An 89Zr-labeled PSMA tracer for PET/CT imaging of prostate cancer patients

The short half-life of existing prostate-specific membrane antigen (PSMA) tracers limits their time for internalization into tumor cells after injection, which is an essential prerequisite for robust detection of tumor lesions with low PSMA expression on PET/CT scans. Due to its longer half-life, the 89Zr-labeled ligand 89Zr-PSMA-Df allows acquisition of PET scans up to 6 days after injection, thereby overcoming the above limitation. We investigated whether 89Zr-PSMA-Df allowed more sensitive detection of weak PSMA-positive prostate cancer lesions. Methods: We selected 14 prostate cancer patients with biochemical recurrence who exhibited no PSMA-positive lesions on a PET scan acquired with existing PSMA tracers (68Ga-PSMA-11, 18F-JK-PSMA-7). Within 5 weeks after the negative scan, we performed a second PSMA-PET scan using 89Zr-PSMA-Df (117±16 MBq, PET acquisition within 6 days of injection). Results:89Zr-PSMA-Df detected 15 PSMA-positive lesions in 8/14 patients, who had a PET-negative reading of their initial PET scans with existing tracers. In these 8 patients, the new scans revealed localized recurrence of disease (3/8), metastases in lymph nodes (3/8), or lesions at distant sites (2/8). Based on these results, patients received lesion-targeted radiotherapies (5/8), androgen deprivation therapies (2/8), or no therapy (1/8). The plausibility of 14/15 lesions was supported by histology, clinical follow-up after radiotherapy or subsequent imaging. Furthermore, comparison of the 15 89Zr-PSMA-Df-positive lesions with their correlates on the original PET scan revealed that established tracers exhibited mild accumulation in 7/15 lesions but contrast-to-noise ratios (CNR) were too low for robust detection of these lesions (CNR 2.4±3.7 for established tracers vs. 10.2±8.5 for 89Zr-PSMA-Df, P = 0.0014). The SUVmax of the 15 89Zr-PSMA-Df-positive lesions (11.5±5.8) was significantly higher than the SUVmax on the original PET scans (4.7±2.8, P = 0.0001). Kidneys were the most exposed organ with doses of 3.3±0.7 mGy/MBq. The effective dose was 0.15±0.04 mSv/MBq. Conclusion: In patients with weak PSMA expression, a longer period of time might be needed for ligand internalization than that offered by existing PSMA tracers to make lesions visible on PET/CT scans. Hence, 89Zr-PSMA-Df might be of significant benefit to patients in whom the search for weak PSMA-positive lesions is challenging. Radiation exposure should be weighed against the potential benefit of metastasis-directed therapy or salvage radiotherapy, which we initiated in 36% (5/14) of our patients based on their 89Zr-PSMA-Df PET scans.