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Flexible multidentate benzyldiamine derivatives with high affinity for β-amyloid in cerebral amyloid angiopathy

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Abstract

Cerebral amyloid angiopathy (CAA) commonly found in the aged is pathologically characterized by β-amyloid (Aβ) deposition in the walls of arteries and capillaries of brain. In this study, four flexible multidentate benzyldiamine derivatives as potential probes for cerebrovascular Aβ deposition were designed and synthesized. In in vitro inhibition assays, the ligands 18–21 displayed high affinities for Aβ aggregates with Ki values of 1.45 ± 0.53 nM, 1.68 ± 0.35 nM, 1.16 ± 0.23 nM and 1.72 ± 0.19 nM, respectively. A significant improvement in the binding affinity over the monomer, compounds 9–12 or benzyldiamine derivatives, demonstrated the applicability of the multidentate approach. The underlying mechanism of these novel Aβ agents was explored by molecular docking technique, which theoretically verified the high affinities of the multidentate benzyldiamine derivatives for Aβ aggregates. Moreover, the molecular masses of the ligands 18–21 are more than 700 Dalton, which are believed to be hardly capable of penetrating blood brain barrier. In this regard, these ligands could be used to distinguish CAA from Alzheimer’s disease which is another Aβ-related disorder disease. To convert these ligands to positron emission tomography imaging agents, we attempted to radiosynthesize [18F]18. Though the radiolabeling was not very successful, the preliminary results suggested that these newly proposed multidentate benzyldiamine derivatives may be used as potential Aβ imaging agents in cerebral amyloid angiopathy.

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Acknowledgements

This work was funded by National Natural Science Foundation of China (Nos. 81701757 and 81771871), and Natural Science Foundation Project of Chongqing Science and Technology Commission (No. cstc2017jcyjAX0118). The authors present special thanks to Dr. Zhu Xia (Department of Nuclear Medicine, the First Affiliated Hospital, Chongqing Medical University) for providing [18F]fluoride.

Funding

Funding was provided by National Natural Science Foundation of China (Grant Nos. 81701757 and 81771871) and Natural Science Foundation Project of Chongqing Science and Technology Commission (Grant No. cstc2017jcyjAX0118).

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Authors and Affiliations

  1. Department of Radiological Medicine and Oncology, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, People’s Republic of China

    Yujia He, Liang Wang, Mengda Niu, Zhiping Peng & Jianhua Jia

  2. School of Pharmaceutical Sciences, Chongqing University, Chongqing, 401331, People’s Republic of China

    Tingting Fu & Weiwei Xue

  3. Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, People’s Republic of China

    Yuying Li & Mengchao Cui

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  1. Yujia He
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Correspondence to Weiwei Xue, Zhiping Peng or Jianhua Jia.

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He, Y., Fu, T., Li, Y. et al. Flexible multidentate benzyldiamine derivatives with high affinity for β-amyloid in cerebral amyloid angiopathy. Mol Divers 25, 525–533 (2021). https://doi.org/10.1007/s11030-020-10098-y

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