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.

如今，缺乏临床上可用的成像技术来检测和量化特定的免疫细胞群。中性粒细胞是炎症部位最早的免疫细胞之一，它们分泌丝氨酸蛋白酶中性粒细胞弹性蛋白酶（NE），这对于对抗病原体至关重要。然而，中性粒细胞寿命的延长增加了患者出现严重并发症的风险，例如急性呼吸窘迫综合征（ARDS）。在这里，我们在 ARDS 猪模型中评估了新型放射性标记 NE 抑制剂¹¹ C-GW457427，用于检测和定量肺部中性粒细胞活性。方法：对5头猪进行静脉注射油酸诱导ARDS，其中4头作为健康对照。ARDS 的严重程度通过肺功能和血浆生物标志物的临床参数进行监测。^{在用 NE 抑制剂 GW311616 预处理之前和之后，用11} C-GW457427 和 PET/CT对每头猪进行研究，以确定体内结合特异性。PET 图像数据作为 SUV 进行分析，并与活检中 NE 的免疫组织化学染色相关。结果：与健康对照猪相比，诱导 ARDS的猪肺中^{11 C-GW457427 的结合增加（中位 SUV}_{平均值，1.91；四分位数范围 [IQR]，1.67–2.55）（分别为}P < 0.05 和P = 0.03；中位 SUV_平均值，1.04；IQR，0.66–1.47）。免疫组织化学证实，在 NE 水平高且持续炎症的肺部区域，这种结合尤其强烈。^{通过 NE 抑制剂药物的预处理成功阻断了这种结合，这证明了11} C-GW457427的体内特异性（分别为P < 0.05 和P = 0.04；中位 SUV_平均值，0.60；IQR，0.58-0.77）。富含中性粒细胞的组织，例如骨髓（分别为P < 0.05 和P = 0.04；基线中值 SUV_平均值，5.01；IQR，4.48–5.49；块中值 SUV_平均值，1.57；IQR，0.95–1.85）和脾脏中的结合（中位 SUV_平均值，2.14；IQR，1.19-2.36）在所有猪中也很高。结论： ¹¹ C-GW457427 在油酸诱导的体内肺部炎症猪模型中与 NE 结合，局部肺、骨髓和脾脏 SUV 特异性增加。¹¹ C-GW457427 是一种很有前途的工具，可在临床诊断和药物开发中定位、跟踪和量化中性粒细胞促进的炎症。