89 Zr-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 177 Lu-PSMA-617 and 177 Lu-PSMA-I&T. In this study, we present the radiolabeling method of PSMA-617 and PSMA-I&T with the long-lived positron emitter 89 Zr to enable PET imaging up to 7 days post-injection. We compared the biodistribution of 89 Zr-PSMA-617 and 89 Zr-PSMA-I&T to those of 177 Lu-PSMA-617 and 177 Lu-PSMA-I&T, respectively, in a PSMA + xenograft model. Moreover, we provide the first human 89 Zr-PSMA-617 images. Materials and methods PSMA ligands were labeled with 50-55 MBq [ 89 Zr]ZrCl 4 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 89 Zr-PSMA-617, 89 Zr-PSMA-I&T, 177 Lu-PSMA-617, or 177 Lu-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 89 Zr-PSMA-617 followed by PET/CT imaging. Results 89 Zr-labeled PSMA ligands showed a comparable ex vivo biodistribution to its respective 177 Lu-labeled counterparts with high tumor accumulation in the PSMA + xenografts. However, using a dose estimation model for 177 Lu, absorbed radiation dose in bone and kidneys differed among the 177 Lu-PSMA and 89 Zr-PSMA tracers. 89 Zr-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 89 Zr and demonstrated high uptake in PSMA + xenografts, which enabled PET up to 168 h post-injection. The biodistribution of 89 Zr-PSMA-I&T and 89 Zr-PSMA-617 resembled that of 177 Lu-PSMA-I&T and 177 Lu-PSMA-617, respectively. The first patient 89 Zr-PSMA-617 PET images were of high quality warranting further clinical investigation.