Preclinical evaluation of [F-18]PK-209, a new PET ligand for imaging the ion-channel site of NMDA receptors

Introduction: The present study was designed to assess whether [¹⁸F]PK-209 (3-(2-chloro-5-(methylthio)phenyl)-1-(3-([¹⁸F]fluoromethoxy)phenyl)-1-methylguanidine) is a suitable ligand for imaging the ion-channel site of N-methyl-<inf>D</inf>-aspartate receptors (NMDArs) using positron emission tomography (PET). Methods: Dynamic PET scans were acquired from male rhesus monkeys over 120min, at baseline and after the acute administration of dizocilpine (MK-801, 0.3mg/kg; n=3/condition). Continuous and discrete arterial blood samples were manually obtained, to generate metabolite-corrected input functions. Parametric volume-of-distribution (V<inf>T</inf>) 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<inf>T</inf>of [¹⁸F]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 [¹⁸F]PK-209, despite its fast metabolism. Further in vivo evaluation in humans is warranted.