Synthesis and evaluation of stilbene derivatives as a potential imaging agent of amyloid plaques

Objectives We report here the synthesis of systematic derivatization of SB-13 by modifying its A-ring with various electron donating and electron withdrawing substituents, and its B-ring with varying size and polarity of N-substituents.

Methods The stilbene derivatives (13-24) were successfully prepared by a Wadsworth-Emmons reaction. Also, to prepared the stilbene drivatives (25-44) were concerned about lipophilicity and polarity by sodium hydride, diethyl phosphates derivatives (1-12) and 4-(N-methyl-N-2-hydroxyethyl)benzaldehyde or 4-(N-methyl-N-2-cyanoethyl)benzaldehyde in THF at 80 °C for 5 h, giving with 20-48% yields. On the other hand, we could not prepared cyanoethyl group with 3’-or 4’-OCH3 and observed side products which were losing alkylsubstituted compounds (42-44).

Results The synthesized stilbene derivatives were tested 32 compounds in synthetic Aβ40 agregates. Among them, four compounds showed over 6-fold increase at 30 μM concentrations of Aβ40 fibril. Compound 42, exhibited submicromolar dissociation constant (0.6 μM), which is superior than that of Thioflavin T (ThT: KD = 2.3 μM)—a conventional amyloid sensor. We further tested its applicability in the staining of amyloid plaques in AD-mouse brain sections. As compound 42 displays blue fluorescence, ThT (green) was used for complementary staining of amyloid plaques.

Conclusions We prepared 32 new derivatives of the known β-amyloid plaques ligand, SB-13, and among them identified compound 42 with a sub-micromolar dissociation constant (0.6 μM) to Aβ40 aggregates. Compound 42 demonstrated its excellent capability of labeling Aβ aggregates in AD mouse brain with good colocalization with ThT. Based on their delicately high binding affinity to Aβ40 aggregates, these novel stilbene analogues may be good candidates for further modification for in vivo imaging probes by introducing PET or SPECT relevant isotopes