Key Laboratory of Radiopharmaceuticals, Ministry of Education, Beijing Normal University, Beijing 100875, China.
Key Laboratory of Radiopharmaceuticals, Ministry of Education, Beijing Normal University, Beijing 100875, China.
Bioorg Med Chem. 2021 Jan 1;29:115884. doi: 10.1016/j.bmc.2020.115884. Epub 2020 Nov 23.
This study reported the design, synthesis and bio-evaluation of 2-phenylbenzoheterocycles with chiral dihydroxyl side chains as β-amyloid (Aβ) imaging probes. This strategy of introducing two hydroxyls offered a simplified method for effectively reducing the lipophilicity. The probes (R, S)/(S, R)-14-15 with benzothiazole scaffold displayed good binding affinities toward Aβ aggregates with K values ranging from 47.63 to 56.28 nM. Further biological studies shown that (R, S)/(S, R)-[F]14 have no obvious chirality-related discrepancy in binding ability and mice bio-distribution, while (S, R)-enantiomer exhibited slightly faster brain washout rate than (R, S)-enantiomer. Compared to the FDA approved [F]Florbetapir and the fluoro-peglated 2-phenylbenzothiazole derivatives, (S, R)-[F]14 displayed improved brain kinetics (6.40% ID/g at 2 min, brain/brain = 7.80) that is favorable for further application. In vitro autoradiography studies validated its high affinity and specificity to Aβ plaques. Overall, (S, R)-[F]14 deserved further detailed study as a potential PET imaging probe for AD early diagnosis.
本研究报道了具有手性二羟基侧链的 2-苯基苯并杂环作为β-淀粉样蛋白（Aβ）成像探针的设计、合成和生物评价。这种引入两个羟基的策略为有效降低亲脂性提供了一种简化方法。具有苯并噻唑骨架的探针（R，S）/（S，R）-14-15 对 Aβ聚集物具有良好的结合亲和力，K 值范围为 47.63 至 56.28 nM。进一步的生物学研究表明，（R，S）/（S，R）-[F]14 在结合能力和小鼠生物分布方面没有明显的手性相关差异，而（S，R）-对映体的脑洗脱率略快于（R，S）-对映体。与 FDA 批准的[F]Florbetapir 和氟代聚乙二醇化 2-苯基苯并噻唑衍生物相比，（S，R）-[F]14 显示出改善的脑动力学（2 分钟时为 6.40% ID/g，脑/脑=7.80），有利于进一步应用。体外放射自显影研究验证了其对 Aβ斑块的高亲和力和特异性。总的来说，（S，R）-[F]14 值得进一步详细研究，作为 AD 早期诊断的潜在 PET 成像探针。
