title: Enhancement of binding affinity for amyloid aggregates by multivalent interactions of 99mTc-hydroxamamide complexes.
abstract: Deposition of amyloid aggregates has been regarded as an early stage of amyloidosis progression. An imaging probe that can image amyloid aggregates enables the early diagnosis of amyloidosis and contributes to the development of new medical therapies. High binding affinity for amyloid aggregates is essential to develop a useful molecular imaging probe. This article describes a new strategy to enhance the binding affinity of imaging agents targeting amyloid aggregates. We designed and synthesized novel (99m)Tc-hydroxamamide ((99m)Tc-Ham) complexes with a bivalent amyloid ligand and evaluated their binding affinity for amyloid aggregates by using β-amyloid peptide (Aβ(1-42)) aggregates as a model. In vitro inhibition assay indicated that bivalent (99m)Tc-Ham complexes had much higher binding affinity for amyloid aggregates than monovalent complexes. In vitro autoradiography using Tg2576 mice showed the specific binding of bivalent (99m)Tc-Ham complexes to Aβ plaques in the mouse brain, as reflected in the results of the inhibition assay. The preliminary results suggest that a new molecular design based on bivalent (99m)Tc-Ham complexes may be reasonable to develop an imaging probe targeting amyloid aggregates.
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University , 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Shimpei
authors.initials: S
authors.lastname: Iikuni
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ono
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Watanabe
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumura
authors.forename: Masashi
authors.initials: M
authors.lastname: Yoshimura
authors.forename: Naoya
authors.initials: N
authors.lastname: Harada
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kimura
authors.forename: Morio
authors.initials: M
authors.lastname: Nakayama
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000686:Amyloidosis / Q000000981:diagnostic imaging; D000818:Animals; D001345:Autoradiography; D051379:Mice; D015609:Organotechnetium Compounds; D066329:Protein Aggregates; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals
chemical_list: D016229:Amyloid beta-Peptides; D015609:Organotechnetium Compounds; D066329:Protein Aggregates; D019275:Radiopharmaceuticals