PET Imaging of Neutrophil Elastase with11C-GW457427 in Acute Respiratory Distress Syndrome in Pigs

Today, there is a lack of clinically available imaging techniques to detect and quantify specific immune cell populations. Neutrophils are one of the first immune cells at the site of inflammation, and they secrete the serine protease neutrophil elastase (NE), which is crucial in the fight against pathogens. However, the prolonged lifespan of neutrophils increases the risk that patients will develop severe complications, such as acute respiratory distress syndrome (ARDS). Here, we evaluated the novel radiolabeled NE inhibitor ¹¹C-GW457427 in a pig model of ARDS, for detection and quantification of neutrophil activity in the lungs. Methods: ARDS was induced by intravenous administration of oleic acid to 5 farm pigs, and 4 were considered healthy controls. The severity of ARDS was monitored by clinical parameters of lung function and plasma biomarkers. Each pig was studied with ¹¹C-GW457427 and PET/CT, before and after pretreatment with the NE inhibitor GW311616 to determine in vivo binding specificity. PET image data were analyzed as SUVs and correlated with immunohistochemical staining for NE in biopsies. Results: The binding of ¹¹C-GW457427 was increased in pig lungs with induced ARDS (median SUV_mean, 1.91; interquartile range [IQR], 1.67–2.55) compared with healthy control pigs (P < 0.05 and P = 0.03, respectively; median SUV_mean, 1.04; IQR, 0.66–1.47). The binding was especially strong in lung regions with high levels of NE and ongoing inflammation, as verified by immunohistochemistry. The binding was successfully blocked by pretreatment of an NE inhibitor drug, which demonstrated the in vivo specificity of ¹¹C-GW457427 (P < 0.05 and P = 0.04, respectively; median SUV_mean, 0.60; IQR, 0.58–0.77). The binding in neutrophil-rich tissues such as bone marrow (P < 0.05 and P = 0.04, respectively; baseline median SUV_mean, 5.01; IQR, 4.48–5.49; block median SUV_mean, 1.57; IQR, 0.95–1.85) and spleen (median SUV_mean, 2.14; IQR, 1.19–2.36) was also high in all pigs. Conclusion:¹¹C-GW457427 binds to NE in a porcine model of oleic acid–induced lung inflammation in vivo, with a specific increase in regional lung, bone marrow, and spleen SUV. ¹¹C-GW457427 is a promising tool for localizing, tracking, and quantifying neutrophil-facilitated inflammation in clinical diagnostics and drug development.