Analysis of the off-target interaction of amyloid PET tracers with human brain sulfotransferases.

BACKGROUND

Positron emission tomography (PET) tracers targeting amyloid-β (Aβ) are central to the diagnosis and staging of Alzheimer's disease (AD). However, growing evidence indicates that these tracers can engage off-target molecules, complicating signal interpretation. Sulfotransferases (SULTs) have been experimentally identified as binding partners of 11C-Pittsburgh Compound-B (PiB), but whether the clinically used fluorinated PiB derivatives interact with brain-expressed SULTs has not been explored.

OBJECTIVE

To assess whether PiB and its fluorinated derivatives flutemetamol and flutafuranol interact with the SULT isoforms expressed in the human brain, and to characterize the structural features of these interactions.

METHODS

We combined multi-omic transcriptomic profiling of the Genotype-Tissue Expression (GTEx) project and the Human Protein Atlas with molecular docking and molecular dynamics (MD) simulations to evaluate the structural interactions of SULT-tracer complexes.

RESULTS

SULT1A1, SULT1A3, and SULT4A1 were identified as the SULT isoforms predominantly expressed in the human brain, and all three are expressed in the cerebellum, the region used as a reference for Aβ PET signal normalization. Docking and MD simulations showed that all three tracers form energetically comparable complexes within the catalytic pockets of these isoforms, but their dynamic stability varied in an enzyme- and tracer-specific manner. PiB and flutemetamol were stably accommodated in SULT1A1, whereas PiB lost its initial pose in SULT4A1. Flutafuranol showed weaker binding to SULT1A1 but formed stable complexes in SULT1A3 and SULT4A1.

CONCLUSIONS

These findings provide a structural framework for off-target interactions between Aβ PET tracers and brain SULTs and suggest that the intracellular enzymatic environment may contribute to variability in Aβ PET signals beyond fibrillar Aβ deposition.