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Imaging of Cerebral Amyloid Angiopathy with Bivalent (99m)Tc-Hydroxamamide Complexes
Shimpei Iikuni1, Masahiro Ono1, Hiroyuki Watanabe1
1Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Insights
New technetium-99m-hydroxamamide ((99m)Tc-Ham) complexes show promise as imaging probes for cerebral amyloid angiopathy (CAA). These agents effectively target amyloid deposits in human and mouse models, suggesting potential for clinical diagnostic tools.
Area of Science:
- Neuroimaging
- Radiochemistry
- Neuropathology
Background:
- Cerebral amyloid angiopathy (CAA) involves amyloid aggregate deposition in cerebral vasculature, contributing to hemorrhage and cognitive impairment, and is linked to Alzheimer's disease (AD).
- Previous work identified (99m)Tc-hydroxamamide ((99m)Tc-Ham) complexes with bivalent amyloid ligands exhibiting high affinity for amyloid-beta (Aβ(1-42)) aggregates in AD.
Purpose of the Study:
- To evaluate the utility of (99m)Tc-Ham complexes with bivalent amyloid ligands as specific imaging probes for cerebral amyloid angiopathy (CAA).
Main Methods:
- In vitro inhibition assays using Aβ(1-40) aggregates, brain uptake studies, and in vitro/ex vivo autoradiography on human CAA brain sections and Tg2576 mouse models were performed for (99m)Tc-Ham complexes.
- Specific focus on bivalent (99m)Tc-Ham complexes: [(99m)Tc]SB2A and [(99m)Tc]BT2B.
Main Results:
- All tested (99m)Tc-Ham complexes demonstrated binding affinity for Aβ(1-40) aggregates with minimal brain uptake.
- Bivalent complexes [(99m)Tc]SB2A and [(99m)Tc]BT2B showed excellent labeling of Aβ depositions in human CAA brain sections.
- These complexes exhibited high affinity and selectivity for CAA in transgenic mice.
Conclusions:
- The developed (99m)Tc-Ham complexes show significant potential as specific imaging agents for cerebral amyloid angiopathy.
- These findings may pave the way for novel, clinically applicable CAA-specific imaging probes.
Abstract:
Cerebral amyloid angiopathy (CAA), characterized by the deposition of amyloid aggregates in the walls of cerebral vasculature, is a major factor in intracerebral hemorrhage and vascular cognitive impairment and is also associated closely with Alzheimer's disease (AD). We previously reported (99m)Tc-hydroxamamide ((99m)Tc-Ham) complexes with a bivalent amyloid ligand showing high binding affinity for β-amyloid peptide (Aβ(1-42)) aggregates present frequently in the form in AD. In this article, we applied them to CAA-specific imaging probes, and evaluated their utility for CAA-specific imaging. In vitro inhibition assay using Aβ(1-40) aggregates deposited mainly in CAA and a brain uptake study were performed for (99m)Tc-Ham complexes, and all (99m)Tc-Ham complexes with an amyloid ligand showed binding affinity for Aβ(1-40) aggregates and very low brain uptake. In vitro autoradiography of human CAA brain sections and ex vivo autoradiography of Tg2576 mice were carried out for bivalent (99m)Tc-Ham complexes ([(99m)Tc]SB2A and [(99m)Tc]BT2B), and they displayed excellent labeling of Aβ depositions in human CAA brain sections and high affinity and selectivity to CAA in transgenic mice. These results may offer new possibilities for the development of clinically useful CAA-specific imaging probes based on the (99m)Tc-Ham complex.
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