Evaluation of (+)-p-[11C]methylvesamicol for mapping sigma1 receptors: a comparison with [11C]SA4503

Vesamicol is a leading compound for positron emission tomography (PET) and single photon emission computed tomography (SPECT) tracers for mapping the vesicular acetylcholine transporter (VAChT). Recently, we found that (+)-p-methylvesamicol ((+)-PMV) has low affinity for VAChT (Ki=199 nM), but has moderate to high affinity for sigma receptors: Ki=3.0 nM for sigma1 and Ki=40.7 nM for sigma2, and that sigma1-selective SA4503 (Ki=4.4 nM for sigma1 and Ki=242 nM for sigma2) has moderate affinity for VAChT (Ki=50.2 nM). In the present study, we examined the potential of (+)-[11C]PMV as a PET radioligand for mapping sigma1 receptors as compared with [11C]SA4503. In rat brain, similar regional distribution patterns of (+)-[11C]PMV and [11C]SA4503 were shown by tissue dissection and by ex vivo autoradiography. Blocking experiments using (±)-PMV, (−)-vesamicol, SA4503, haloperidol and (±)-pentazocine showed that the two tracers specifically bound to sigma1 receptors, and that [11C]SA4503 exhibited greater specific binding than (+)-[11C]PMV. No sign of VAChT-specific binding by [11C]SA4503 was observed in the striatum, which is rich in VAChT sites. In conclusion, (+)-[11C]PMV specifically bound to sigma1 receptors in the brain, but to a lesser extent than [11C]SA4503, suggesting that (+)-[11C]PMV is a less preferable PET ligand than [11C]SA4503. On the other hand, the moderate affinity of [11C]SA4503 for VAChT is negligible in vivo.