Development of N-[11C]methylamino 4-hydroxy-2(1H)-quinolone derivatives as PET radioligands for the glycine-binding site of NMDA receptors

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

Research output: Contribution to journalArticle

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Abstract

In this study, we synthesized and evaluated several amino 4-hydroxy-2(1H)-quinolone (4HQ) derivatives as new PET radioligand candidates for the glycine site of the NMDA receptors. Among these ligands, we discovered that 7-chloro-4-hydroxy-3-{3-(4-methylaminobenzyl) phenyl}-2-(1H)-quinolone (12) and 5-ethyl-7-chloro-4-hydroxy-3-(3-methylaminophenyl)-2(1H)-quinolone (32) have high affinity for the glycine site (Ki values; 11.7 nM for 12 and 11.8 nM for 32). In vitro autoradiography experiments indicated that [11C]12 and [11C]32 showed high specific binding in the brain slices, which were strongly inhibited by both glycine agonists and antagonists. In vivo brain uptake of these 11C-labeled 4HQs were examined in normal mice. Cerebellum to blood ratio of accumulation, of both [11C]12 and [11C]32 at 30 min were 0.058, which were slightly higher than those of cerebrum to blood ratio (0.043 and 0.042, respectively). These results indicated that [11C]12 and [11C]32 have poor blood brain barrier permeability. Although the plasma protein-binding ratio of [11C]32 was much lower than methoxy analogs (71% vs 94-98%, respectively), [11C]32 still binds with plasma protein strongly. It is conjectured that still acidic moiety and high affinity with plasma protein of [11C]32 may prevent in vivo brain uptake. In conclusion, [11C]12 and [11C]32 are unsuitable for imaging cerebral NMDA receptors.

Original languageEnglish
Pages (from-to)5665-5675
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number15
DOIs
Publication statusPublished - Aug 1 2009

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Quinolones
N-Methyl-D-Aspartate Receptors
Glycine
Blood Proteins
Brain
Binding Sites
Derivatives
Blood
Cerebrum
Blood-Brain Barrier
Autoradiography
Protein Binding
Cerebellum
Permeability
Ligands
Imaging techniques
carbostyril
Experiments

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Development of N-[11C]methylamino 4-hydroxy-2(1H)-quinolone derivatives as PET radioligands for the glycine-binding site of NMDA receptors. / Fuchigami, Takeshi; Haradahira, Terushi; Fujimoto, Noriko; Nojiri, Yumiko; Mukai, Takahiro; Yamamoto, Fumihiko; Okauchi, Takashi; Maeda, Jun; Suzuki, Kazutoshi; Suhara, Tetsuya; Yamaguchi, Hiroshi; Ogawa, Mikako; Magata, Yasuhiro; Maeda, Minoru.

In: Bioorganic and Medicinal Chemistry, Vol. 17, No. 15, 01.08.2009, p. 5665-5675.

Research output: Contribution to journalArticle

Fuchigami, T, Haradahira, T, Fujimoto, N, Nojiri, Y, Mukai, T, Yamamoto, F, Okauchi, T, Maeda, J, Suzuki, K, Suhara, T, Yamaguchi, H, Ogawa, M, Magata, Y & Maeda, M 2009, 'Development of N-[11C]methylamino 4-hydroxy-2(1H)-quinolone derivatives as PET radioligands for the glycine-binding site of NMDA receptors', Bioorganic and Medicinal Chemistry, vol. 17, no. 15, pp. 5665-5675. https://doi.org/10.1016/j.bmc.2009.06.014
Fuchigami, Takeshi ; Haradahira, Terushi ; Fujimoto, Noriko ; Nojiri, Yumiko ; Mukai, Takahiro ; Yamamoto, Fumihiko ; Okauchi, Takashi ; Maeda, Jun ; Suzuki, Kazutoshi ; Suhara, Tetsuya ; Yamaguchi, Hiroshi ; Ogawa, Mikako ; Magata, Yasuhiro ; Maeda, Minoru. / Development of N-[11C]methylamino 4-hydroxy-2(1H)-quinolone derivatives as PET radioligands for the glycine-binding site of NMDA receptors. In: Bioorganic and Medicinal Chemistry. 2009 ; Vol. 17, No. 15. pp. 5665-5675.
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abstract = "In this study, we synthesized and evaluated several amino 4-hydroxy-2(1H)-quinolone (4HQ) derivatives as new PET radioligand candidates for the glycine site of the NMDA receptors. Among these ligands, we discovered that 7-chloro-4-hydroxy-3-{3-(4-methylaminobenzyl) phenyl}-2-(1H)-quinolone (12) and 5-ethyl-7-chloro-4-hydroxy-3-(3-methylaminophenyl)-2(1H)-quinolone (32) have high affinity for the glycine site (Ki values; 11.7 nM for 12 and 11.8 nM for 32). In vitro autoradiography experiments indicated that [11C]12 and [11C]32 showed high specific binding in the brain slices, which were strongly inhibited by both glycine agonists and antagonists. In vivo brain uptake of these 11C-labeled 4HQs were examined in normal mice. Cerebellum to blood ratio of accumulation, of both [11C]12 and [11C]32 at 30 min were 0.058, which were slightly higher than those of cerebrum to blood ratio (0.043 and 0.042, respectively). These results indicated that [11C]12 and [11C]32 have poor blood brain barrier permeability. Although the plasma protein-binding ratio of [11C]32 was much lower than methoxy analogs (71{\%} vs 94-98{\%}, respectively), [11C]32 still binds with plasma protein strongly. It is conjectured that still acidic moiety and high affinity with plasma protein of [11C]32 may prevent in vivo brain uptake. In conclusion, [11C]12 and [11C]32 are unsuitable for imaging cerebral NMDA receptors.",
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AU - Fuchigami, Takeshi

AU - Haradahira, Terushi

AU - Fujimoto, Noriko

AU - Nojiri, Yumiko

AU - Mukai, Takahiro

AU - Yamamoto, Fumihiko

AU - Okauchi, Takashi

AU - Maeda, Jun

AU - Suzuki, Kazutoshi

AU - Suhara, Tetsuya

AU - Yamaguchi, Hiroshi

AU - Ogawa, Mikako

AU - Magata, Yasuhiro

AU - Maeda, Minoru

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