Cis-4-[¹⁸F]Fluoro-l-Proline PET Imaging of Pulmonary Fibrosis in a Rabbit Model

Abstract

A fluorinated analog of proline amino acid, cis-4-[¹⁸F]fluoro-l-proline (FP), was tested for potential use in PET for detection and evaluation of pulmonary response to respirable crystalline silica. The purpose of the study was to determine whether PET imaging with FP is sensitive for detection of pulmonary fibrosis. Methods: Experimental silicosis was produced in rabbits by airway instillation of 300 mg respirable silica in 0.9% sterile saline; control rabbits received only saline. After 1, 2, 4, or 5 mo, animals were injected with 37 MBq (1 mCi) FP, and imaged in sets of 2 to 3 in a PET scanner using a dynamic scanning protocol over a 3-h period. Each imaging set contained at least 1 control rabbit. FP uptake in each lung was scored from 0 to 5 (PET score) by consensus of 3 readers blinded to animals’ exposure status. Animals were humanely killed 2 d after the last imaging, and tissue sections from each lung lobe were graded from 0 to 5 by histopathology examination (histopathology score) for severity and distribution of fibrosis. Results: Silicotic animals had significantly higher (P < 0.05) PET scores at each time point than did control animals. Repeated-measures ANOVA showed significant differences in PET scores between silicotic and control animals for the total lung field, but there were no statistically significant time trends for either group. Presence of fibrosis (i.e., histopathology score > 1) showed a significant association with elevated PET score (i.e., PET score > 1) using Fisher’s exact test (P < 0.05). PET scores also showed excellent predictive ability, as all animals (18/18) with fibrosis also had elevated PET scores, and 95% (18/19) of animals with PET scores > 1 showed evidence of fibrosis. Localization of activity to specific lung areas was less exact, perhaps due in part to the small animal size for the resolution of the clinical PET imager used. PET scores were elevated (>1) for 67% (10/15) of silicotic right lungs and 75% (12/16) of silicotic left lungs; fibrosis scores > 1 were measured in 91% (10/11) of right lungs with PET scores > 1, and in 92% (12/13) of such left lungs. Conclusion: The FP tracer provided sensitive and specific identification of silicotic animals in early stages of the disease. This suggests that FP PET imaging has the potential sensitivity to detect active fibrosis in silicosis and other lung diseases. Additional studies are needed to determine the specificity of the FP tracer for fibrosis versus inflammatory processes.