Kashiyama Rikuto, Watanabe Hiroyuki, Akasaka Takahiro, Fujimoto Hiroyuki, Murakami Masashi, Ooe Kazuhiro, Toyoshima Atsushi, Nakashima Kazuma, Ono Masahiro
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
Radioisotope Research Center, Agency for Health, Safety and Environment, Kyoto University, Kyoto, 606-8501, Japan.
Ann Nucl Med. 2025 Aug 12. doi: 10.1007/s12149-025-02095-8.
Amyloid-β (Aβ) aggregates have been recognized as therapeutic targets for Alzheimer's disease (AD). Targeted alpha therapy (TAT) using α-particles has the potential to be applied as a novel treatment approach for AD by reducing the quantity of Aβ aggregates. In this study, we developed a novel astatine-211-labeled pyridyl benzofuran (PBF) derivative, [At]APBF-2, as a small molecule-based Aβ-TAT agent and evaluated its potential for in vivo use.
[At]APBF-2 was synthesized in a one-step astatination process using the tributyltin precursor. In the Aβ aggregation inhibition assay, [At]APBF-2 was added to a sample containing Aβ monomers and thioflavin-T (ThT) and the mixture was incubated for 24 h. The quantity of Aβ aggregates was evaluated by measuring ThT fluorescence intensity. The biodistribution of [At]APBF-2 (25 kBq/100 μL) was evaluated using ddY mice (n = 5).
[At]APBF-2 was synthesized in radiochemical yield of 57% with a radiochemical purity of over 95%. In the in vitro assay, [At]APBF-2 showed a dose-dependent decrease in ThT fluorescence intensity, suggesting the ability of [At]APBF-2 to inhibit Aβ aggregation. In the biodistribution study using normal mice, the initial brain uptake of [At]APBF-2 was observed (2.95% injected dose/g at 2 min), demonstrating favorable Blood-brain barrier permeability.
These results suggest the feasibility of using [At]APBF-2 as an Aβ-TAT agent for in vivo applications.
淀粉样β蛋白（Aβ）聚集体已被确认为阿尔茨海默病（AD）的治疗靶点。使用α粒子的靶向α治疗（TAT）有潜力通过减少Aβ聚集体的数量，作为AD的一种新型治疗方法应用。在本研究中，我们开发了一种新型的砹 - 211标记的吡啶基苯并呋喃（PBF）衍生物[At]APBF - 2，作为一种基于小分子的Aβ - TAT试剂，并评估了其体内应用潜力。
[At]APBF - 2使用三丁基锡前体通过一步砹化过程合成。在Aβ聚集抑制试验中，将[At]APBF - 2加入含有Aβ单体和硫黄素 - T（ThT）的样品中，并将混合物孵育24小时。通过测量ThT荧光强度评估Aβ聚集体的数量。使用ddY小鼠（n = 5）评估[At]APBF - 2（25 kBq/100 μL）的生物分布。
[At]APBF - 2的合成放射化学产率为57%，放射化学纯度超过95%。在体外试验中，[At]APBF - 2显示出ThT荧光强度呈剂量依赖性降低，表明[At]APBF - 2具有抑制Aβ聚集的能力。在使用正常小鼠的生物分布研究中，观察到[At]APBF - 2最初在脑中的摄取（2分钟时为注射剂量的2.95%/g），表明其具有良好的血脑屏障通透性。
这些结果表明使用[At]APBF - 2作为体内应用的Aβ - TAT试剂是可行的。
