Literature DB >> 25648682

Synthesis, structure activity relationship, radiolabeling and preclinical evaluation of high affinity ligands for the ion channel of the N-methyl-d-aspartate receptor as potential imaging probes for positron emission tomography.

Pieter J Klein1, Johannes A M Christiaans2, Athanasios Metaxas2, Robert C Schuit2, Adriaan A Lammertsma2, Bart N M van Berckel2, Albert D Windhorst2.   

Abstract

The N-methyl-d-aspartate receptor (NMDAr) is involved in many neurological and psychiatric disorders including Alzheimer's disease and schizophrenia. Currently, it is not possible to assess NMDAr availability in vivo. The purpose of this study was to develop a positron emission tomography (PET) ligand for the NMDAr ion channel. A series of di- and tri-N-substituted diarylguanidines was synthesized. In addition, in vitro binding affinity for the NMDAr ion channel in rat forebrain membrane fractions was assessed. Compounds 10, 11 and 32 were radiolabeled with either carbon-11 or fluorine-18. Ligands [(11)C]10 and [(18)F]32 were evaluated ex vivo in B6C3 mice. Biodistribution studies showed higher uptake of [(11)C]10 and [(18)F]32 in forebrain regions compared with cerebellum. In addition, for [(11)C]10 54% and for [(18)F]32 70% of activity in the brain at 60min was due to intact tracer. Pre-treatment with MK-801 (0.6mg·kg(-1), ip) slightly decreased uptake in NMDAr-specific regions for [(18)F]32, but not for [(11)C]10. As such [(18)F]32 has the best characteristics as a PET tracer for the ion channel of the NMDAr.
Copyright © 2014 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  Guanidines; Ion channel; NMDA; PET; Radiolabeling; Uncompetitive antagonists

Mesh：

Substances：

Year:  2014        PMID： 25648682     DOI： 10.1016/j.bmc.2014.12.029

Source DB:  PubMed          Journal:  Bioorg Med Chem        ISSN： 0968-0896            Impact factor:   3.641


  4 in total

1.  Evaluation of the Novel PET Tracer [11C]HACH242 for Imaging the GluN2B NMDA Receptor in Non-Human Primates.

Authors:  Jasper van der Aart; Maqsood Yaqub; Esther J M Kooijman; Jaco Bakker; Jan A M Langermans; Robert C Schuit; Mark B M Hofman; Johannes A M Christiaans; Adriaan A Lammertsma; Albert D Windhorst; Bart N M van Berckel
Journal:  Mol Imaging Biol       Date:  2019-08       Impact factor: 3.488

2.  N'-3-(Trifluoromethyl)phenyl Derivatives of N-Aryl-N'-methylguanidines as Prospective PET Radioligands for the Open Channel of the N-Methyl-d-aspartate (NMDA) Receptor: Synthesis and Structure-Affinity Relationships.

Authors:  Gregory R Naumiec; Kimberley J Jenko; Sami S Zoghbi; Robert B Innis; Lisheng Cai; Victor W Pike
Journal:  J Med Chem       Date:  2015-12-04       Impact factor: 7.446

3.  First in human evaluation of [18F]PK-209, a PET ligand for the ion channel binding site of NMDA receptors.

Authors:  Jasper van der Aart; Sandeep S V Golla; Marieke van der Pluijm; Lothar A Schwarte; Robert C Schuit; Pieter J Klein; Athanasios Metaxas; Albert D Windhorst; Ronald Boellaard; Adriaan A Lammertsma; Bart N M van Berckel
Journal:  EJNMMI Res       Date:  2018-07-27       Impact factor: 3.138

4.  Binding characterization of N-(2-chloro-5-thiomethylphenyl)-N'-(3-[3 H]3 methoxy phenyl)-N'-methylguanidine ([3 H]GMOM), a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist.

Authors:  Athanasios Metaxas; Bart N M van Berckel; Pieter J Klein; Joost Verbeek; Emily C Nash; Esther J M Kooijman; Véronique A Renjaän; Sandeep S V Golla; Ronald Boellaard; Johannes A M Christiaans; Albert D Windhorst; Josée E Leysen
Journal:  Pharmacol Res Perspect       Date:  2019-02
  4 in total

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