Detection of Intestinal Inflammation by Vascular Adhesion Protein-1-Targeted [68Ga]Ga-DOTA-Siglec-9 Positron Emission Tomography in Murine Models of Inflammatory Bowel Disease

Abstract

<p><strong>Purpose</strong><br></p><p>Inflammatory bowel disease (IBD) can be imaged with positron emission tomography (PET), but existing PET radiopharmaceuticals have limited diagnostic accuracy. Vascular adhesion protein-1 (VAP-1) is an endothelial cell surface molecule that controls leukocyte extravasation into sites of inflammation. However, the role of inflammation-induced VAP-1 expression in IBD is still unclear. Therefore, this study investigated the utility of VAP-1-targeted [⁶⁸Ga]Ga-DOTA-Siglec-9 positron emission tomography/computed tomography (PET/CT) for assessing inflammation in two mouse models of IBD.<br></p><p><strong>Procedures</strong><br></p><p>Studies were performed using K8^−/− mice that develop a chronic colitis-phenotype and C57Bl/6NCrl mice with acute intestinal inflammation chemically-induced using 2.5% dextran sodium sulfate (DSS) in drinking water. In both diseased and control mice, uptake of the VAP-1-targeting peptide [⁶⁸Ga]Ga-DOTA-Siglec-9 was assessed in intestinal regions of interest using <i>in vivo</i> PET/CT, after which <i>ex vivo</i> gamma counting, digital autoradiography, and histopathological analyses were performed. Immunofluorescence staining was performed to determine VAP-1-expression in the intestine, including in samples from patients with ulcerative colitis.<br></p><p><strong>Results</strong><br></p><p>Intestinal inflammation could be visualized by [⁶⁸Ga]Ga-DOTA-Siglec-9 PET/CT in two murine models of IBD. In both models, the <i>in vivo</i> PET/CT and <i>ex vivo</i> studies of [⁶⁸Ga]Ga-DOTA-Siglec-9 uptake were significantly higher than in control mice. The <i>in vivo</i> uptake was increased on average 1.4-fold in the DSS model and 2.0-fold in the K8^−/− model. Immunofluorescence staining revealed strong expression of VAP-1 in the inflamed intestines of both mice and patients.<br></p><p><strong>Conclusions</strong><br></p><p>This study suggests that the VAP-1-targeting [⁶⁸Ga]Ga-DOTA-Siglec-9 PET tracer is a promising tool for non-invasive imaging of intestinal inflammation. Future studies in patients with IBD and evaluation of the potential value of [⁶⁸Ga]Ga-DOTA-Siglec-9 in diagnosis and monitoring of the disease are warranted.<br></p>