Structure-activity relationship of imidazo[1,2-a]pyridines as ligands for detecting beta-amyloid plaques in the brain.

Abstract

A series of novel beta-amyloid (A beta) aggregate-specific ligands, 2-(4'-dimethylaminophenyl)-6-iodoimidazo[1,2-a]pyridine, 16(IMPY), and its related derivatives were prepared. An in vitro binding study with preformed A beta aggregates showed that 16(IMPY) and its bromo derivative competed with binding of 2-(4'-dimethylaminophenyl)-6-iodobenzothiazole, [125I]7(TZDM), a known ligand for A beta aggregates, with high binding affinities (K(i) = 15 and 10 nM, respectively). In vitro autoradiography of brain sections of a transgenic mouse (Tg2576) with [125I]16(IMPY) displayed high selective binding to amyloid-like structures, comparable to that observed by staining with thioflavin-S visualized under fluorescence. In vivo biodistribution after an intravenous injection of [125I]16(IMPY) in normal mice showed a high initial brain uptake and fast washout, indicating a low background activity associated with this iodinated ligand. Taken together, the data suggests that [123I]16(IMPY) may be useful for imaging A beta aggregates in patients with Alzheimer's disease.

• Authors: Zhi-Ping Zhuang, Mei-Ping Kung, Alan Wilson, Chi-Wan Lee, Karl Plössl, Catherine Hou, David M Holtzman, Hank F Kung
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 46 Issue 2 Pg. 237-43 (Jan 16 2003) ISSN: 0022-2623 [Print] United States
• PMID: 12519062 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 6-iodo-2-(4'-dimethylamino-)phenyl-imidazo(1,2-a)pyridine
• Amyloid beta-Peptides
• Imidazoles
• Iodine Radioisotopes
• Ligands
• Pyridines
• Radiopharmaceuticals

Topics

• Alzheimer Disease (diagnosis)
• Amyloid beta-Peptides (metabolism)
• Animals
• Brain (metabolism, pathology)
• Imidazoles (chemical synthesis, chemistry, pharmacokinetics)
• In Vitro Techniques
• Iodine Radioisotopes
• Ligands
• Male
• Mice
• Mice, Inbred ICR
• Pyridines (chemical synthesis, chemistry, pharmacokinetics)
• Radiopharmaceuticals (chemical synthesis, chemistry, pharmacokinetics)
• Structure-Activity Relationship