Development of Phenothiazine-Based Theranostic Compounds That Act Both as Inhibitors of β-Amyloid Aggregation and as Imaging Probes for Amyloid Plaques in Alzheimer's Disease

Early detection of Alzheimer's disease (AD) is imperative in enabling the understanding and clinical treatment of this disorder, as well as in preventing its progression. Imaging agents specifically targeting A beta plaques in the brain and the retina may lead to the early diagnosis of AD. Among them, near-infrared fluorescent (NIRF) imaging has emerged as an attractive tool to noninvasively identify and monitor diseases during the preclinical and early, stages. In the present study, we report the design, synthesis, and evaluation of a series of new near-infrared fluorescent probes. Most of these probes displayed maximum emission in PBS (> 650 nm), which falls in the goad range for NIRF probes. Among them, 4a1 showed the highest affinity toward A beta aggregates (K-d = 7.5 nM) and an excellent targeting ability for A beta plaques in slices of brain and retina tissue from double transgenic mice. These compounds are also found to effectively prevent A beta fibril formation and disaggregate preformed A beta fibrils, showing a promising potential as theranostic agents for the diagnosis and therapy of AD.