Iterative Design of Near-Infrared Fluorescent Probes for Early Diagnosis of Alzheimer's Disease by Targeting Aβ Oligomers.

Amyloid-β oligomers (AβOs), crucial toxic proteins in early Alzheimer's disease (AD), precede the formation of Aβ plaques and cognitive impairment. In this context, we present our iterative process for developing novel near-infrared fluorescent (NIRF) probes specifically targeting AβOs, aimed at early AD diagnosis. An initial screening identified compound as being highly selective for AβOs. Subsequent analysis revealed that compound improved serum stability while retaining affinity for AβOs. The most promising iteration, compound , demonstrated exceptional qualities: a high affinity for AβOs, emission in the near-infrared region, and good biocompatibility. Significantly, double staining indicated that compound detected AβOs in AD mouse brain and imaging experiments showed that compound could differentiate between 4-month-old AD mice and age-matched wild-type mice. Therefore, compound has emerged as a valuable NIRF probe for early detection of AD and a useful tool in exploring AD's pathological mechanisms.