Development of novel beta-amyloid probes based on 3,5-diphenyl-1,2,4-oxadiazole.
In the search for novel probes for the imaging in vivo of beta-amyloid plaques in Alzheimer's disease (AD) brain, we have synthesized and evaluated a series of 3,5-diphenyl-1,2,4-oxadiazole (DPOD) derivatives. The affinity for beta-amyloid plaques was assessed by an in vitro-binding assay using pre-formed synthetic Abeta42 aggregates. The new series of DPOD derivatives showed excellent affinity for Abeta aggregates with K(i) values ranging from 4 to 47nM. In biodistribution experiments using normal mice, [(125)I]12, [(125)I]13, [(125)I]14, and [(125)I]15 examined displayed sufficient uptake for imaging, ranging from 2.2 to 3.3% ID/g. But the washout of the four ligands from the brain was relatively slow. Although additional modifications are necessary to improve the uptake and rapid clearance of non-specifically bound radiotracers, the DPOD pharmacophore with high-binding affinity for Abeta aggregates may be useful as a backbone structure to develop novel beta-amyloid imaging agents.
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan. ono@pharm.kyoto-u.ac.jp
Masahiro
M
Ono
Mamoru
M
Haratake
Hideo
H
Saji
Morio
M
Nakayama
D000544:Alzheimer Disease / Q000175:diagnosis; D016229:Amyloid beta-Peptides / Q000032:analysis*; D000818:Animals; D001921:Brain; D003952:Diagnostic Imaging; D007457:Iodine Radioisotopes; D051379:Mice; D015335:Molecular Probes / Q000138:chemical synthesis*; D010069:Oxadiazoles / Q000737:chemistry / Q000493:pharmacokinetics; D058225:Plaque, Amyloid / Q000473:pathology*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D014018:Tissue Distribution
D016229:Amyloid beta-Peptides; D007457:Iodine Radioisotopes; D015335:Molecular Probes; D010069:Oxadiazoles; D019275:Radiopharmaceuticals