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: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

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

Access to Document

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

Klein, Pieter J. ; Chomet, Marion ; Metaxas, Athanasios ; Christiaans, Johannes A. M. ; Kooijman, Esther ; Schuit, Robert C. ; Lammertsma, Adriaan A. ; van Berckel, Bart N. M. ; Windhorst, Albert D. / 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. In: European Journal of Medicinal Chemistry. 2016 ; Vol. 118. pp. 143-160.

@article{4d18de1e693e46a9b48e6f106c474116,

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

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",

month = aug,

day = "8",

doi = "10.1016/j.ejmech.2016.04.022",

language = "English",

volume = "118",

pages = "143--160",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

publisher = "Elsevier Masson SAS",

}

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; Christiaans, Johannes A. M.; Kooijman, Esther; Schuit, Robert C.; Lammertsma, Adriaan A.; van Berckel, Bart N. M.; Windhorst, Albert D.

In: European Journal of Medicinal Chemistry, Vol. 118, 08.08.2016, p. 143-160.

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

TY - JOUR

T1 - 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

AU - Klein, Pieter J.

AU - Chomet, Marion

AU - Metaxas, Athanasios

AU - Christiaans, Johannes A. M.

AU - Kooijman, Esther

AU - Schuit, Robert C.

AU - Lammertsma, Adriaan A.

AU - van Berckel, Bart N. M.

AU - Windhorst, Albert D.

PY - 2016/8/8

Y1 - 2016/8/8

N2 - 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.

AB - 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.

KW - PET

KW - NMDA

KW - Radiolabeling

KW - SAR

KW - Non-competitive antagonists

U2 - 10.1016/j.ejmech.2016.04.022

DO - 10.1016/j.ejmech.2016.04.022

M3 - Article

C2 - 27128179

VL - 118

SP - 143

EP - 160

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -

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