Theranostic advances in Alzheimer's disease: structure-guided design of near-infrared fluorescent probes targeting amyloid-β and cholinergic dysfunction

Abstract

Alzheimer's disease (AD) is a complex neurodegenerative disorder, with unmet clinical challenges due to the lack of early diagnosis and an efficient treatment. Theranostics, an integrated approach that combines diagnosis and therapy, has emerged as a viable option, particularly with the use of near-infrared fluorescence probes (NIRFPs), which allow real-time in vivo imaging and therapeutic monitoring. This review article discusses recent breakthroughs in the rational design of alkene-bridged donor–π–acceptor (D–π–A) NIRFPs that target AD hallmarks such as amyloid-β (Aβ) aggregation and cholinergic dysfunction. We specifically focused on multifunctional probes like THK-565 (fluorescent compound), and a dihydrotetramethyl-indocyanine theranostic near-infrared probe (DTNP), which exhibit high blood–brain barrier (BBB) permeability, target selectivity, and dual imaging/therapeutic capabilities. Furthermore, emerging probes can distinguish between Aβ and cholinesterase (ChEs) with high resolution and low toxicity. Together, these molecular imaging technologies provide a game-changing platform for detection of early-stage AD and multiple intervention approaches. We explore structure–activity connections, molecular processes, and future directions for the clinical translation of NIRFP-based theranostic agents in AD.