Flexible Multidentate Benzyldiamine Derivatives with High Affinity for Β-Amyloid in Cerebral Amyloid Angiopathy

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.