title: Preclinical evaluation of [(18)F]PK-209, a new PET ligand for imaging the ion-channel site of NMDA receptors.
abstract: BACKGROUND
  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 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 (VT) 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 VT 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.
authors.affiliation: Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Sandeep S V
authors.initials: SS
authors.lastname: Golla
authors.affiliation: Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Klein
authors.affiliation: Biomedical Primate Research Centre, Rijswijk, the Netherlands.
authors.forename: Jaco
authors.initials: J
authors.lastname: Bakker
authors.affiliation: Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Schuit
authors.affiliation: Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Johannes A M
authors.initials: JA
authors.lastname: Christiaans
authors.affiliation: Biomedical Primate Research Centre, Rijswijk, the Netherlands.
authors.forename: Leo
authors.initials: L
authors.lastname: van Geest
authors.affiliation: Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Esther J M
authors.initials: EJ
authors.lastname: Kooijman
authors.affiliation: Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Gisela M
authors.initials: GM
authors.lastname: Oropeza-Seguias
authors.affiliation: Biomedical Primate Research Centre, Rijswijk, the Netherlands.
authors.forename: Jan A M
authors.initials: JA
authors.lastname: Langermans
authors.affiliation: Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Josée E
authors.initials: JE
authors.lastname: Leysen
authors.affiliation: Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: Boellaard
authors.affiliation: Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Albert D
authors.initials: AD
authors.lastname: Windhorst
authors.affiliation: Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Bart N M
authors.initials: BN
authors.lastname: van Berckel
authors.affiliation: Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands. Electronic address: ametaxas@rnc.vu.nl.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Metaxas
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005462:Fluorine Radioisotopes; D019791:Guanidine / Q000378:metabolism; D006146:Guanidines / Q000378:metabolism; D008024:Ligands; D008253:Macaca mulatta; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
chemical_list: C000601032:3-(2-chloro-5-(methylthio)phenyl)-1-(3-(fluoromethoxy)phenyl)-1-methylguanidine; D005462:Fluorine Radioisotopes; D006146:Guanidines; D008024:Ligands; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D019791:Guanidine
keywords: Brain; Imaging; Ion-channel; NMDA; PET; [(18)F]PK-209