Usefulness of ${}^{18}$F-FPP-RGD${}_2$ PET in pathophysiological evaluation of lung fibrosis using a bleomycin-induced rat model

Integrins α${}_v$ are key molecules in the pathogenesis of fibrosis in multiple organs. To assess the potential utility of integrin α${}_v$β${}_3$ imaging for idiopathic pulmonary fibrosis (IPF), we evaluated an ${}^{18}$F-FPP-RGD${}_2$ PET probe in a rat model of bleomycin-induced lung fibrosis. Pulmonary fibrosis was induced by single intratracheal instillation of bleomycin (3 mg/rat). Positron emission tomography (PET)/computerized tomography scans were performed 4 weeks after bleomycin administration using ${}^{18}$F-FPP-RGD${}_2$. Total distribution volume (V${}_T$) was estimated using one-tissue/two-compartment, two-tissue/three-compartment models, and Logan graphical analysis (Logan plot; t* = 30 min). Plasma-free fractions were estimated from images of the left ventricle. Correlation between Logan V${}_T$ and lung pathology was assessed by Spearman's rank correlation. Histopathological evaluation demonstrated the development of fibrosis in IPF-model group. Integrin α${}_v$ protein expression and lung radioactivity were higher in IPF-model group compared with control group. The lung radioactivity of ${}^{18}$F-FPP-RGD${}_2$ rapidly reached the peak after administration and then gradually decreased, whereas left ventricular radioactivity rapidly disappeared. Logan graphical analysis was found to be suitable for ${}^{18}$F-FPP-RGD${}_2$ kinetic analysis in the IPF-model lung. Logan V${}_T$ values for ${}^{18}$F-FPP-RGD${}_2$ were significantly higher in IPF rats compared with control rats and strongly correlated with lung fibrosis, pathology, integrin α${}_v$ protein expression, and oxygen partial pressure. Our findings demonstrate that the integrin α${}_v$β${}_3$ PET probe ${}^{18}$F-FPP-RGD${}_2$ can detect pathophysiological changes in lungs, including fibrosis accompanying upregulated integrin α${}_v$ of IPF-model rats. These findings support the utility of ${}^{18}$F-FPP-RGD${}_2$ PET imaging for the pathophysiological evaluation of pulmonary fibrosis.