(-)-o-[ C]methyl-trans-decalinvesamicol ((-)-[ 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-[ C]methyl-trans-decalinvesamicol ([ 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. [ 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 [ 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 ((-)-[ C]OMDV and (+)-[ C]OMDV) was similarly high (about 1.0%ID/g) at 2 min post-injection. However, (+)-[ C]OMDV clearance from the brain was faster than (-)-[ C]OMDV. In the in vivo blocking study, accumulation of (-)-[ C]OMDV in the cortex was markedly decreased (approximately 30% of control) by coadministration of vesamicol, and brain uptake of (-)-[ 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 (-)-[ C]OMDV by coadministration of vesamicol. In conclusion, (-)-[ C]OMDV, which is an enantiomer of OMDV, selectively binds to VAChT with high affinity in the rat brain in vivo. (-)-[ C]OMDV may be utilized as a potential PET ligand for studying presynaptic cholinergic neurons in the brain.