Radiolabeling of PSMA-617 with Zr: A Novel Use of DMSO to Improve Radiochemical Yield and Preliminary Small-animal PET Results

Introduction: Novel diagnostic and therapeutic options are urgently needed for patients with metastatic castration-resistant prostate cancer (CRPC). PSMA-617 is one of the most promising ligands that bind to prostate specific membrane antigen (PSMA), the cell surface biomarker of CRPC. Of the radiolabeled PSMA ligands developed to date, [Ga]Ga-PSMA-617 is most commonly used for PSMA positron emission tomography (PET) prior to radioligand therapy (RLT) with [Lu]Lu-PSMA-617. However, the presence of Ga radioactivity (half-life 68 m) in urine at the early PET imaging time point complicates optimization of the therapeutic dose of PSMA-617 labeled with Lu (half-life 6.7 d). Thus, PET imaging with the long-lived positron emitter Zr (half-life 3.3 d) would be better suited in order to optimize the dose of [Lu]Lu-PSMA-617 as Zr PET allows scans after excretion of the radioactive urine. Until now, PSMA-617 could not be radiolabeled with Zr with high radiochemical yield due to poor incorporation of Zr into 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Here we report a novel method for radiolabeling PSMA-617 with Zr and the preliminary results of small-animal PET with [Zr]Zr-PSMA-617.

Methods: We labeled PSMA-617 with Zr in a 1:1 mixture of DMSO and HEPES buffer at 90 °C for 30 min, followed by quality control analysis by HPLC. We then determined the dissociation constant (K) and logD values of [Zr]Zr-PSMA-617. We obtained PET images of [Zr]Zr-PSMA-617 at 24 h in mice bearing both LNCaP (PSMA-positive) and PC-3 (PSMA-negative) tumors (N = 5). The ex vivo [Zr]Zr-PSMA-617 biodistribution was then examined separately using tissue samples of LNCaP-bearing mice at 2 h (N = 4) and 24 h (N = 4).

Results: [Zr]Zr-PSMA-617 was prepared with a radiochemical yield of 70 ± 9%. The K value was 6.8 ± 3.5 nM. The logD value was -4.05 ± 0.20. PET images showed the highest uptake in LNCaP tumors (maximum standardized uptake value, SUV = 0.98 ± 0.32) and low uptake in kidneys (SUV = 0.18 ± 0.7) due to the absence of urine radioactivity.

Conclusion: [Zr]Zr-PSMA-617 was successfully prepared using DMSO and HEPES buffer. [Zr]Zr-PSMA-617 visualized PSMA-positive LNCaP tumors in the absence of radioactive urine 24 h p.i.

Advances In Knowledge And Implications For Patient Care: This method of radiolabeling PSMA-617 with Zr using DMSO would be suitable for future clinical trials. Prediction of radiation dose by using [Zr]Zr-PSMA-617 leads to the safe and effective RLT with [Lu]Lu-PSMA-617.