⁸⁹Zr-labeled PSMA ligands for pharmacokinetic PET imaging and dosimetry of PSMA-617 and PSMA-I&T: a preclinical evaluation and first in man

Rationale: Prolonged in vivo evaluation of PSMA tracers could improve tumor imaging and patient selection for ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-PSMA-I&T. In this study, we present the radiolabeling method of PSMA-617 and PSMA-I&T with the long-lived positron emitter ⁸⁹Zr to enable PET imaging up to 7 days post-injection. We compared the biodistribution of ⁸⁹Zr-PSMA-617 and ⁸⁹Zr-PSMA-I&T to those of ¹⁷⁷Lu-PSMA-617 and ¹⁷⁷Lu-PSMA-I&T, respectively, in a PSMA⁺ xenograft model. Moreover, we provide the first human ⁸⁹Zr-PSMA-617 images.

Materials and methods: PSMA ligands were labeled with 50-55 MBq [⁸⁹Zr]ZrCl₄ using a two-step labeling protocol. For biodistribution, BALB/c nude mice bearing PSMA⁺ and PSMA^- xenografts received 0.6 µg (0.6-1 MBq) of ⁸⁹Zr-PSMA-617, ⁸⁹Zr-PSMA-I&T, ¹⁷⁷Lu-PSMA-617, or ¹⁷⁷Lu-PSMA-I&T intravenously. Ex vivo biodistribution and PET/SPECT imaging were performed up to 168 h post-injection. Dosimetry was performed from the biodistribution data. The patient received 90.5 MBq ⁸⁹Zr-PSMA-617 followed by PET/CT imaging.

Results: ⁸⁹Zr-labeled PSMA ligands showed a comparable ex vivo biodistribution to its respective ¹⁷⁷Lu-labeled counterparts with high tumor accumulation in the PSMA⁺ xenografts. However, using a dose estimation model for ¹⁷⁷Lu, absorbed radiation dose in bone and kidneys differed among the ¹⁷⁷Lu-PSMA and ⁸⁹Zr-PSMA tracers. ⁸⁹Zr-PSMA-617 PET in the first human patient showed high contrast of PSMA expressing tissues up to 48 h post-injection.

Conclusion: PSMA-617 and PSMA-I&T were successfully labeled with ⁸⁹Zr and demonstrated high uptake in PSMA⁺ xenografts, which enabled PET up to 168 h post-injection. The biodistribution of ⁸⁹Zr-PSMA-I&T and ⁸⁹Zr-PSMA-617 resembled that of ¹⁷⁷Lu-PSMA-I&T and ¹⁷⁷Lu-PSMA-617, respectively. The first patient ⁸⁹Zr-PSMA-617 PET images were of high quality warranting further clinical investigation.