Integrating molecular imaging with near-infrared theranostics to improve early detection and therapy of Alzheimer's disease.

Alzheimer's disease (AD) remains a significant unmet clinical need due to its asymptomatic prodromal phase and multifaceted pathophysiology, which comprises amyloid-β (Aβ) plaques characterized by neurofibrillary tangles (NFTs) of hyperphosphorylated tau. Conventional diagnostic methods, such as magnetic resonance imaging (MRI) and positron emission tomography (PET), detect AD only after extensive neuronal loss. Recent progress in chemical biology has enabled the creation of multifunctional small-molecule theranostic probes that integrate diagnostic imaging with therapeutic intervention. This review emphasizes the design and molecular engineering of new probes in particular, near-infrared (NIR) dyes, aryl quinolines, cyanine-based fluorophores, and curcumin derivatives, which are highly specific for Aβ and tau aggregates, penetrate the blood-brain barrier (BBB) effectively, and are amenable to multimodal imaging including near-infrared imaging (NIR) fluorescence, MRI, PET. These probes commonly contain donor-acceptor motifs and exhibit environment-sensitive fluorescence, allowing for the real-time imaging of pathological protein aggregation. Furthermore, we consider dual-mode probes, such as PiB-C and BTTA, which combine metal chelation therapy with imaging, providing a targeted approach to disaggregate Aβ plaques concurrently visualizing therapeutic effectiveness. Through the combination of synthetic chemistry, molecular imaging, and neurotherapeutics, this transdisciplinary approach outlines a promising new paradigm for early AD detection and treatment. The development of these small-molecule theranostics presents new opportunities for personalized medicine in treating neurodegenerative diseases.