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

INTRODUCTION: We focused on the vesicle acetyl choline transporter (VAChT) as target for early diagnosis of Alzheimer's diseases because the dysfunction of the cholinergic nervous system is closely associated with the symptoms of AD, such as problem in recognition, memory, and learning. Due to its low binding affinity for the sigma receptors (σ-1 and σ-2), o-methyl-trans-decalinvesamicol (OMDV) demonstrated a high binding affinity and selectivity for vesicular acetyl choline transporter (VAChT). [(11)C]OMDV was prepared and investigated the potential as a new PET ligand for VAChT imaging through in vivo evaluation. METHOD: [(11)C]OMDV was prepared by a palladium-promoted cross-coupling reaction using [(11)C]methyl iodide, with a radiochemical yield of 60-75%, a radiochemical purity of greater than 98%, and a specific activity of 5-10 TBq/mmol 30 min after EOB. In vivo biodistribution study of [(11)C]OMDV in blood, brain regions and major organs of rats was performed at 2, 10, 30 and 60 min post-injection. In vivo blocking study and PET-CT imaging study were performed to check the binding selectivity of [(11)C]OMDV for VAChT. RESULTS: In vivo studies demonstrated [(11)C]OMDV passage through the blood-brain barrier (BBB) and accumulation in the rat brain. The regional brain accumulation of [(11)C]OMDV was significantly inhibited by co-administration of vesamicol. In contrast, brain accumulation of [(11)C]OMDV was not significantly altered by co-administration of (+)-pentazocine, a selective σ-1 receptor ligand, or (+)-3-(3-hydroxyphenyl)-N-propylpiperidine [(+)-3-PPP], a σ-1 and σ-2 receptor ligand. PET-CT imaging revealed inhibition of [(11)C]OMDV accumulation in the brain by co-administration of vesamicol. CONCLUSION: [(11)C]OMDV selectively binds to VAChT with high affinity in the rat brain in vivo, and that [(11)C]OMDV may be utilized in the future as a specific VAChT ligand for PET imaging.