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Introduction The present study was designed to assess whether [ 18 F]PK-209 (3-(2-chloro-5-(methylthio)phenyl)-1-(3-([ 18 F]fluoromethoxy)phenyl)-1-methylguanidine) is a suitable ligand for imaging the ion-channel site of N -methyl- D -aspartate receptors (NMDArs) using positron emission tomography (PET). Methods Dynamic PET scans were acquired from male rhesus monkeys over 120 min, at baseline and after the acute administration of dizocilpine (MK-801, 0.3 mg/kg; n = 3/condition). Continuous and discrete arterial blood samples were manually obtained, to generate metabolite-corrected input functions. Parametric volume-of-distribution (V T ) images were obtained using Logan analysis. The selectivity profile of PK-209 was assessed in vitro , on a broad screen of 79 targets. Results PK-209 was at least 50-fold more selective for NMDArs over all other targets examined. At baseline, prolonged retention of radioactivity was observed in NMDAr-rich cortical regions relative to the cerebellum. Pretreatment with MK-801 reduced the V T of [ 18 F]PK-209 compared with baseline in two of three subjects. The rate of radioligand metabolism was high, both at baseline and after MK-801 administration. Conclusions PK-209 targets the intrachannel site with high selectivity. Imaging of the NMDAr is feasible with [ 18 F]PK-209, despite its fast metabolism. Further in vivo evaluation in humans is warranted. [ABSTRACT FROM AUTHOR]