First-in-Human PET Imaging of Prostate Cancer Using [ ⁶⁸ Ga]Ga-AZ-093 and Its Nitroimidazole-Conjugated Derivative [ ⁶⁸ Ga]Ga-AZ-NI-093

Our team previously reported a preclinical study of 2 novel prostate-specific membrane antigen (PSMA)-targeted compounds that incorporate a hypoxia-sensitive nitroimidazole (NI) moiety-6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid-PSMA-093 (AZ-093) and its hypoxia-responsive derivative 6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid-NI-PSMA-093 (AZ-NI-093). This prospective trial aims to evaluate the clinical value of both agents in patients with prostate cancer, specifically exploring the impact of NI on tumor uptake. <b>Methods:</b> Sixty patients were enrolled in this PET/CT imaging study. Thirty patients underwent a head-to-head comparison of [⁶⁸Ga]Ga-AZ-093 with [⁶⁸Ga]Ga-PSMA-11 or [⁶⁸Ga]Ga-PSMA-617, and 30 patients underwent a head-to-head comparison of [⁶⁸Ga]Ga-AZ-NI-093 with [⁶⁸Ga]Ga-AZ-093. The number of tumors and SUV for tumors and organs were measured and recorded. SUV_max differences between [⁶⁸Ga]Ga-AZ-NI-093 and [⁶⁸Ga]Ga-AZ-093 PET/CT were calculated for further analysis. Immunohistochemical staining for hypoxia-inducible factor 1 was performed on 12 surgical specimens of intraprostatic tumors. <b>Results:</b> All patients tolerated [⁶⁸Ga]Ga-based PET/CT scans without adverse effects. The initial biodistribution of [⁶⁸Ga]Ga-AZ-093 and [⁶⁸Ga]Ga-AZ-NI-093 in humans, as assessed by PET/CT, was comparable to that of other PSMA-targeted radiopharmaceuticals, with respective effective absorbed doses of 0.0128 ± 0.00594 and 0.0160 ± 0.000869 mSv/MBq. [⁶⁸Ga]Ga-AZ-093 exhibited higher tumor uptake 60 min after injection compared with [⁶⁸Ga]Ga-PSMA-11 (SUV_max, 22.2 ± 10.8 vs. 20.4 ± 14.8; <i>P</i> = 0.025) and [⁶⁸Ga]Ga-PSMA-617 (SUV_max, 20.1 ± 12.7 vs. 10.8 ± 8.7; <i>P</i> < 0.001), while maintaining comparable tumor detection rates. [⁶⁸Ga]Ga-AZ-NI-093 showed further improved tumor uptake relative to [⁶⁸Ga]Ga-AZ-093 at 60 min (SUV_max, 17.8 ± 14.0 vs. 16.3 ± 11.5; <i>P</i> = 0.009) and 150 min (31.3 ± 18.5 vs. 28.7 ± 17.5; <i>P</i> = 0.003), especially in large-volume, high-grade intraprostatic tumor and metastatic sites. The expression of hypoxia-inducible factor 1 in tumors, as an indicator of hypoxia, demonstrated a significant association with International Society of Urological Pathology grade (<i>r</i> = 0.519; <i>P</i> = 0.038) and difference in SUV_max (<i>r</i> = 0.629; <i>P</i> = 0.023). <b>Conclusion:</b> Both [⁶⁸Ga]Ga-AZ-093 and [⁶⁸Ga]Ga-AZ-NI-093 represent promising PSMA-targeted radiopharmaceuticals. [⁶⁸Ga]Ga-AZ-NI-093 demonstrated potential in targeting hypoxic tumor tissues. Future studies with larger sample sizes are needed to further explore the clinical value of these radiopharmaceuticals.