Alzheimer's disease (AD) is a neurodegenerative disease characterized by slow cognitive decline. Major neuropathology of AD brains include the presence of senile plaques containing β-amyloid (Aβ) aggregates. Evidence suggests the aggregation of Aβ in the brain is key in AD and the accumulation of plaques may represent the beginning of the Aβ cascade toward neurodegeneration. The only definitive method of diagnosis of these Aβ plaques in the brain is via post-mortem autopsy staining. Therefore, a reliable noninvasive probe for Aβ plaques is greatly needed and could help in early diagnosis and aid in the study of the progression of AD in patients.

Based on the dye Congo red, bis-styrylbenzenes have been shown to bind Aβ plaques with high specificity. However, limited research had been done to elucidate the structure-activity relationship for this class of compounds in Aβ plaque binding assays. This study focused on optimizing reaction conditions for bis-styrylbenzene compounds based on literature preparations and applying these syntheses to design and create a library of unique symmetrical and unsymmetrical bis-styrylbenzenes to further elucidate the SAR of this class of compounds in Aβ binding affinity and specificity assays. This work led to identifying substitution patterns for optimal Aβ binding affinity and specificity in an attempt to develop lead compounds for early diagnosis of AD. We have identified more efficient, higher yielding reactions for symmetrical bis-styrylbenzenes, and developed a novel one-pot synthesis for unsymmetrical bis-styrylbenzenes. It was also shown that acidic functional groups are not necessary for optimal binding to Aβ plaques and that addition of fluorine atoms on the central benzene ring enhances the binding affinity of these compounds. The 1,4-orientation of the bis-styrylbenzene about the central benzene ring was determined to be optimal, and in the distal benzene rings, both 3 or 4-hydroxy regioisomers had good affinity and specificity. Finally, selected compounds were shown to bind to Aβ plaques in human AD brain sections, and upon administration to transgenic mice, penetrated the blood-brain barrier and bound to Aβ plaques in vivo. With these data, it was determined that with further studies, bis-styrylbenzenes have the potential to be developed into reliable early diagnosis probes for AD.