Positron Emission Tomography imaging of tumor necrosis factor in lung injury.

Abstract

INTRODUCTION: Tumor necrosis factor (TNF) is a key pro-inflammatory cytokine involved in various pulmonary diseases, including idiopathic pulmonary fibrosis (IPF), where it contributes to immune cell recruitment, tissue remodeling, and disease progression. Despite the therapeutic potential of TNF-targeting strategies, the lack of non-invasive tools to assess TNF activity in the lungs limits personalized treatment and trial stratification. This study aimed to evaluate the novel Affibody molecule-based positron emission tomography (PET) tracer [Ga]Z, targeting TNF, for its ability to detect inflammation in vivo using the bleomycin (BLM)-induced lung injury model in rats. METHODS: DOTA-Zwas generated by solid phase peptide synthesis, and a method for labeling by Gallium-68 was developed. The resulting PET tracer [Ga]Zwas evaluated for binding to recombinant TNF by a radioimmuno-assay. [Ga]Zwas further evaluated by PET imaging and ex vivo biodistribution studies in a bleomycin rat model of lung injury in comparison with healthy rats. RESULTS: DOTA-Zwas consistently radiolabeled with a radiochemical purity of at least 95%. [Ga]Zbound to recombinant human TNF in vitro with a mechanism that could be partially inhibited by etanercept (131.8 &#xb1; 12.0 vs. 74.2 &#xb1; 5.6 fmol,< 0.05). [Ga]Zuptake was significantly higher in injured pulmonary regions in BLM-treated rats compared to lung tissue in control animals (SUV0.58 &#xb1; 0.22 vs. 0.25 &#xb1; 0.07,< 0.05) as analyzed by PET/computed tomography (CT) in vivo imaging. These regions corresponded with histologically confirmed areas of inflammation, with dense CD68+ macrophage infiltration. CONCLUSION: [Ga]Zenables non-invasive detection of localized TNF-driven inflammation in the lung. This approach offers a promising imaging tool for patient stratification, therapy monitoring, and guiding anti-TNF interventions in pulmonary diseases.