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

To develop a PET imaging agent to visualize brain cholinergic neurons and synaptic changes caused by Alzheimer's disease, (−)‐ and (+)‐ o ‐[ 11 C]methyl‐ trans ‐decalinvesamicol ([ 11 C]OMDV) were isolated and investigated for differences in not only their binding affinity and selectivity to vesicular acetylcholine transporter (VAChT), but also their in vivo activities. [ 11 C]OMDV has a high binding affinity for VAChT both in vitro and in vivo. Racemic OMDV and o ‐trimethylstannyl‐ trans ‐decalinvesamicol (OTDV), which are precursors for synthesis of [ 11 C]OMDV, were separated into (−)‐optical isomers ((−)‐OMDV and (−)‐OTDV) and (+)‐optical isomers ((+)‐OMDV and (+)‐OTDV) by HPLC. In the in vitro binding assay, (−)‐OMDV(7.2 nM) showed eight times higher binding affinity (Ki) to VAChT than that of (+)‐OMDV(57.5 nM). In the biodistribution study, the blood–brain barrier permeability of both enantiomers ((−)‐[ 11 C]OMDV and (+)‐[ 11 C]OMDV) was similarly high (about 1.0%ID/g) at 2 min post‐injection. However, (+)‐[ 11 C]OMDV clearance from the brain was faster than (−)‐[ 11 C]OMDV. In the in vivo blocking study, accumulation of (−)‐[ 11 C]OMDV in the cortex was markedly decreased (approximately 30% of control) by coadministration of vesamicol, and brain uptake of (−)‐[ 11 C]OMDV was not significantly altered by coadministration of (+)‐pentazocine or (+)‐3‐(3‐hydroxyphenyl)‐N‐propylpiperidine ((+)‐3‐PPP). PET‐CT imaging revealed inhibition of the rat brain uptake of (−)‐[ 11 C]OMDV by coadministration of vesamicol. In conclusion, (−)‐[ 11 C]OMDV, which is an enantiomer of OMDV, selectively binds to VAChT with high affinity in the rat brain in vivo. (−)‐[ 11 C]OMDV may be utilized as a potential PET ligand for studying presynaptic cholinergic neurons in the brain.