title: 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 (K(i) 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 [(125)I]8 and [(125)I]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 [(125)I]8 and [(125)I]9 for the NR2B subunit. In mice, the regional brain uptakes of [(125)I]8 and [(125)I]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 [(125)I]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 [(125)I]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.
authors.affiliation: Photon Medical Research Center, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fuchigami
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Mikako
authors.initials: M
authors.lastname: Ogawa
authors.forename: Le
authors.initials: L
authors.lastname: Biao
authors.forename: Morio
authors.initials: M
authors.lastname: Nakayama
authors.forename: Mamoru
authors.initials: M
authors.lastname: Haratake
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Magata
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry*; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D003287:Contrast Media / Q000138:chemical synthesis* / Q000737:chemistry; D007455:Iodine / Q000737:chemistry; D007457:Iodine Radioisotopes / Q000737:chemistry; D007553:Isotope Labeling; D051379:Mice; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry; D016194:Receptors, N-Methyl-D-Aspartate / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000378:metabolism; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: C555723:2-((4-(4-iodobenzyl)piperidin-1-yl)methyl)benzimidazol-5-ol; D001562:Benzimidazoles; D003287:Contrast Media; D007457:Iodine Radioisotopes; C555724:N-(2-(4-(4-iodobenzyl)piperidin-1-ylmethyl)benzoimidazol-5-yl)-methanesulfonamide; C121001:NR2B NMDA receptor; D019275:Radiopharmaceuticals; D016194:Receptors, N-Methyl-D-Aspartate; D013449:Sulfonamides; D007455:Iodine