Enhancement of Binding Affinity for Amyloid Aggregates by Multivalent Interactions
of 99mTc-Hydroxamamide Complexes
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 99mTc-hydroxamamide (99mTc-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 99mTc-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 99mTc-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 99mTc-Ham complexes may be reasonable to develop an imaging probe targeting amyloid aggregates.