Selective Imaging of Soluble Amyloid Beta Species Using Near Infrared Fluorescent Curcumin Analogues

389 Objectives Recent evidence shows that soluble Aβs are more neurotoxic than insoluble deposits, and thus could potentially serve as biomarkers for pre-symptomatic stages of Alzheimer’s disease (AD). Originally, the burden of insoluble deposits was thought to cause neurodegeneration, but it correlates poorly with Alzheimer’s disease severity. Previously, strategies using insoluble Aβ deposits as evaluation biomarkers in AD drug development have failed, and this failure has promoted a shift towards targeting soluble Aβs. In addition, the failure also has led to more clinical trials to be conducted at the early/pre-symptomatic stage. However, no imaging probe is available for detecting soluble Aβs either in preclinical animal research or clinical trial stages. Methods The use of small molecules to differentiate soluble and insoluble Aβs is challenging, because they sharethe same amino acid sequence. To the best of our knowledge, no small-molecule probe has been reported for selective detection of soluble Aβs. We hypothesized that the different accessibility of the secondary/tertiary structures of Aβs can be harnessed to differentiate soluble and insoluble Aβs. Our preliminary SAR (structure activity relationship) studies suggest that a planar curcumin scaffold has access to both soluble and insoluble Aβs. We reason that sterically non-coplanar curcumin analogues have reduced accessibility to the insoluble Aβs, thus increasing their selectivity for soluble Aβs. A series of curcumin analogues with a bulky group at 4-position were designed and synthesized. Results In vivo two-photon imaging showed that CRANAD-75, a curcumin analogue with a bulky group at 4-poistion of the curcumin scaffold, could easily cross the BBB in mice. In addition, our data demonstrated that CRANAD-75 could selectively detect soluble Aβs in vitro, ex vivo and in vivo. Conclusions We believe that our imaging probes can be used to monitor the changes of soluble Aβs after treatment, and have tremendous potential for AD drug development. Research Support This research is supoorted by NIH/NIA K25AG036760.