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Mol Pharm. 2014 Apr 7;11(4):1132-9. doi: 10.1021/mp400499y. Epub 2014 Mar 27.

Enhancement of binding affinity for amyloid aggregates by multivalent interactions of 99mTc-hydroxamamide complexes.

Author information

1
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University , 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.

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.

PMID:
24673484
DOI:
10.1021/mp400499y
[Indexed for MEDLINE]

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