TY - JOUR
T1 - Development of N-[11C]methylamino 4-hydroxy-2(1H)-quinolone derivatives as PET radioligands for the glycine-binding site of NMDA receptors
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
PY - 2009/8/1
Y1 - 2009/8/1
N2 - 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.
AB - 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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U2 - 10.1016/j.bmc.2009.06.014
DO - 10.1016/j.bmc.2009.06.014
M3 - Article
C2 - 19586774
AN - SCOPUS:67651089892
SN - 0968-0896
VL - 17
SP - 5665
EP - 5675
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 15
ER -