Amyloid-β oligomer selective heteroaromatic-derived multifunctional near-infrared theranostic probe for in vivo imaging, anti-amyloid-β aggregation, and neuroprotection

The formation of neurotoxic amyloid-β (Aβ) oligomers begins much earlier than the deposit of plaques in Alzheimer’s disease (AD), which still poses a great challenge to detect and monitor for early diagnosis and intervention of the disease. Herein, the rational design and investigation of a series of novel multifunctional heteroaromatic-derived and ethylene π-bridge free near-infrared (NIR) cyanine probes with high Aβ 42 oligomers selectivity and sensitivity for real-time imaging of Aβ aggregates is reported. Intriguingly, these heteroaromatic-derived fluorophores showed selectively large fluorescence turn-on up to a 53-fold increase and strong binding affinity with dissociation constant ( K d ) of 198–525 nM upon interacting with Aβ 42 oligomers. Molecular docking analyses revealed that the strong binding selectivity and interactions were synergistically driven by the hydrogen bonds and van der Waals forces between those probes particularly with acetamido-substituent and Aβ 42 tetramer model. Because of excellent Aβ oligomers selectivity, biocompatibility, and blood-brain barrier penetrability, the application of the probe, SLTAD for real-time detection and visualization of Aβ aggregates in different age groups of AD mice was demonstrated. Additionally, SLTAD was found to inhibit Aβ 42 aggregates/fibrils formation (IC 50 = 312 nM) and attenuate neuronal toxicity induced by Aβ, underscoring its uniqueness as a theranostic probe for AD. • A series of highly Aβ oligomer-selective theranostic probes derived from five-membered ring heteroaromatics was developed. • SLTAD with acetamido-substituent on quinolinium ring showed high binding selectivity and affinity toward Aβ-oligomers. • SLTAD was highly viable for real-time detection and visualization of Aβ aggregates in different ages of AD mice. • The anti-Aβ aggregation and neuroprotection functions of SLTAD rendered the beneficial therapeutic potential for AD.