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

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.