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論文
タイトル
タイトル(英)
Synthesis and Evaluation of 18F-Labeled Chalcone Analogue for Detection of α-Synuclein Aggregates in the Brain Using the Mouse Model.
参照URL
https://researchmap.jp/masatohasegawa/published_papers/40778609
著者
著者(英)
Sho Kaide,Hiroyuki Watanabe,Shimpei Iikuni,Masato Hasegawa,Masahiro Ono
担当区分
概要
概要(英)
In the brains of patients with synucleinopathies such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, α-synuclein (α-syn) aggregates deposit abnormally to induce neurodegeneration, although the mechanism is unclear. Thus, in vivo imaging studies targeting α-syn aggregates have attracted much attention to guide medical intervention against synucleinopathy. In our previous study, a chalcone analogue, [125I]PHNP-3, functioned as a feasible probe in terms of α-syn binding in vitro; however, it did not migrate to the mouse brain, and further improvement of brain uptake was required. In the present study, we designed and synthesized two novel 18F-labeled chalcone analogues, [18F]FHCL-1 and [18F]FHCL-2, using a central nervous system multiparameter optimization (CNS MPO) algorithm with the aim of improving blood-brain barrier permeation in the mouse brain. Then, we evaluated their utility for in vivo imaging of α-syn aggregates using a mouse model. In the competitive inhibition assay, both chalcone analogues exhibited high binding affinity for α-syn aggregates (Ki = 2.6 and 3.4 nM, respectively), while no marked amyloid β (Aβ)-binding was observed. The 18F-labeling reaction was successfully performed. In a biodistribution experiment, brain uptake of both chalcone analogues in normal mice (2.09 and 2.40% injected dose/gram (% ID/g) at 2 min postinjection, respectively) was higher than that of [125I]PHNP-3, suggesting that the introduction of 18F into the chalcone analogue led to an improvement in brain uptake in mice while maintaining favorable binding ability for α-syn aggregates. Furthermore, in an ex vivo autoradiography experiment, [18F]FHCL-2 showed the feasibility of the detection of α-syn aggregates in the mouse brain in vivo. These preclinical studies demonstrated the validity of the design of α-syn-targeting probes based on the CNS MPO score and the possibility of in vivo imaging of α-syn aggregates in a mouse model using 18F-labeled chalcone analogues.
出版者・発行元
出版者・発行元(英)
誌名
誌名(英)
ACS chemical neuroscience
13
20
開始ページ
2982
終了ページ
2990
出版年月
2022年10月19日
査読の有無
招待の有無
掲載種別
研究論文(学術雑誌)
ISSN
DOI URL
https://doi.org/10.1021/acschemneuro.2c00473
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研究者