# Potential Off-Target Interaction of the Amyloid PET Imaging Tracer PiB with Acetylcholinesterase

## TL;DR

This study shows that the Alzheimer's PET tracer PiB can bind to an enzyme called acetylcholinesterase, which may affect how PiB PET scans are interpreted.

## Contribution

The novel finding is that PiB interacts with acetylcholinesterase, suggesting off-target effects that could influence PET signal interpretation in Alzheimer's disease.

## Key findings

- PiB binds to the peripheral anionic site of acetylcholinesterase with energy comparable to known ligands.
- In vitro assays confirmed PiB's interaction with acetylcholinesterase, implicating the peripheral anionic site.
- This off-target interaction may affect PiB-PET signal interpretation in brain regions with altered acetylcholinesterase levels.

## Abstract

Pittsburgh compound
B (PiB) is a widely used Positron
Emission
Tomography (PET) tracer for detecting amyloid-β (Aβ) deposits
in Alzheimer’s disease (AD). While PiB is assumed to bind selectively
to Aβ, emerging evidence suggests off-target interactions that
may complicate PET signal interpretation. Here, we report that PiB
can interact with acetylcholinesterase (AChE), a key enzyme in the
cholinergic system. Similarity screening identified the AChE ligand
thioflavin T (ThT) as the top structural analogue of PiB. Docking
studies and molecular dynamics simulations showed that PiB stably
binds the peripheral anionic site (PAS) of AChE, with binding energies
comparable to ThT and clinically relevant AChE inhibitors. In vitro fluorescence-based assays confirmed this interaction
and suggest an involvement of the PAS. These findings indicate a plausible,
stable off-target interaction between PiB and AChE with implications
for interpreting PiB-PET signals in AD, particularly in reference
regions with altered AChE expression or under AChE inhibitor therapy.