Collagen Hybridizing Peptide–Based Radiotracers for Molecular Imaging of Collagen Turnover in Pulmonary Fibrosis

肺纤维化 纤维化 化学 病理 医学 生物化学
作者
Azmi A. Ahmad,Mean Ghim,Gunjan Kukreja,Afarin Neishabouri,Zhengxing Zhang,Jie Li,Mani Salarian,Jakub Toczek,Kiran Gona,Keshvad Hedayatyanfard,T. Morrison,Jiasheng Zhang,Yiyun Huang,Chi Liu,S. Michael Yu,Mehran M. Sadeghi
出处
期刊:The Journal of Nuclear Medicine [Society of Nuclear Medicine and Molecular Imaging]
卷期号:: jnumed.124.268832-jnumed.124.268832
标识
DOI:10.2967/jnumed.124.268832
摘要

Pulmonary fibrosis is a characteristic feature of interstitial lung disease. Current clinical diagnostic methods provide a snapshot of the lung structure without information on disease activity. Collagen hybridizing peptides offer the opportunity to detect collagen remodeling through their hybridization with denatured collagen. Here, we sought to develop a 99mTc-labeled collagen hybridizing tracer to track denatured collagen in vivo and validate it in a murine model of pulmonary fibrosis. Methods: Imaging agents consisting of a polyhistidine or a poly–histidine–glutamic acid [(HE)3] peptide connected to an N-terminal targeting moiety with 9 glycine–proline–hydroxyproline repeats [(GPO)9] through a 3-glycine linker were synthesized. After radiolabeling with 99mTc-tricarbonyl, the labeled products' purity and stability were evaluated by high-performance liquid chromatography and γ-well counting, and their biodistributions were compared in mice. To induce pulmonary fibrosis, the lungs of 8- to 10-wk-old mice were exposed to bleomycin (or saline as control). At 3 wk after induction, SPECT/CT imaging with 99mTc-(HE)3-(GPO)9 was performed 1 h after injection and was followed by tissue collection to assess 99mTc-(HE)3-(GPO)9 biodistribution by γ-well counting and to evaluate lung histology. The specificity of the tracer uptake was assessed using a scrambled homolog. A group of animals underwent serial imaging 3 and 8–10 wk after induction. Results: The specific activity of the final radiolabeled product was 70.3 ± 14.8 GBq/µmol. Radiolabeled tracers were stable in blood for at least 2 h and showed rapid blood clearance. 99mTc-(HE)3-(GPO)9 showed lower liver uptake in biodistribution studies and was selected for in vivo imaging studies. SPECT/CT imaging of bleomycin-treated mice 3 wk after induction showed higher specific 99mTc-(HE)3-(GPO)9 lung uptake than that of control mice (P < 0.01) and that of bleomycin-treated mice 8–10 wk after induction, when fibrosis was resolved (P < 0.05). There was a significant correlation between lung uptake quantified by SPECT/CT and γ-well counting (Pearson R = 0.83, P < 0.001) and significant correlations between tracer uptake and indices of tissue fibrosis. Conclusion:99mTc-(HE)3-(GPO)9 enables SPECT imaging of collagen turnover in pulmonary fibrosis. This approach expands the scope of existing diagnostic tools in fibrosis and can lead to better patient management by monitoring the effect of antifibrotic therapies.
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