Clinical [¹⁸F]FSPG Positron Emission Tomography Imaging Reveals Heterogeneity in Tumor-Associated System x_c⁻ Activity

Background: (4S)-4-(3-[¹⁸F]fluoropropyl)-L-glutamic acid ([¹⁸F]FSPG) positron emission tomography/computed tomography (PET/CT) provides a readout of system x_c⁻ transport activity and has been used for cancer detection in clinical studies of different cancer types. As system x_c⁻ provides the rate-limiting precursor for glutathione biosynthesis, an abundant antioxidant, [¹⁸F]FSPG imaging may additionally provide important prognostic information. Here, we performed an analysis of [¹⁸F]FSPG radiotracer distribution between primary tumors, metastases, and normal organs from cancer patients. We further assessed the heterogeneity of [¹⁸F]FSPG retention between cancer types, and between and within individuals. Methods: This retrospective analysis of prospectively collected data compared [¹⁸F]FSPG PET/CT in subjects with head and neck squamous cell cancer (HNSCC, n = 5) and non-small-cell lung cancer (NSCLC, n = 10), scanned at different institutions. Using semi-automated regions of interest drawn around tumors and metastases, the maximum standardized uptake value (SUV_max), SUV_mean, SUV standard deviation and SUV_peak were measured. [¹⁸F]FSPG time–activity curves (TACs) for normal organs, primary tumors and metastases were subsequently compared to ¹⁸F-2-fluoro-2-deoxy-D-glucose ([¹⁸F]FDG) PET/CT at 60 min post injection (p.i.). Results: The mean administered activity of [¹⁸F]FSPG was 309.3 ± 9.1 MBq in subjects with NSCLC and 285.1 ± 11.3 MBq in those with HNSCC. The biodistribution of [¹⁸F]FSPG in both cohorts showed similar TACs in healthy organs from cancer patients. There was no statistically significant overall difference in the average SUV_max of tumor lesions at 60 min p.i. for NSCLC (8.1 ± 7.1) compared to HNSCC (6.0 ± 4.1; p = 0.29) for [¹⁸F]FSPG. However, there was heterogeneous retention between and within cancer types; the SUV_max at 60 min p.i. ranged from 1.4 to 23.7 in NSCLC and 3.1–12.1 in HNSCC. Conclusion: [¹⁸F]FSPG PET/CT imaging from both NSCLC and HNSCC cohorts showed the same normal-tissue biodistribution, but marked tumor heterogeneity across subjects and between lesions. Despite rapid elimination through the urinary tract and low normal-background tissue retention, the diagnostic potential of [¹⁸F]FSPG was limited by variability in tumor retention. As [¹⁸F]FSPG retention is mediated by the tumor’s antioxidant capacity and response to oxidative stress, this heterogeneity may provide important insights into an individual tumor’s response or resistance to therapy.