title: Synthesis, radiolabeling and evaluation of novel amine guanidine derivatives as potential positron emission tomography tracers for the ion channel of the N-methyl-d-aspartate receptor.
abstract: The N-Methyl-d-Aspartate receptor (NMDAR) is involved in many neurological and psychiatric disorders including Alzheimer's disease and schizophrenia. The aim of this study was to develop a positron emission tomography (PET) ligand to assess the bio-availability of the NMDAR ion channel in vivo. A series of tri-N-substituted diarylguanidines was synthesized and their in vitro binding affinities for the NMDAR ion channel assessed in rat forebrain membrane fractions. Compounds 21, 23 and 26 were radiolabeled with either carbon-11 or fluorine-18 and ex vivo biodistribution and metabolite studies were performed in Wistar rats. Biodistribution studies showed high uptake especially in prefrontal cortex and lowest uptake in cerebellum. Pre-treatment with MK-801, however, did not decrease uptake of the radiolabeled ligands. In addition, all three ligands showed fast metabolism.
authors.affiliation: Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. Electronic address: pj.klein@vumc.nl.
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Klein
authors.affiliation: Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
authors.forename: Marion
authors.initials: M
authors.lastname: Chomet
authors.affiliation: Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Metaxas
authors.affiliation: Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
authors.forename: Johannes A M
authors.initials: JA
authors.lastname: Christiaans
authors.affiliation: Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Kooijman
authors.affiliation: Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB 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, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Lammertsma
authors.affiliation: Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB 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, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
authors.forename: Albert D
authors.initials: AD
authors.lastname: Windhorst
mesh_terms: D000588:Amines / Q000737:chemistry*; D000818:Animals; D060326:Chemistry Techniques, Synthetic; D019791:Guanidine / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D057927:Hydrophobic and Hydrophilic Interactions; D007553:Isotope Labeling; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D011849:Radioactive Tracers; D011854:Radiochemistry; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D000588:Amines; D011849:Radioactive Tracers; D016194:Receptors, N-Methyl-D-Aspartate; D019791:Guanidine
keywords: NMDA; Non-competitive antagonists; PET; Radiolabeling; SAR