While it is well known that idiopathic pulmonary fibrosis (IPF) has a devastating disease course, approximately 30% of individuals with non-IPF interstitial lung disease (ILD) will develop progressive pulmonary fibrosis (PPF), with an overall poor survival worse than most cancers. A diagnosis of PPF carries significant therapeutic implications. Based on the results of the INBUILD trial, patients with non-IPF ILD who experience disease progression benefit from antifibrotic therapy with nintedanib. A major clinical challenge is that a diagnosis of PPF can only be made after evidence of disease progression via worsening respiratory symptoms, decline in pulmonary function, or progressive changes on high-resolution computed tomography (HRCT). Early identification of patients at the highest risk for developing PPF is a crucial unmet need to improve outcomes of those with non-IPF ILD. The capacity to predict the development of PPF with high accuracy would allow (1) early initiation of anti-fibrotic therapy for those at highest risk of PPF, (2) improved prognostication to enable care plans to be tailored accordingly (i.e. early referral for lung transplantation), and (3) enrichment of clinical trials with subjects at the highest risk for PPF. We have developed two innovative and complementary advanced imaging technologies that we will employ simultaneously to determine if our imaging measurements can predict which individuals will develop PPF. We have developed a PET probe that binds type I collagen with high specificity. This probe, 68Ga-CBP8, can stage the degree of new collagen formation in a mouse model of pulmonary fibrosis, measure response to therapy with an αvβ6 inhibitor in a murine model, and detect increased collagen in the lungs of IPF subjects. We have data that 68Ga-CBP8 preferentially binds recently deposited collagen as opposed to established scar and that higher 68Ga-CBP8 lung uptake is followed by disease progression in subjects with ILD. We have employed dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to obtain complementary measurements of tissue injury (e.g., microvascular changes and changes in the extravascular extracellular space) in subjects with ILD. In IPF subjects, we have shown that DCE-MRI can distinguish subsequent stable versus progressive disease. We will build on these findings by performing a longitudinal observational study in subjects with non-IPF ILD to determine if our PET-MRI measurements predict PPF as determined by subsequent changes in pulmonary function tests and quantitative measurements on HRCT. We will determine if the combination of PET and DCE-MRI measurements improves the diagnostic accuracy of either measurement alone. We will also use these technologies to understand the effect of immunosuppression treatment on collagen deposition. If successful, these studies will provide a non- invasive tool for single timepoint disease activity assessment that could enable early initiation of antifibro...