Fibroblast Activation Protein Inhibitor, a Promising Radiotracer inFibrogenesis

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible interstitial lung diseasefor which biomarker of the fibrotic activity of the disease are lacking. Fibroblast activation protein-α(FAP) is a marker of activated fibroblasts. The development of quinoline-based PET tracers that actas FAP inhibitors (FAPIs) demonstrated promising results in oncology with a high and selectivetumor uptake. In the present study, we evaluated the potential role of FAPI as a biomarker of lungfibrogenesis. Methods: The lung uptake of FAPI and its kinetic was assessed in a mouse model ofpulmonary fibrosis. Thus, intratracheal instillation of bleomycin (0.02U/mouse) was performed onC56BL/6 mice. Control mice received an intratracheal instillation of NaCl 0.9%. FAPI was providedby SOFIE (Totowa, USA) and the radiotracer 18F-FAPI was produced in the department of NuclearMedicine of Erasme Hospital. PET/CT imaging were determined at different timepoints (days 3, 10,16 and 28) after the instillation of bleomycin. A time course of uptake of the radiotracer wasevaluated. The results are presented as the mean standardized uptake value (SUV mean) in thelungs and the calculation of a lung-to-muscle ratio (LMR). To correlate with the PET scan results, theextent of fibrosis was assessed by measuring lung content of hydroxyproline and by evaluating theAshcroft modified scale. Results: The optimal imaging window was determined between 40 and 90minutes after radiotracer injection. Bleomycin-treated mice presented a significantly higher uptakeof 18F-FAPI (both SUV mean and LMR) at days 10 and 16 after instillation as compared to controlmice (p < 0.01). No significant statistical difference was observed at day 3 and day 28 afterinstillation. At day 10 and day 16, a strong correlation between 18F-FAPI uptake and hydroxyprolinelung content was observed, as well as a moderate correlation with the Ashcroft modified score.Conclusions: Our results suggest that FAPI constitutes a promising marker of fibrogenesis whoseexpression can be assessed by PET/CT imaging in a mouse model of lung fibrosis. Interestingly, nosignificant increase of lung FAPI uptake was observed during the initial inflammatory phase afterbleomycin instillation as well as at the later stage when fibrotic changes are established and nolonger grow. 18F-FAPi PET/CT could be a useful tool for preclinical evaluation of antifibrotic drugsand further studies should assess its value in patients with IPF.