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This study investigated whether amyloid-beta PET tracers used in Alzheimer's disease diagnosis bind to sulfotransferase enzymes (SULTs) in the human brain, potentially creating off-target signals. Using computational modeling and brain gene expression data, researchers found that three PET tracers (PiB, flutemetamol, and flutafuranol) all bind to the three main brain-expressed SULT isoforms (SULT1A1, SULT1A3, and SULT4A1), though with varying stability depending on the specific enzyme-tracer combination. Importantly, all three SULT isoforms are expressed in the cerebellum, which is used as a reference region when normalizing amyloid PET scans.
Why it matters
These findings suggest that amyloid PET scan results may be influenced by off-target binding to brain enzymes, not just amyloid plaques, potentially affecting the accuracy of Alzheimer's disease diagnosis and staging. Understanding these interactions could help explain variability in PET signals across patients and improve interpretation of clinical scans.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Positron emission tomography (PET) tracers targeting amyloid-{beta} (A{beta}) 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). However, whether the clinically used fluorinated PiB derivatives flutemetamol and flutafuranol interact with brain-expressed SULTs is yet unexplored. Here, we combined multi-omic transcriptomic profiling with molecular docking and molecular dynamics (MD) simulations to assess the structural interactions of SULT-tracer complexes. Analysis of the Genotype-Tissue Expression project and the Human Protein Atlas identified SULT1A1, SULT1A3, and SULT4A1 as the SULT isoforms predominantly expressed in the human brain. Docking and MD simulations showed that all three tracers form energetically comparable complexes within the catalytic pockets of these isoforms, yet their dynamic stability varied in an enzyme- and tracer-specific manner. PiB and flutemetamol were stably accommodated in SULT1A1, but PiB lost its initial pose in SULT4A1. Flutafuranol showed weaker binding in SULT1A1, yet formed stable complexes in SULT1A3 and SULT4A1. Notably, SULT1A1, SULT1A3, and SULT4A1 are all expressed in the cerebellum, the brain region used as a reference for A{beta} PET signal normalization. These findings provide a structural framework for off-target tracer interaction with brain SULTs and suggest that the intracellular enzymatic environment may contribute to variability in A{beta} PET signals beyond fibrillar A{beta} deposition.
Source: Analysis of the off-target interaction of amyloid PET tracers with human brain sulfotransferases