Synthesis, radiolabeling and preclinical evaluation of a [11C]GMOM derivative as PET radiotracer for the ion channel of the N-methyl-D-aspartate receptor

Pieter J. Klein, Robert C. Schuit, Athanasios Metaxas, Johannes AM Christiaans, Esther Kooijman, Adriaan A. Lammertsma, Bart NM van Berckel, Albert D. Windhorst

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Introduction Presently available PET ligands for the NMDAr ion channel generally suffer from fast metabolism. The purpose of this study was to develop a metabolically more stable ligand for the NMDAr ion channel, taking [11C]GMOM ([11C]1) as the lead compound. Methods [11C]1, its fluoralkyl analogue [18F]PK209 ([18F]2) and the newly synthesized fluorovinyloxy analogue [11C]7b were evaluated ex vivo in male Wistar rats for metabolic stability. In addition, [11C]7b was subjected to a biodistribution study and its affinity (Ki) and lipophilicity (logD7.4) values were determined. Results The addition of a vinyl chain in the fluoromethoxy moiety did not negatively alter the affinity of [11C]7b for the NMDAr, while lipophilicity was increased. Biodistribution studies showed higher uptake of [11C]7b in forebrain regions compared with cerebellum. Pre-treatment with MK-801 decreased the overall brain uptake significantly, but not in a region-specific manner. 45 min after injection 78, 90 and 87% of activity in the brain was due to parent compound for [11C]1, [18F]2 and [11C]7b, respectively. In plasma, 26–31% of activity was due to parent compound. Conclusion Complete substitution of the alpha-carbon increased lipophilicity to more favorable values. Substitution of one or more hydrogens of the alpha-carbon atom in the methoxy moiety improved metabolic stability. In plasma, more parent compound was found for [18F]2 and [11C]7b then for [11C]1, although differences were not significant. At 45 min, significantly more parent [18F]2 and [11C]7b was measured in the brain compared with [11C]1.

Original languageEnglish
Pages (from-to)25-32
Number of pages8
JournalNuclear Medicine and Biology
Volume51
DOIs
Publication statusPublished - 1 Aug 2017

Cite this

@article{d9917292c20d408ba3db64fcf4b55cc6,
title = "Synthesis, radiolabeling and preclinical evaluation of a [11C]GMOM derivative as PET radiotracer for the ion channel of the N-methyl-D-aspartate receptor",
abstract = "Introduction Presently available PET ligands for the NMDAr ion channel generally suffer from fast metabolism. The purpose of this study was to develop a metabolically more stable ligand for the NMDAr ion channel, taking [11C]GMOM ([11C]1) as the lead compound. Methods [11C]1, its fluoralkyl analogue [18F]PK209 ([18F]2) and the newly synthesized fluorovinyloxy analogue [11C]7b were evaluated ex vivo in male Wistar rats for metabolic stability. In addition, [11C]7b was subjected to a biodistribution study and its affinity (Ki) and lipophilicity (logD7.4) values were determined. Results The addition of a vinyl chain in the fluoromethoxy moiety did not negatively alter the affinity of [11C]7b for the NMDAr, while lipophilicity was increased. Biodistribution studies showed higher uptake of [11C]7b in forebrain regions compared with cerebellum. Pre-treatment with MK-801 decreased the overall brain uptake significantly, but not in a region-specific manner. 45 min after injection 78, 90 and 87{\%} of activity in the brain was due to parent compound for [11C]1, [18F]2 and [11C]7b, respectively. In plasma, 26–31{\%} of activity was due to parent compound. Conclusion Complete substitution of the alpha-carbon increased lipophilicity to more favorable values. Substitution of one or more hydrogens of the alpha-carbon atom in the methoxy moiety improved metabolic stability. In plasma, more parent compound was found for [18F]2 and [11C]7b then for [11C]1, although differences were not significant. At 45 min, significantly more parent [18F]2 and [11C]7b was measured in the brain compared with [11C]1.",
keywords = "GMOM, Ion channel, NMDA, PET, Uncompetitive antagonists, [F]PK-209",
author = "Klein, {Pieter J.} and Schuit, {Robert C.} and Athanasios Metaxas and Christiaans, {Johannes AM} and Esther Kooijman and Lammertsma, {Adriaan A.} and {van Berckel}, {Bart NM} and Windhorst, {Albert D.}",
year = "2017",
month = "8",
day = "1",
doi = "10.1016/j.nucmedbio.2017.05.003",
language = "English",
volume = "51",
pages = "25--32",
journal = "Nuclear Medicine and Biology",
issn = "0969-8051",
publisher = "Elsevier Inc.",

}

Synthesis, radiolabeling and preclinical evaluation of a [11C]GMOM derivative as PET radiotracer for the ion channel of the N-methyl-D-aspartate receptor. / Klein, Pieter J.; Schuit, Robert C.; Metaxas, Athanasios; Christiaans, Johannes AM; Kooijman, Esther; Lammertsma, Adriaan A.; van Berckel, Bart NM; Windhorst, Albert D.

In: Nuclear Medicine and Biology, Vol. 51, 01.08.2017, p. 25-32.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Synthesis, radiolabeling and preclinical evaluation of a [11C]GMOM derivative as PET radiotracer for the ion channel of the N-methyl-D-aspartate receptor

AU - Klein, Pieter J.

AU - Schuit, Robert C.

AU - Metaxas, Athanasios

AU - Christiaans, Johannes AM

AU - Kooijman, Esther

AU - Lammertsma, Adriaan A.

AU - van Berckel, Bart NM

AU - Windhorst, Albert D.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Introduction Presently available PET ligands for the NMDAr ion channel generally suffer from fast metabolism. The purpose of this study was to develop a metabolically more stable ligand for the NMDAr ion channel, taking [11C]GMOM ([11C]1) as the lead compound. Methods [11C]1, its fluoralkyl analogue [18F]PK209 ([18F]2) and the newly synthesized fluorovinyloxy analogue [11C]7b were evaluated ex vivo in male Wistar rats for metabolic stability. In addition, [11C]7b was subjected to a biodistribution study and its affinity (Ki) and lipophilicity (logD7.4) values were determined. Results The addition of a vinyl chain in the fluoromethoxy moiety did not negatively alter the affinity of [11C]7b for the NMDAr, while lipophilicity was increased. Biodistribution studies showed higher uptake of [11C]7b in forebrain regions compared with cerebellum. Pre-treatment with MK-801 decreased the overall brain uptake significantly, but not in a region-specific manner. 45 min after injection 78, 90 and 87% of activity in the brain was due to parent compound for [11C]1, [18F]2 and [11C]7b, respectively. In plasma, 26–31% of activity was due to parent compound. Conclusion Complete substitution of the alpha-carbon increased lipophilicity to more favorable values. Substitution of one or more hydrogens of the alpha-carbon atom in the methoxy moiety improved metabolic stability. In plasma, more parent compound was found for [18F]2 and [11C]7b then for [11C]1, although differences were not significant. At 45 min, significantly more parent [18F]2 and [11C]7b was measured in the brain compared with [11C]1.

AB - Introduction Presently available PET ligands for the NMDAr ion channel generally suffer from fast metabolism. The purpose of this study was to develop a metabolically more stable ligand for the NMDAr ion channel, taking [11C]GMOM ([11C]1) as the lead compound. Methods [11C]1, its fluoralkyl analogue [18F]PK209 ([18F]2) and the newly synthesized fluorovinyloxy analogue [11C]7b were evaluated ex vivo in male Wistar rats for metabolic stability. In addition, [11C]7b was subjected to a biodistribution study and its affinity (Ki) and lipophilicity (logD7.4) values were determined. Results The addition of a vinyl chain in the fluoromethoxy moiety did not negatively alter the affinity of [11C]7b for the NMDAr, while lipophilicity was increased. Biodistribution studies showed higher uptake of [11C]7b in forebrain regions compared with cerebellum. Pre-treatment with MK-801 decreased the overall brain uptake significantly, but not in a region-specific manner. 45 min after injection 78, 90 and 87% of activity in the brain was due to parent compound for [11C]1, [18F]2 and [11C]7b, respectively. In plasma, 26–31% of activity was due to parent compound. Conclusion Complete substitution of the alpha-carbon increased lipophilicity to more favorable values. Substitution of one or more hydrogens of the alpha-carbon atom in the methoxy moiety improved metabolic stability. In plasma, more parent compound was found for [18F]2 and [11C]7b then for [11C]1, although differences were not significant. At 45 min, significantly more parent [18F]2 and [11C]7b was measured in the brain compared with [11C]1.

KW - GMOM

KW - Ion channel

KW - NMDA

KW - PET

KW - Uncompetitive antagonists

KW - [F]PK-209

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U2 - 10.1016/j.nucmedbio.2017.05.003

DO - 10.1016/j.nucmedbio.2017.05.003

M3 - Article

VL - 51

SP - 25

EP - 32

JO - Nuclear Medicine and Biology

JF - Nuclear Medicine and Biology

SN - 0969-8051

ER -