Synthesis and biological evaluation of radio-iodinated benzimidazoles as SPECT imaging agents for NR2B subtype of NMDA receptor.
ABSTRACT
In this study, the benzimidazole derivatives were synthesized and evaluated
as imaging agents for the NR2B subtype of NMDA receptor. Among these ligands,
2-{[4-(4-iodobenzyl)piperidin-1-yl]methyl}benzimidazol-5-ol (8) and N-{2-[4-(4-iodobenzyl)-piperidin-1-ylmethyl]benzoimidazol-5-yl}-methanesulfonamide
(9) exhibited high affinity for the NR2B subunit (Ki values; 7.28 nM for 8 and 5.75 nM for 9). In vitro autoradiography experiments demonstrated high accumulation
in the forebrain regions but low in the cerebellum for both [125I]8 and [125I]9. These regional distributions of the radioligands correlated with the
expression of the NR2B subunit. The in vitro binding of these ligands was
inhibited by NR2B antagonist but not by other site ligands, which suggested
the high selectivity of [125I]8 and [125I]9 for the NR2B subunit. In mice, the regional brain uptakes of [125I]8 and [125I]9 at 5-180 min after administration were 0.42-0.56% and 0.44-0.67% dose/g,
respectively. The brain-to-blood ratio of [125I]8 at 180 min was reduced by 34% in the presence of non-radioactive ligands and by 59% in the presence of the NR2B ligand Ro-25,6981. These results indicated that [125I]8 could be partially bound to the NR2B subunit in vivo. Although the brain
uptake of these benzimidazole derivatives was too low to allow for in vivo
SPECT imaging, these compounds might be useful scaffolds for the development
of imaging probes specific for the NMDA receptors.