PT  - JOURNAL ARTICLE
AU  - Carolina Ferreira
AU  - Zachary Rosenkrans
AU  - Ksenija Bernau
AU  - Melissa Moore
AU  - Frank Valla
AU  - Jeanine Batterton
AU  - Christopher Drake
AU  - Christopher Massey
AU  - Alan McMillan
AU  - Nathan Sandbo
AU  - Ali Pirasteh
AU  - Reinier Hernandez
TI  - Targeting Activated Fibroblasts for non-invasive detection of Lung Fibrosis
DP  - 2021 May 01
TA  - Journal of Nuclear Medicine
PG  - 10--10
VI  - 62
IP  - supplement 1
4099  - http://jnm.snmjournals.org/content/62/supplement_1/10.short
4100  - http://jnm.snmjournals.org/content/62/supplement_1/10.full
SO  - J Nucl Med2021 May 01; 62
AB  - 10Objectives: Interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF), are characterized by progressive lung fibrosis and cause significant morbidity and mortality in the U.S., with over 40,000 annual deaths. A major challenge in IPF clinical management is lack of a direct noninvasive biomarker for early detection and monitoring of disease activity. In IPF, activated fibroblasts are a central mediator of extracellular matrix deposition that drives fibrosis and ultimately progressive decline in lung function. The fibroblast activation protein (FAP) is a cell surface serine protease and upregulated in a subset of activated fibroblasts associated with matrix remodeling in IPF and could serve as a target for disease activity assessment. FAP inhibitors (FAPIs) have recently emerged as promising imaging agents in FAP-positive environments, such as cancer. Herein, we utilized a FAPI-based PET/CT radiotracer (68Ga-FAPI-46) for noninvasive early detection and monitoring of pulmonary fibrosis in a mouse model. Methods: To induce pulmonary fibrosis, a single intratracheal dose of bleomycin (1U/kg) was delivered into the lungs of 13-week-old C57BL/6J mice (n=6). Control mice were given 0.9% normal saline (n=6). FAPI-46 precursor was radiolabeled with 68GaCl3 in sodium acetate buffer (pH = 4.0) containing sodium ascorbate at 95°C for 15 minutes and purified by reversed-phase solid phase extraction. Radiochemical yield and purity were determined by reversed-phase HPLC. For dynamic PET scans, on post-bleomycin days 7 and 14 , subgroups of mice (n=3) were anesthetized and the lateral tail vein was catheterized. Simultaneous with the administration of 1.7 MBq (50 µCi) of 68Ga-FAPI-46 (68Ga-FAPI) as a fast intravenous bolus, dynamic 1 hr PET images were acquired (Inveon microPET/CT; 46 frames) and reconstructed using the OSEM3D/MAP algorithm. CT images (80 kVp, 900 μA, resolution 105 μm) were acquired for anatomical co-registration and to detect fibrosis based on lung CT density in Hounsfield units (HU). Quantification of decay corrected PET/CT images, expressed as percent injected dose (%ID), was performed using Inveon Research Workspace by manually drawing region-of-interest (ROI) over the lungs and other tissues of interest. Following imaging, the mice were sacrificed and major organs were collected and counted in a calibrated gamma counter for confirmatory biodistribution evaluation. Results: At 7 and 14 days post bleomycin administration, CT images demonstrated radiological evidence of fibrosis with a significantly higher CT density in the lungs of animals injected with bleomycin compared to the control (p < 0.05). Dynamic PET images demonstrated prompt uptake and clearance of radiotracer from the blood, kidneys, and bladder, indicating a predominantly renal radiotracer elimination. Compared to control animals, FAPI uptake in the lungs was markedly higher in the animals given bleomycin starting at 15 minutes after radiotracer injection, at both 7 and 14 days after bleomycin instillation. FAPI uptake in fibrotic lung, 1 hr post-injection, was twice (0.33 ± 0.08 vs 0.16 ± 0.01 %ID/g, p = 0.03) and three-time as high (1.01 ± 0.11 vs 0.36 ± 0.05 %ID/g, p < 0.001) as the control group at days 7 and 14 post-bleomycin, respectively, indicating disease progression. Biodistribution data were in agreement with the lung FAPI uptake, showing bleomycin vs control group %IDs of 0.18 ± 0.05 vs 0.03 ± 0.01 (p = 0.008) and 0.54 ± 0.32 vs 0.11 ± 0.03 (p = 0.002) at 7 and 14 days post-injection, respectively. Conclusion: 68Ga-FAPI-46 PET/CT can be utilized for detection and monitoring of progression of pulmonary fibrosis by directly targeting the fibroblast activation protein expression in a preclinical murine model. Our results suggest the potential of 68Ga-FAPI-46 PET as a noninvasive tool for early diagnosis and monitoring of pulmonary fibrosis and warrant further exploration of this tool in other translationally relevant models of fibrosis.