“Turn-On” Quinoline-Based Fluorescent Probe for Selective Imaging of Tau Aggregates in Alzheimer’s Disease: Rational Design, Synthesis, and Molecular Docking

Abstract

Tau aggregation is believed to have a strong association with the level of cognitive deficits in Alzheimer's disease (AD). Thus, optical brain imaging of tau aggregates has recently gained substantial attention as a promising tool for the early diagnosis of AD. However, selective imaging of tau aggregates is a major challenge due to sharing similar β−sheet structures with homologous Aβ fibrils. Herein, four quinoline-based fluorescent probes (Q-tau) were judiciously designed using the donor− acceptor architecture for selective imaging of tau aggregates. In particular, probe Q-tau 4 exhibited a strong intramolecular charge transfer and favorable photophysical profile, such as a large Stokes' shift and fluorescence emission wavelength of 630 nm in the presence of tau aggregates. The probe also displayed a "turn-on" fluorescence behavior toward tau fibrils with a 3.5-fold selectivity versus Aβ fibrils. In addition, Q-tau 4 exhibited nanomolar binding affinity to tau aggregates (K d = 16.6 nM), which was 1.4 times higher than that for Aβ fibrils. The mechanism of "turn-on" fluorescence was proposed to be an environment-sensitive molecular rotor-like response. Moreover, ex vivo labeling of human AD brain sections demonstrated favorable colocalization of Q-tau 4 and the phosphorylated tau antibody, while comparable limited staining was observed with Aβ fibrils. Molecular docking was conducted to obtain insights into the tau-binding mode of the probe. Collectively, Q-tau 4 has successfully been used as a tau-specific fluorescent imaging agent with lower background interference.

Rational design and synthesis of a novel BODIPY-based probe for selective imaging of tau tangles in human iPSC-derived cortical neurons

“…Moreover, heterogeneous structural organization of tau aggregates has been observed in AD and non-AD-related tauopathies. Thus, the need for non-toxic fluorescence dyes bearing better selectivity, affinity, and specificity for tau proteins is fostering the development of a novel generation of tracers 31 , 32 . In this regard, the recent characterization of tau protein structure at the atomic 33 , 34 might represent an outstanding milestone for better tackling such needs 35 .…”

Cyclic dipeptide‐based small molecules modulate zinc‐mediated liquid–liquid phase separation of tau

“…In case of 1c with highest binding affinity toward tau, there are two conventional hydrogen bonding interactions with Lys311 and Lys375 residues of I chain in addition to weaker van der Waals interactions. The π–stacking interactions, viz., π–π stacking, amide–π stacking, and π–alkyl interactions, are essential to biological processes like protein‐ligand recognition 58 and induction of protein nucleation 59 . SMM 1c has shown amide–π stacking interaction with Lys311 and π‐alkyl interaction with Leu376 residues of I chain of tau protofibril.…”

Multipronged diagnostic and therapeutic strategies for Alzheimer's disease

“…Inspired by THK family PET tracers, push–pull fluorescent probes composed of dimethylaminophenyl/pyridinyl as the donor and the quinoline moiety as the acceptor group with a π-bridge were designed. 47 Among them, Q-tau 4 exhibits strong intramolecular charge transfer and marked fluorescence response selectively in the presence of tau aggregates over Aβ. Molecular docking with VQIVYK revealed that Q-tau-4 interacts with the hydrophobic surface of Gln307 along the fibril axis.…”