[¹⁸F]FDG interactions with human serum albumin: Binding and molecular modeling studies

Using a set of techniques, including radiometric binding assays, kinetic measurements, fluorescence displacement, and molecular modeling, the interaction of [¹⁸F]FDG with human serum albumin (HSA) was characterized. [¹⁸F]FDG was found to display weak, saturable binding to HSA, with a maximal bound fraction of ∼40% and an apparent dissociation constant of ∼43 µM in the presence of glucose physiological concentration. Equilibrium was reached within ∼30-35 min, which is consistent with rapid, reversible association. Binding saturated near ∼100 µM HSA, a concentration relevant to the lower range of serum albumin in hypoalbuminemic patients. Molecular docking and 100-ns molecular dynamics simulations indicated [¹⁸F]FDG engagement at the Sudlow's site I, without perturbing albumin structure. Modest and concentration-dependent displacement of warfarin by cold analog 2-deoxy-D-glucose supported partial competition at this site. Collectively, the obtained results indicate that [¹⁸F]FDG exists partly in a transient albumin-associated state rather than exclusively in a freely diffusible form. While modest in magnitude, this interaction may contribute to variability in blood-pool and liver background uptake in patients with altered albumin or glucose levels, and provides quantitative reference values to refine interpretation of PET imaging under diverse metabolic and nutritional states. Recognizing this albumin-associated fraction may help interpret subtle variations in liver and blood-pool reference regions, improving the reliability of SUV-based assessments in patients with low albumin or altered glucose metabolism.