The development of antibody tracers for positron emission tomography (PET) imaging enables real-time monitoring of tumor expression of programmed cell death ligand 1 (PD-L1) in vivo, aiming to facilitate the selection of immunotherapy responders. However, the slow pharmacokinetics of the antibodies in vivo limits their applications in PET imaging with commonly used radionuclides with short half-lives. In this study, we developed a pretargeted PET imaging strategy based on Diels–Alder (IEDDA) click chemistry to overcome these limitations. Atezolizumab and durvalumab, the most commonly used PD-L1 antibodies in cancer immunotherapy, were selected and compared in the development of the pretargeted PET imaging strategy. Fluorine-18-labeled derivatives of methyl tetrazine ([18F]Tz, [18F]PEG6-Tz, and [18F]PEG12-Tz) were tested in biodistribution and PET imaging of A549-PDL1 xenografts (PD-L1 positive) pretargeted with the trans-cyclooctene (TCO)-functionalized atezolizumab/durvalumab. The biodistribution and imaging results indicated that atezolizumab-TCO/[18F]PEG12-Tz was more suitable for pretargeted PET imaging strategy, and the optimal interval time was 48 h after atezolizumab-TCO administration, where the atezolizumab-TCO/[18F]PEG12-Tz pretargeted approach clearly delineated the A549-PDL1 tumor with a tumor-to-muscle ratio of 5.33, while the ratios are 3.39 and 2.39 for durvalumab/[18F]PEG12-Tz and mock-pretargeting controls, respectively. In conclusion, a pretargeted 18F-immuno-PET imaging technology was successfully established on atezolizumab. The high-contrast PET images of the A549-PDL1 tumor models demonstrate that the pretargeting strategy incorporating short-lived fluorine-18 is viable in identifying tumors with high PD-L1 expression, marking this strategy as a potential candidate for further clinical translation.
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