Fibroblast Activation Protein-Specific PET/CT Imaging in Fibrotic Interstitial Lung Diseases and Lung Cancer: A Translational Exploratory Study

Interstitial lung diseases (ILDs) comprise over 200 parenchymal lung disorders. Among them, fibrosing ILDs, especially idiopathic pulmonary fibrosis, are associated with a poor prognosis, whereas some other ILDs, such as sarcoidosis, have a much better prognosis. A high proportion manifests as fibrotic ILD (fILD). Lung cancer (LC) is a frequent complication of fILD. Activated fibroblasts are crucial for fibrotic processes in fILD. The aim of this exploratory study was to evaluate the imaging properties of static and dynamic fibroblast activation protein (FAP) inhibitor (FAPI) PET/CT in various types of fILD and to confirm FAP expression in fILD lesions by FAP immunohistochemistry of human fILD biopsy samples and of lung sections of genetically engineered (Nedd4-2^-/- ) mice with an idiopathic pulmonary fibrosislike lung disease. Methods: PET scans of 15 patients with fILD and suspected LC were acquired 10, 60, and 180 min after the administration of 150-250 MBq of a ⁶⁸Ga-labeled FAPI tracer (FAPI-46). In 3 patients, dynamic scans over 40 min were performed instead of imaging after 10 min. The SUV_max and SUV_mean of fibrotic lesions and LC were measured and CT-density-corrected. Target-to-background ratios (TBRs) were calculated. PET imaging was correlated with CT-based fibrosis scores. Time-activity curves derived from dynamic imaging were analyzed. FAP immunohistochemistry of 4 human fILD biopsy samples and of fibrotic lungs of Nedd4-2^-/- mice was performed. Results: fILD lesions as well as LC showed markedly elevated ⁶⁸Ga-FAPI uptake (density-corrected SUV_max and SUV_mean 60 min after injection: 11.12 ± 6.71 and 4.29 ± 1.61, respectively, for fILD lesions and 16.69 ± 9.35 and 6.44 ± 3.29, respectively, for LC) and high TBR (TBR of density-corrected SUV_max and SUV_mean 60 min after injection: 2.30 ± 1.47 and 1.67 ± 0.79, respectively, for fILD and 3.90 ± 2.36 and 2.37 ± 1.14, respectively, for LC). SUV_max and SUV_mean decreased over time, with a stable TBR for fILD and a trend toward an increasing TBR in LC. Dynamic imaging showed differing time-activity curves for fILD and LC. ⁶⁸Ga-FAPI uptake showed a positive correlation with the CT-based fibrosis index. Immunohistochemistry of human biopsy samples and the lungs of Nedd4-2^-/- mice showed a patchy expression of FAP in fibrotic lesions, preferentially in the transition zone to healthy lung parenchyma. Conclusion:⁶⁸Ga-FAPI PET/CT imaging is a promising new imaging modality for fILD and LC. Its potential clinical value for monitoring and therapy evaluation of fILD should be investigated in future studies.