Project Summary/Abstract The goal of this project is to use quantitative PET-MR imaging of the lung to accurately quantify molecular abnormalities associated with pulmonary fibrosis, to predict disease progression, and to provide an early indication of whether anti-fibrotic therapy is likely to be effective. Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease with a median survival of less than 4 years from the time of diagnosis. The treatment options remain limited due to highly variable clinical course and poorly understood pathogenic mechanisms. Current strategies to diagnose and monitor IPF include lung biopsy, pulmonary function tests that measure global lung function, and anatomic imaging tools such as high-resolution computed tomography (HRCT). Yet these methods are limited in their ability to detect disease early, determine disease activity at any one measure, or monitor the therapeutic response. Molecular imaging may be an alternative approach that is more sensitive to detect early fibrosis and potentially capable of distinguishing new, active fibrosis from stable disease – urgent and unmet clinical needs. Our group recently developed a type I collagen-specific positron emission tomography (PET) probe, 68Ga-CBP8, which was shown in animal models to detect pulmonary fibrosis at an early stage and was capable of monitoring treatment response. Preliminary data with this probe in healthy volunteers and IPF patients demonstrated that 68Ga-CBP8 had significantly higher uptake in IPF lungs than in normal lungs. This data also showed that in addition to probe uptake in regions of lung with fibrosis as established by HRCT, there were additional areas of probe uptake in radiographically “normal” lung suggesting that the probe may be sensitive to lower levels of fibrosis than HRCT and/or sensitive to disease activity, i.e. newly formed collagen. Magnetic resonance imaging (MRI) on the other hand can provide multiple readouts of morphology, physiology, and function. Preliminary data from our lab using dynamic contrast enhanced-MRI (DCE-MRI) in healthy controls and IPF subjects indicated that DCE parameters can distinguish abnormal from normal lung, and that these measures may predict disease progression. Quantitative MRI-PET in lung has been historically limited because of low proton density and the fast signal decay due to susceptibility artefacts at air- tissue interfaces for MRI, while PET quantification remains challenging due to respiratory motion, photon attenuation and regional variations in tissue, air and blood fractions. However, combining the two modalities holds great potential to overcome some of these limitations. Our central hypothesis is that non-invasive molecular imaging of collagen accumulation will allow us to capture the extent of ongoing lung injury in IPF patients and that a bi-modal imaging approach using collagen-targeted PET augmented by DCE-MRI will enable more accurate detection of disease a...