Abstract
There is a large unmet need for a simple, accurate, non-invasive, quantitative and high resolution imaging modality to detect lung fibrosis at early stage and to monitor disease progression. Overexpression of collagen is a hallmark of organ fibrosis. Here, we describe the optimization of a collagen-targeted positron emission tomography (PET) probe for staging pulmonary fibrosis. Methods: Six peptides were synthesized, conjugated to a copper chelator, and radiolabeled with copper-64. The collagen affinity of each probe was measured in a plate-based assay. The pharmacokinetics and metabolic stability of the probes were studied in healthy rats. The capacity of these probes to detect and stage pulmonary fibrosis in vivo was assessed in a mouse model of bleomycin (BM)-induced fibrosis using PET imaging. Results: All probes exhibit affinities in the low micromolar range (1.6 μM < Kd < 14.6 μM) and have rapid blood clearance. The probes showed 2- to 8-fold greater uptake in the lungs of BM-treated mice compared to sham treated mice, while the distribution in other organs was similar between BM-treated and sham mice. Probe 64Cu-CBP7 showed the highest uptake in fibrotic lungs and the highest target:background ratios. The superiority of 64Cu-CBP7 was traced to a much higher metabolic stability compared to the other probes. The specificity of 64Cu-CBP7 for collagen was confirmed by comparison with a non-binding isomer. Conclusion: 64Cu-CBP7 is a promising candidate for in vivo imaging of pulmonary fibrosis.
- Copyright © 2017 by the Society of Nuclear Medicine and Molecular Imaging, Inc.