title: Development of N-[11C]methylamino 4-hydroxy-2(1H)-quinolone derivatives as PET radioligands for the glycine-binding site of NMDA receptors.
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 (K(i) values; 11.7 nM for 12 and 11.8 nM for 32). In vitro autoradiography experiments indicated that [(11)C]12 and [(11)C]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 (11)C-labeled 4HQs were examined in normal mice. Cerebellum to blood ratio of accumulation, of both [(11)C]12 and [(11)C]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 [(11)C]12 and [(11)C]32 have poor blood brain barrier permeability. Although the plasma protein-binding ratio of [(11)C]32 was much lower than methoxy analogs (71% vs 94-98%, respectively), [(11)C]32 still binds with plasma protein strongly. It is conjectured that still acidic moiety and high affinity with plasma protein of [(11)C]32 may prevent in vivo brain uptake. In conclusion, [(11)C]12 and [(11)C]32 are unsuitable for imaging cerebral NMDA receptors.
authors: Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors: Takeshi
authors: T
authors: Fuchigami
authors: Terushi
authors: T
authors: Haradahira
authors: Noriko
authors: N
authors: Fujimoto
authors: Yumiko
authors: Y
authors: Nojiri
authors: Takahiro
authors: T
authors: Mukai
authors: Fumihiko
authors: F
authors: Yamamoto
authors: Takashi
authors: T
authors: Okauchi
authors: Jun
authors: J
authors: Maeda
authors: Kazutoshi
authors: K
authors: Suzuki
authors: Tetsuya
authors: T
authors: Suhara
authors: Hiroshi
authors: H
authors: Yamaguchi
authors: Mikako
authors: M
authors: Ogawa
authors: Yasuhiro
authors: Y
authors: Magata
authors: Minoru
authors: M
authors: Maeda
mesh_terms: D000818:Animals; D001345:Autoradiography; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D015363:Quinolones / Q000097:blood / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics; D011854:Radiochemistry; D019275:Radiopharmaceuticals / Q000097:blood / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000032:analysis* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D015363:Quinolones; D019275:Radiopharmaceuticals; D016194:Receptors, N-Methyl-D-Aspartate; D005998:Glycine