Analysis of the off-target interaction of amyloid PET tracers with human brain sulfotransferases
- 1University G. d'Annunzio of Chieti-Pescara
Abstract
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.
Versions
Related
- PeTMiner: Mining plant endogenous target mimics via ternary interaction modeling with hierarchical attention and adaptive weighted loss
- The impact of luteinizing hormone and testosterone on beta amyloid (Aβ) accumulation: Animal and human clinical studies
- ProDTI: prior-guided positive-unlabeled learning for robust drug-target interaction prediction.
- A fibril-selective single-domain antibody targets pathogenic amyloid-β assemblies and protects human neurons
- An amyloid-β/APP regulatory layer in human brown adipocyte recruitment identifies repurposable drugs for thermogenic fat expansion
BibTeX
@misc{miccoli2026analysis,
title = {{Analysis of the off-target interaction of amyloid PET tracers with human brain sulfotransferases}},
author = {L. Miccoli and R. Fullone and S. Delli Pizzi and F. Tomaiuolo and S. L. Sensi and G. Floresta and A. Granzotto},
howpublished = {bioRxiv},
year = {2026},
month = jun,
doi = {10.64898/2026.06.16.732640},
url = {https://www.biorxiv.org/content/10.64898/2026.06.16.732640v2},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Analysis of the off-target interaction of amyloid PET tracers with human brain sulfotransferases
AU - L. Miccoli
AU - R. Fullone
AU - S. Delli Pizzi
AU - F. Tomaiuolo
AU - S. L. Sensi
AU - G. Floresta
AU - A. Granzotto
PY - 2026
DA - 2026/06/16
PB - bioRxiv
DO - 10.64898/2026.06.16.732640
UR - https://www.biorxiv.org/content/10.64898/2026.06.16.732640v2
AB - 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.
ER -