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The ability to image early treatment response to radiotherapy in head and neck squamous cell carcinoma (HNSCC) will enable the identification of radioresistant tumor volumes suitable for treatment intensification. Here, we propose the system x c - radiotracer (4 S )-4-(3-[ 18 F]fluoropropyl)-L-glutamate ([ 18 F]FSPG) as a non-invasive method to monitor radiation response in HNSCC. We assessed temporal changes in cell death, antioxidant status, and [ 18 F]FSPG retention following a single dose of 10 Gy irradiation in FaDU HNSCC cells. Next, using a fractionated course of radiotherapy, we assessed tumor volume changes and performed [ 18 F]FSPG-PET imaging in FaDU-bearing mouse xenografts, followed by ex vivo response assessment. In cells, 10 Gy irradiation reduced [ 18 F]FSPG retention, coinciding with the induction of apoptosis and the production of reactive oxygen species. In vivo, [ 18 F]FSPG tumor retention was halved seven days after the start of treatment, which preceded radiotherapy-induced tumor shrinkage, thereby confirming [ 18 F]FSPG-PET as an early and sensitive marker of radiation response., Competing Interests: Competing interestsT.H.W. is the Editor-in-Chief of npj Imaging. He was blinded to this manuscript's editorial and peer review process. All other authors declare no competing financial or non-financial interests., (© The Author(s) 2024.)

Mouse models are invaluable tools for radiotracer development and validation. They are, however, expensive, low throughput, and are constrained by animal welfare considerations. Here, we assessed the chicken chorioallantoic membrane (CAM) as an alternative to mice for preclinical cancer imaging studies. NCI-H460 FLuc cells grown in Matrigel on the CAM formed vascularized tumors of reproducible size without compromising embryo viability. By designing a simple method for vessel cannulation it was possible to perform dynamic PET imaging in ovo, producing high tumor-to-background signal for both 18 F-2-fluoro-2-deoxy-D-glucose ( 18 F-FDG) and (4S)-4-(3- 18 F-fluoropropyl)-L-glutamate ( 18 F-FSPG). The pattern of 18 F-FDG tumor uptake were similar in ovo and in vivo, although tumor-associated radioactivity was higher in the CAM-grown tumors over the 60 min imaging time course. Additionally, 18 F-FSPG provided an early marker of both treatment response to external beam radiotherapy and target inhibition in ovo. Overall, the CAM provided a low-cost alternative to tumor xenograft mouse models which may broaden access to PET and SPECT imaging and have utility across multiple applications., Competing Interests: Competing Interests The authors declare no competing interests.