Difference in brain distributions of carbon 11-labeled 4-hydroxy-2(1H)-quinolones as PET radioligands for the glycine-binding site of the NMDA ion channel

Fuchigami, Takeshi; Haradahira, Terushi; Fujimoto, Noriko; Okauchi, Takashi; Maeda, Jun; Suzuki, Kazutoshi; Suhara, Tetsuya; Yamamoto, Fumihiko; Sasaki, Shigeki; Mukai, Takahiro; Yamaguchi, Hiroshi; Ogawa, Mikako; Magata, Yasuhiro; Maeda, Minoru

doi:10.1016/j.nucmedbio.2007.10.007

« Previous Next »Nuclear Medicine and Biology
Volume 35, Issue 2 , Pages 203-212, February 2008

Difference in brain distributions of carbon 11-labeled 4-hydroxy-2(1H)-quinolones as PET radioligands for the glycine-binding site of the NMDA ion channel

Takeshi Fuchigami
- Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
- Photon Medical Research Center, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan
Terushi Haradahira
- Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan
- Corresponding author. Tel.: +81 956 20 5714; fax: +81 956 20 5622.
Noriko Fujimoto
- Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
Takashi Okauchi
- Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan
Jun Maeda
- Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan
Kazutoshi Suzuki
- Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan
Tetsuya Suhara
- Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan
Fumihiko Yamamoto
- Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
Shigeki Sasaki
- Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
Takahiro Mukai
- Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
Hiroshi Yamaguchi
- Molecular Imaging Frontier Research Center, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan
Mikako Ogawa
- Photon Medical Research Center, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan
Yasuhiro Magata
- Photon Medical Research Center, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan
- Molecular Imaging Frontier Research Center, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan
Minoru Maeda
- Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan

Received 19 June 2006; received in revised form 2 October 2007; accepted 17 October 2007.

Abstract

High-affinity iodine- and ethyl-C-5 substituted analogs of 4-hydroxy-3-(3-[¹¹C]methoxyphenyl)-2(1H)-quinolone ([¹¹C]4HQ) were synthesized as new positron emission tomography radioligands for the glycine-binding sites of the N-methyl-d-aspartate (NMDA) ion channel. Although both radioligands showed high in vitro specific binding to rat brain slices, their binding characteristics were quite different from each other. 5-Ethyl-[¹¹C]4HQ (5Et-[¹¹C]4HQ) showed higher in vitro binding in the forebrain regions than in the cerebellum, bindings that were strongly inhibited by both glycine-site agonists and antagonists. In contrast, 5-iodo-[¹¹C]4HQ (5I-[¹¹C]4HQ) showed a homogeneous in vitro binding throughout the brain, which was inhibited by antagonists but not by agonists. This difference in in vitro binding between 5Et-[¹¹C]4HQ and 5I-[¹¹C]4HQ was quite similar to that previously observed between [¹¹C]L-703,717 and [¹¹C]4HQ, both glycine-site antagonists. In vivo brain uptakes of these ¹¹C-labeled 4-hydroxyquinolones were examined in mice. Initial brain uptakes of 5Et- and 5I-[¹¹C]4HQ at 1 min after intravenous injections were comparable to that of [¹¹C]4HQ, but they were 1.3–2.1 times higher than that of [¹¹C]L-703,717. The treatment with an anticoagulant, warfarin, only slightly increased the initial uptakes of [¹¹C]4HQ and 5Et-[¹¹C]4HQ in contrast to [¹¹C]L-703,717. The in vivo regional brain distributions were slightly different between the two radioligands. Pretreatment with nonradioactive ligand (2 mg/kg) slightly inhibited the binding of 5Et-[¹¹C]4HQ (16–36% inhibition) but not that of 5I-[¹¹C]4HQ.

In this study, it was found that a small structural change in [¹¹C]4HQ resulted in a major change in binding characteristics and distributions, suggesting the existence of two binding sites for [¹¹C]4-hydroxyquinolones on the NMDA ion channel — agonist-sensitive and agonist-insensitive (or antagonist-preferring) sites.

Keywords: Agonist sensitivity, Glycine-site antagonist, 4-hydroxy-2(1H)-quinolone, PET