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 18 as being highly selective for AβOs. Subsequent analysis revealed
that compound 20 improved serum stability while retaining
affinity for AβOs. The most promising iteration, compound 37, demonstrated exceptional qualities: a high affinity for
AβOs, emission in the near-infrared region, and good biocompatibility.
Significantly, ex vivo double staining indicated
that compound 37 detected AβOs in AD mouse brain
and in vivo imaging experiments showed that compound 37 could differentiate between 4-month-old AD mice and age-matched
wild-type mice. Therefore, compound 37 has emerged as
a valuable NIRF probe for early detection of AD and a useful tool
in exploring AD’s pathological mechanisms.