(R)-N-[11C]methyl-3-pyrrolidyl benzilate, a high-affinity reversible radioligand for PET studies of the muscarinic acetylcholine receptor

We recently reported the synthesis and binding affinity of ligands for the muscarinic acetylcholine receptor (mAChR) based on both the pyrrolidyl and piperidyl benzilate scaffold. One of these, (R)-3-pyrrolidyl benzilate, was successfully radiolabeled with [C-11]methyl triflate and the resulting compound, (R)-N-[C-11]methyl-3-pyrrolidyl benzilate (3-[C-11]NMPYB), was evaluated as a reversible, acetylcholine-sensitive tracer for the mAChR (K-i of unlabeled 3-NMPYB is 0.72 nM). This compound displayed high, receptor-mediated retention in regions of the mouse and rat brain known to have high concentrations of mAChRs. Moreover, bolus studies in a pigtail monkey showed that this compound had superior clearance from the brain when compared to muscarinic radiotracers previously employed in human PET studies. Infusion studies in the same monkey revealed that it was possible to achieve equilibrium of radiotracer distribution for 3-[C-11]NMPYB in both the striatum and cortex. Sensitivity to endogenous acetylcholine levels was evaluated by injecting phenserine (5 mg/kg) into rats prior to administration of 3-[C-11]NMPYB in an equilibrium infusion protocol. This pretreatment produced a modest, statistically significant decrease (9-11%) in the distribution volume ratios for muscarinic receptor rich regions of the rat brain as compared to controls. (C) 2002 Wiley-Liss, Inc.