PET imaging of atherosclerotic plaques using the stabilin-2-targeted tracer ¹⁸F-S2P in preclinical models

Elevated Stabilin-2 (STAB2) expression in macrophages within atherosclerotic plaques offers a promising molecular target for imaging vascular inflammation. The S2P peptide specifically binds STAB2. This study aims to evaluate the feasibility of using the STAB2-targeted ¹⁸F-labeled tracer (¹⁸F-S2P) for positron emission tomography (PET) imaging to identify atherosclerotic plaques.

Stab2 expression was validated via single-cell RNA sequencing of Ldlr^-/- mouse samples. Biodistribution and micro-PET/CT imaging were performed in high-fat diet-fed Ldlr^-/- mice (3-12 weeks) and chow-fed controls, with comparisons to ¹⁸F-FDG and ¹⁸F-Pentixafor. Plaque burden and macrophage infiltration were evaluated using Oil Red O, H&E, and immunofluorescence staining. Immunohistochemical staining was used to detect STAB2 expression in human atherosclerotic specimens.

ScRNA-seq analysis identified Stab2 as a macrophage-specific marker in atherosclerosis plaque. In vivo micro-PET/CT quantification revealed disease duration-dependent uptake (1.41 ± 0.31 ID%/g at 3 weeks vs. 2.17 ± 0.19 ID%/g at 12 weeks, P < 0.0001), which positively correlated with histological plaque burden. ¹⁸F-S2P PET imaging demonstrated 5.4-fold higher plaque uptake in Ldlr^-/- mice compared to wild-type controls (P < 0.0001), significantly outperforming ¹⁸F-FDG (1.52-fold) and ¹⁸F-Pentixafor (1.89-fold) in atherosclerotic lesions. Furthermore, STAB2 was also detectable in human atherosclerotic plaques.

This study introduces a novel STAB2-targeted PET probe (¹⁸F-S2P) for non-invasive imaging of atherosclerotic plaques in preclinical models, enabling the detection of atherosclerotic inflammation. The endogenous expression of STAB2 in human atherosclerotic lesions further strengthens the translational potential of this imaging strategy.