Optimization of PET probe for imaging lung fibrogenesis

项目总结/文摘

Project Summary/Abstract The goal of this project is to optimize a positron emission tomography (PET) probe to quantify fibrogenesis (active disease) in the lung to ultimately provide an early diagnosis of idiopathic pulmonary fibrosis (IPF), to predict disease progression, and to provide an early indication of whether anti-fibrotic therapy is likely to be effective. 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. Our group recently demonstrated that oxidized collagen is a marker of active disease in pulmonary fibrosis. In animal models, using molecular probes that target the allysine residue on oxidized collagen, we showed that a molecular probe targeted to allysine could detect fibrogenesis, monitor treatment response and could distinguish active fibrogenesis from stable scar in models of lung fibrosis. We further showed that by modifying the affinity and reactivity (on-rate), that probe uptake in areas of active disease could be increased in a rational manner. In this Catalyze: Preliminary Product/Lead Series Identification proposal, we aim to optimize our lead PET probe with respect to its uptake in areas of disease and its elimination from non-diseased lung and surrounding tissues, thus providing a very high target to background ratio and enabling accurate quantification of lung fibrogenesis. With the optimized probe in hand, we will then demonstrate its efficacy in different animal models of pulmonary fibrosis, demonstrate its specificity to quantify active disease, and show that it can monitor treatment response. At the end of this two year project we will have an optimized and validated PET probe for imaging lung fibrogenesis and be poised to translate this probe to human clinical trials.