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

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 [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.