivity for VAChT compared to DV. The brain uptake of [ 11 C]OMDV(0.65 %ID/g) 30 min post-injection was approximately 1.5 times higher than that of [ 125 I]OIDV (0.42 %ID/g), a VAChT imaging probe for SPECT previously reported [22]. Therefore, the high brain accumulation of [ 11 C]OMDV may be advantageous for its in vivo visualization of brain.…”

“…This low accumulation in the blood and rapid clearance are advantageous for brain imaging. The metabolic process of [ 11 C]OMDV may be similar to that of [ 125 I]OIDV, due to similar time-course distributions in the blood, heart, lung, pancreas, kidney, stomach, and small intestine [22].…”

“…We designed a DV compound with halogen or methyl group at the ortho-position of the 4-phenylpiperidine moiety as a new radiolabeled vesamicol analog. We have previously reported the high potential of radioiodinated o-iodo-trans-decalinvesamicol (OIDV) and radiobrominated o-bromo-trans-decalinvesamicol (OBDV) as a VAChT ligand for SPECT and PET imaging, respectively [21][22][23]. However, the sensitivity, resolution and quantitative analysis of SPECT imaging are inferior to those of PET imaging.…”

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

“…In a recent report, we synthesized 2-Hydroxy-3-(4-( o -Iodo-phenylpiperidino))- trans -decalinvesamicol (OIDV), a new vesamicol analog with the framework of decalinvesamicol (DV)[ 31 ] and with radioiodine at the ortho -position of the 4-phenylpiperidine moiety. We demonstrated the high affinity and selectivity of the radioiodinated OIDV for VAChT both in vitro and in vivo [ 32 , 33 ]. In many cases, it is not uncommon for the optical isomers of a neuroreceptor agonist or antagonist to differ in their affinities and activities.…”

(−)‐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).…”