The
self-assembly of amyloid-β (Aβ) peptides into amyloid
aggregates is a pathological hallmark of Alzheimer’s Disease.
We previously reported a fluorescent Aryl Cyano Amide (ARCAM) probe
that exhibits an increase in fluorescence emission upon binding to
Aβ aggregates in solution and in neuronal tissue. Here, we investigate
the effect of introducing small aliphatic substituents on the spectroscopic
properties of ARCAM both free in solution and when bound to aggregated
Aβ. We found that introducing substituents designed to hinder
the rotation of bonds between the electron donor and acceptor on these
fluorophores can affect the overall brightness of fluorescence emission
of the probes in amyloid-free solutions, but the relative fluorescence
enhancement of these probes in amyloid-containing solutions is dependent
on the location of the substituents on the ARCAM scaffold. We also
observed the capability to tune the excitation or emission wavelength
of these probes by introducing electron-donating or -withdrawing substituents
that putatively affect either the energy required for photoexcitation
or the stability of the photoexcited state. These studies reveal new
design principles for developing ARCAM-based fluorescent Aβ-binding
probes with an enhanced fluorescence signal compared to background
and tunable spectroscopic properties, which may lead to improved chemical
tools for aiding in the diagnosis of amyloid-associated neurodegenerative
diseases.
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