Tuning Stereo-hindrance of Curcumin Scaffold for Selective Imaging of Soluble Forms of Amyloid Beta Species

Abstract:

Amyloid peptides and proteins are associated with pathologies of numerous diseases. In the progression of a disease, amyloids exist in soluble and insoluble forms, which are dominated species at different stages of the disease and have different degree of toxicities. However, differentiating the soluble and insoluble forms is very challenging with small molecule probes, due to multiple layers of hurdles. Inspired by the recognition principle of antibodies for sAβ, we hypothesized that the accessibility/tightness of soluble and insoluble amyloids could be utilized to design imaging probes to recognize different amyloid forms, and stereo-hindrance tuning strategy could be used to design imaging probes for selectively detecting soluble amyloid beta (sAβ) species in Alzheimer’s disease (AD). Herein, we demonstrated that tuning the stereo-hindrance of phenoxy-alkyl chains at 4-position of curcumin scaffold could lead to certain selectivity for sAβ over insoluble Aβs (insAβ). Among the designed compounds, CRANAD-102 showed a 68-fold higher affinity to sAβ than insAβ (7.5±10 nM vs. 505.9±275.9 nM). Moreover, our imaging data indicated that CRANAD-102 was indeed capable of detecting sAβ in vivo using 4-months old APP/PS1 mice, in which sAb are the predominant species in the brains. In addition, we also demonstrted that CRANAD-102 could be used to monitor the increasing of sAβ loading from the ages of 4-months old to 12-months old. We believe that CRANAD-102 can be a useful probe for selectively detecting sAβ species in AD, and  our probe designing strategy can be applied to other amyloids, and will have tremendous impact on AD drug development and other amyloid research.