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Title: Novel Bivalent 99mTc-Complex with N-Methyl-Substituted Hydroxamamide as Probe for Imaging of Cerebral Amyloid Angiopathy
Authors: Iikuni, Shimpei
Ono, Masahiro  kyouindb  KAKEN_id  orcid (unconfirmed)
Watanabe, Hiroyuki  kyouindb  KAKEN_id
Yoshimura, Masashi
Ishibashi-Ueda, Hatsue
Ihara, Masafumi
Saji, Hideo
Author's alias: 佐治, 英郎
Issue Date: 30-Sep-2016
Publisher: Public Library of Science
Journal title: PLOS ONE
Volume: 11
Issue: 9
Thesis number: e0163969
Abstract: Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid aggregates in the walls of the cerebral vasculature. Recently, the development of molecular imaging probes targeting CAA has been attracting much attention. We previously reported the 99mTc-hydroxamamide (99mTc-Ham) complex with a bivalent benzothiazole scaffold as a binding moiety for amyloid aggregates ([99mTc]BT2) and its utility for CAA-specific imaging. However, the simultaneous generation of two radiolabeled complexes derived from the geometric isomers was observed in the 99mTc-labeling reaction. It was recently reported that the complexation reaction of 99Tc with N-methyl-substituted Ham provided a single 99Tc-Ham complex consisting of two N-methylated Ham ligands with marked stability. In this article, we designed and synthesized a novel N-methylated bivalent 99mTc-Ham complex ([99mTc]MBT2) and evaluated its utility for CAA-specific imaging. N-Methyl substitution of [99mTc]BT2 prevented the generation of its isomer in the 99mTc-labeling reaction. Enhanced in vitro stability of [99mTc]MBT2 as compared with [99mTc]BT2 was observed. [99mTc]MBT2 showed very low brain uptake, which is favorable for CAA-specific imaging. An in vitro inhibition assay using β-amyloid aggregates and in vitro autoradiographic examination of brain sections from a Tg2576 mouse and a CAA patient showed a decline in the binding affinity for amyloid aggregates due to N-methylation of the 99mTc-Ham complex. These results suggest that the scaffold of the 99mTc-Ham complex may play important roles in the in vitro stability and the binding affinity for amyloid aggregates.
Rights: © 2016 Iikuni et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI(Published Version): 10.1371/journal.pone.0163969
PubMed ID: 27689870
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