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

Pieter J. Klein; Marion Chomet; Athanasios Metaxas; Johannes A. M. Christiaans; Esther Kooijman; Robert C. Schuit; Adriaan A. Lammertsma; Bart N. M. van Berckel; Albert D. Windhorst

doi:https://doi.org/10.1016/j.ejmech.2016.04.022

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

Pieter J. Klein, Marion Chomet, Athanasios Metaxas, Johannes A. M. Christiaans, Esther Kooijman, Robert C. Schuit, Adriaan A. Lammertsma, Bart N. M. van Berckel, Albert D. Windhorst

Research output: Contribution to journal › Article › Academic › peer-review

11 Citations (Scopus)

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.

Original language	English
Pages (from-to)	143-160
Journal	European Journal of Medicinal Chemistry
Volume	118
DOIs	https://doi.org/10.1016/j.ejmech.2016.04.022
Publication status	Published - 8 Aug 2016

Keywords

NMDA
Non-competitive antagonists
PET
Radiolabeling
SAR

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https://doi.org/10.1016/j.ejmech.2016.04.022

Cite this

Klein, P. J., Chomet, M., Metaxas, A., Christiaans, J. A. M., Kooijman, E., Schuit, R. C., Lammertsma, A. A., van Berckel, B. N. M., & Windhorst, A. D. (2016). 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. European Journal of Medicinal Chemistry, 118, 143-160. https://doi.org/10.1016/j.ejmech.2016.04.022

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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.",

keywords = "NMDA, Non-competitive antagonists, PET, Radiolabeling, SAR",

author = "Klein, {Pieter J.} and Marion Chomet and Athanasios Metaxas and Christiaans, {Johannes A. M.} and Esther Kooijman and Schuit, {Robert C.} and Lammertsma, {Adriaan A.} and {van Berckel}, {Bart N. M.} and Windhorst, {Albert D.}",

year = "2016",

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doi = "https://doi.org/10.1016/j.ejmech.2016.04.022",

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Klein, PJ, Chomet, M, Metaxas, A, Christiaans, JAM, Kooijman, E, Schuit, RC , Lammertsma, AA , van Berckel, BNM & Windhorst, AD 2016, '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', European Journal of Medicinal Chemistry, vol. 118, pp. 143-160. https://doi.org/10.1016/j.ejmech.2016.04.022

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. / Klein, Pieter J.; Chomet, Marion; Metaxas, Athanasios et al.
In: European Journal of Medicinal Chemistry, Vol. 118, 08.08.2016, p. 143-160.

Research output: Contribution to journal › Article › Academic › peer-review

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Klein PJ, Chomet M, Metaxas A, Christiaans JAM, Kooijman E, Schuit RC et al. 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. European Journal of Medicinal Chemistry. 2016 Aug 8;118:143-160. doi: https://doi.org/10.1016/j.ejmech.2016.04.022