A new benzomorphane derivative, [11C]methyl-BIII277CL, was evaluated as a potential radiotracer for visualizing the PCP-binding site of the N-methyl-D-aspartate (NMDA) receptor by positron emission tomography (PET). Methyl-BIII277CL was prepared by reacting the desmethyl compound (BIII277CL) with dimethylsulfate. The pharmacological profile of methyl-BIII277CL was determined by in vitro receptor-screening assays. At a concentration of 100 nM, methyl-BIII277CL showed a significant interaction with the PCP-binding site of the NMDA receptor (79% inhibition of specific binding) and the sigma-binding site (46% inhibition). In displacement assays using mice cortical membranes, methyl-BIII277CL displayed a high affinity at the PCP-binding site of the NMDA receptor (Ki = 49 +/- 14 nmol/L) and a 130-fold lower interaction with the sigma1-binding site (Ki = 6.35 +/- 0.26 micromol/L). For saturation experiments and in vivo studies, methyl-BIII277CL was radiolabeled with 11C at the O-position of the desmethyl precursor (BIII277CL) using [11C]methyliodide with a specific activity of 35-70 GBq/micromol at the end of synthesis (EOS). In saturation assays using rat whole brain membranes [11C]methyl-BIII277CL showed a Kd of 6 +/- 1 nmol/L and a Bmax of 670 +/- 154 fmol/mg protein. Biodistribution and PET studies in rats and pigs, however, indicated a lack of specific binding and unfavorable pharmacokinetics. Kinetic modeling using the 1-tissue compartment model demonstrated for [11C]methyl-BIII277CL a low distribution volume (Dv = 0.98 mL/mL(tissue)) and very high values for the kinetic parameters K1 and k2 (K1 = 0.36 mL/mL(tissue)/min and k2 = 0.37min(-1)) in pig cortex. [11C]methyl-BIII277CL, due to the lack of specificity in vivo, may not be a candidate for imaging the PCP-binding site of the NMDA receptor.