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

• DOI: 10.1007/s00259-021-05661-0
• Publication Date: 2021-12-21T05:02:25Z
• Authors: Bastiaan M. Privé; Yvonne H. W. Derks; Florian Rosar; Gerben M. Franssen; Steffie M. B. Peters; Fadi Khreish; Mark Bartholomä; Stephan Maus; Martin Gotthardt; Peter Laverman; Mark W. Konijnenberg; Samer Ezziddin; James Nagarajah; Sandra Heskamp
• Keywords: Mice, Nude; Lutetium; Ligands; Heterocyclic Compounds, 1-Ring; Mice; 03 medical and health sciences; 0302 clinical medicine; Cell Line, Tumor; Positron Emission Tomography Computed Tomography; Medical Imaging - Radboud University Medical Center; Animals; Humans; Tissue Distribution; Radioisotopes; Radboudumc 19: Nanomedicine RIMLS: Radboud Institute for Molecular Life Sciences; Dipeptides; Prostate-Specific Antigen; Radboudumc 14: Tumours of the digestive tract RIHS: Radboud Institute for Health Sciences; Radboudumc 9: Rare cancers RIMLS: Radboud Institute for Molecular Life Sciences; 3. Good health; Radboudumc 14: Tumours of the digestive tract RIMLS: Radboud Institute for Molecular Life Sciences; Positron-Emission Tomography; Radiopharmaceuticals; Radboudumc 0: Other Research RIHS: Radboud Institute for Health Sciences

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.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.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.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.