Preclinical and First-In-Human Evaluation of ⁶⁸Ga-PSMA-33, a Novel PSMA Radiotracer with Low Background Signal

this study aimed to investigate the potential of a novel ⁶⁸Ga-labeled PSMA-targeted radiotracer, ⁶⁸Ga-PSMA-33, as a diagnostic tool for prostate cancer in preclinical and pilot clinical studies.

⁶⁸Ga-PSMA-33 was radiolabeled using an iQS-TS automated module, and its radiochemical purity and in vitro stability were analyzed via radio-HPLC. The specificity and binding affinity for PSMA were determined in LNCaP (PSMA+) cells. A head-to-head comparison with ⁶⁸Ga-PSMA-617 was performed in murine models through biodistribution, pharmacokinetic, and micro-PET/CT imaging studies. The clinical phase involved ⁶⁸Ga-PSMA-33 PET/CT imaging in seven patients with prostate cancer, two of whom also underwent ⁶⁸Ga-PSMA-617 imaging for direct comparison. Semiquantitative assessment of physiologic biodistribution and tumor burden was conducted, and the radiation dosimetry of 68Ga-PSMA-33 was estimated.

⁶⁸Ga-PSMA-33 was efficiently prepared with a labeling yield of 77.5 ± 7.23%, radiochemical purity exceeding 99%, and specific activity of 45.28 ± 6.37 GBq/μmol. The labeled compound demonstrated a high affinity for PSMA (0.103 ± 0.03 nM), along with high hydrophilicity (Log P = -2.84 ± 0.13). Micro-PET/CT imaging revealed rapid clearance and prominent tumor uptake of the tracer, achieving a significantly higher tumor-to-muscle ratio than ⁶⁸Ga-PSMA-617 (88.85 ± 8.39 vs 30.18 ± 3.39, p < 0.001) at 4 h postinjection. A total of nearly 400 tumor lesions were identified in PET/CT imaging across the 7 patients with prostate cancer. The mean SUVmax values of primary tumors, lymph node metastases, liver metastases, and bone metastases were 22.24 ± 4.77, 10.48 ± 2.16, 21.76 ± 3.82, and 30.25 ± 2.80 at 1 h postinjection, respectively. Clinical ⁶⁸Ga-PSMA-33 PET/CT studies further confirmed its favorable biodistribution and kinetics, exhibiting a significantly higher tumor-to-muscle ratio than ⁶⁸Ga-PSMA-617 at 3 h postinjection in both lymph node metastases (23.64 ± 6.68 vs 17.47 ± 7.53, p < 0.01) and bone metastases (83.33 ± 18.80 vs 61.63 ± 13.26, p < 0.001). The radiation dose of ⁶⁸Ga-PSMA-33 was within an acceptable range, with an effective dose of (7.38 ± 1.44) × 10^-3 mSv/MBq. The kidneys were the critical organ, receiving the highest absorbed dose of (7.35 ± 2.64) × 10^-2 mGy/MBq.

⁶⁸Ga-PSMA-33 demonstrated comparable tumor uptake while providing a higher tumor-to-background ratio and lower radiation exposure than ⁶⁸Ga-PSMA-617, making it a promising novel tracer for prostate cancer diagnosis.