Aminonaphthalene 2-Cyanoacrylate (ANCA) Probes Fluorescently Discriminate between Amyloid-β and Prion Plaques in Brain

Abstract

A major challenge for diagnosing and monitoring the progression of amyloid-based diseases is the capability to distinguish between amyloid deposits that are associated with related, but distinctly different, diseases. Here, we demonstrate that Amino Naphthalenyl-2-Cyano-Acrylate (ANCA)-based probes can fluorescently discriminate between different types of amyloid deposits in brain. This discriminating behavior is due to the stabilization of the ground versus excited states of these probes as a function of the polarity of their microenvironment (i.e. within the binding pocket on the amyloid). This property makes it possible for the first time to estimate the inherent static relative permittivity of the binding pocket of each amyloid within tissue. The capability to selectively follow the deposition of specific amyloids in tissue may provide important information for therapeutic development that is not readily accessible from currently available technology.

Real-Time Monitoring of Alzheimer’s-Related Amyloid Aggregation via Probe Enhancement–Fluorescence Correlation Spectroscopy

“…This probe displayed an ∼8-fold increase (at a λ em (bound) of ∼540 nm) in fluorescence emission upon binding to aggregated A β in solution versus probe without A β (Figure 1C). The affinity of ARCAM 1 for aggregated A β (K d = 870 ± 280 nM at pH 7.4) was comparable to the binding of similar fluorescent probes 18 (see Figure S1 in the Supporting Information). An important advantage of ARCAM 1 for aggregation studies is its stability in aqueous solutions (Figure S2) and broad insensitivity of fluorescence as a function of pH (Figure S3).…”

Dual Functional Small Molecule Probes as Fluorophore and Ligand for Misfolding Proteins

“…Very recently, Yang et al . demonstrated that 2-cyanoacrylate probes could fluorescently differentiate Aβ and prion protein in tissue slice due to their different ground states once the probe binds to Aβ and prion protein, and the ground state disparity is probably due to the different polarity of binding microenvironment [121]. We believe the different residues nearby the hydrophobic core fragment could provide varied microenvironments that could lead to different ground or excitation states upon interaction.…”

Intramolecular Didehydro-Diels–Alder Reaction and Its Impact on the Structure–Function Properties of Environmentally Sensitive Fluorophores.

“…Previously, Theodorakis designed 6-aminonaphthalenyl-2-cyano-acrylate (ANCA) sensors that displayed increases in emission intensity or brightness (B), which is directly proportional to the extinction coefficient (ε) and the quantum yield (B = ε·ϕ f ), upon increases in solution viscosity and subsequently applied these sensors to the selective recognition and binding of β-amyloid plaques. 30 Compounds 44 and 45 displayed two distinct emission peaks, the emission intensity of which increased with increasing solvent viscosity. Whereas a hypsochromic shift in the longerwavelength emission band of 44 was observed at higher viscosities, no similar trend was noted for 45.…”