Targeted Dual-Modality Imaging of Inflammation Using ¹⁸ F-Radiolabeled Iron Oxide Microparticles

The ability to noninvasively map vascular inflammation with high spatial and molecular resolution remains a major challenge in biomedical imaging. The integration of both positron emission tomography (PET) and magnetic resonance imaging (MRI) through a dual-modality imaging probe represents a highly attractive approach. Here, we introduce a ¹⁸F-labeled hydrophilic sulfotetrazine engineered for rapid and robust bioorthogonal inverse electron demand Diels-Alder (IEDDA) conjugation to BCN (bicyclo[6.1.0]nonyne)-functionalized microsized particles of iron oxides (MPIOs) targeting vascular cell adhesion molecules-1 (VCAM-1) known as key markers of endothelial inflammation. The clickable ¹⁸F-reagent exhibits exceptional aqueous solubility and stability, fast second-order kinetics (<i>k</i>₂ = 827 M^-1·s^-1) in the reaction with BCN, and compatibility with automated radiosynthesis platforms. We exploited this tool to generate dual-modality PET/MR ¹⁸F-MPIOs@αVCAM-1 by conjugation with MPIOs coated with anti-VCAM-1 antibodies incorporating BCN. Dynamic immuno-PET/MR imaging in a murine model of LPS-induced sepsis revealed strong and specific tracer accumulation in lungs and kidneys in accordance with VCAM-1 overexpression, while high-resolution T2*-MRI confirmed cortical kidney retention with high precision. Thus, the ¹⁸F-sulfotetrazine offers a powerful and modular strategy for late-stage functionalization of nanocarriers and sets the stage for the next generation of multimodal probes tailored for real-time tracking of inflammatory pathologies.