Positron Emission Tomography imaging of tumor necrosis factor in lung injury

Olivia Wegrzyniak; Huayi Han; Olof Eriksson

doi:10.48101/ujms.v131.13817

Olivia Wegrzyniak Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
Huayi Han Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
Olof Eriksson Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden https://orcid.org/0000-0002-2515-8790

DOI: https://doi.org/10.48101/ujms.v131.13817

Keywords: Tumor necrosis factor, inflammatory diseases, positron emitted tomography, molecular imaging, inflammation

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 [⁶⁸Ga]Z₀₁₈₅, targeting TNF, for its ability to detect inflammation in vivo using the bleomycin (BLM)-induced lung injury model in rats.

Methods: DOTA-Z₀₁₈₅ was generated by solid phase peptide synthesis, and a method for labeling by Gallium-68 was developed. The resulting PET tracer [⁶⁸Ga]Z₀₁₈₅ was evaluated for binding to recombinant TNF by a radioimmuno-assay. [⁶⁸Ga]Z₀₁₈₅ was 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-Z₀₁₈₅ was consistently radiolabeled with a radiochemical purity of at least 95%. [⁶⁸Ga]Z₀₁₈₅ bound to recombinant human TNF in vitro with a mechanism that could be partially inhibited by etanercept (131.8 ± 12.0 vs. 74.2 ± 5.6 fmol, P < 0.05). [⁶⁸Ga]Z₀₁₈₅ uptake was significantly higher in injured pulmonary regions in BLM-treated rats compared to lung tissue in control animals (SUV_mean 0.58 ± 0.22 vs. 0.25 ± 0.07, P < 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: [⁶⁸Ga]Z₀₁₈₅ enables 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.

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