PET imaging of neutrophil elastase with 11C-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 for patients to develop severe complications, such as Acute Respiratory Distress Syndrome (ARDS). Here, we evaluated 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 on 5 farm pigs and 4 were considered as 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 was analyzed as Standard Uptake Values (SUV) and correlated to immunohistochemical staining for NE in biopsies. Results: The binding of 11C-GW457427 was increased in pig lungs with induced ARDS (median SUVmean = 1.91, inter-quartile range (IQR) = 1.67-2.55) compared with healthy controls pigs (P <0.05, P = 0.03, median SUVmean = 1.04, IQR= 0.66-1.47). The binding was especially strong in lung regions with high levels of neutrophil elastase and ongoing inflammation, as verified by immunohistochemistry. The binding was successfully blocked by pretreatment of a NE inhibitor drug, which demonstrated the in vivo specificity of 11C-GW457427 (P <0.05, P = 0.04, median SUVmean = 0.60, IQR= 0.58-0.77). The binding in neutrophil rich tissues such as bone marrow (P <0.05, P = 0.04, baseline median SUVmean = 5.01, IQR= 4.48-5.49, block median SUVmean = 1.57, IQR= 0.95-1.85) and spleen (median SUVmean = 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 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.