1. 18 F-AzaFol for Detection of Folate Receptor-β Positive Macrophages in Experimental Interstitial Lung Disease-A Proof-of-Concept Study.
- Author
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Schniering J, Benešová M, Brunner M, Haller S, Cohrs S, Frauenfelder T, Vrugt B, Feghali-Bostwick C, Schibli R, Distler O, Müller C, and Maurer B
- Subjects
- Animals, Bleomycin adverse effects, Bleomycin pharmacology, Female, Gene Expression Regulation drug effects, Gene Expression Regulation immunology, Humans, Mice, Proof of Concept Study, Fluorine Radioisotopes chemistry, Fluorine Radioisotopes pharmacology, Folate Receptor 2 immunology, Folic Acid analogs & derivatives, Folic Acid chemistry, Folic Acid pharmacology, Lung Diseases, Interstitial chemically induced, Lung Diseases, Interstitial diagnostic imaging, Lung Diseases, Interstitial immunology, Macrophages immunology, Positron Emission Tomography Computed Tomography, Radiopharmaceuticals chemistry, Radiopharmaceuticals pharmacology
- Abstract
Background: Interstitial lung disease (ILD) is a common and severe complication in rheumatic diseases. Folate receptor-β is expressed on activated, but not resting macrophages which play a key role in dysregulated tissue repair including ILD. We therefore aimed to pre-clinically evaluate the potential of
18 F-AzaFol-based PET/CT (positron emission computed tomography/computed tomography) for the specific detection of macrophage-driven pathophysiologic processes in experimental ILD. Methods: The pulmonary expression of folate receptor-β was analyzed in patients with different subtypes of ILD as well as in bleomycin (BLM)-treated mice and respective controls using immunohistochemistry. PET/CT was performed at days 3, 7, and 14 after BLM instillation using the18 F-based folate radiotracer18 F-AzaFol. The specific pulmonary accumulation of the radiotracer was assessed by ex vivo PET/CT scans and quantified by ex vivo biodistribution studies. Results: Folate receptor-β expression was 3- to 4-fold increased in patients with fibrotic ILD, including idiopathic pulmonary fibrosis and connective tissue disease-related ILD, and significantly correlated with the degree of lung remodeling. A similar increase in the expression of folate receptor-β was observed in experimental lung fibrosis, where it also correlated with disease extent. In the mouse model of BLM-induced ILD, pulmonary accumulation of18 F-AzaFol reflected macrophage-related disease development with good correlation of folate receptor-β positivity with radiotracer uptake. In the ex vivo imaging and biodistribution studies, the maximum lung accumulation was observed at day 7 with a mean accumulation of 1.01 ± 0.30% injected activity/lung in BLM-treated vs. control animals (0.31 ± 0.06% % injected activity/lung; p < 0.01). Conclusion: Our preclinical proof-of-concept study demonstrated the potential of18 F-AzaFol as a novel imaging tool for the visualization of macrophage-driven fibrotic lung diseases., (Copyright © 2019 Schniering, Benešová, Brunner, Haller, Cohrs, Frauenfelder, Vrugt, Feghali-Bostwick, Schibli, Distler, Müller and Maurer.)- Published
- 2019
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