[64Cu]Cu-NODAGA-PSMA-617 targeted prostate cancer PET imaging: From radiotracer development to initial clinical PET imaging at early and late time points

Introduction The demand for theranostic radiotracers enabling diagnosis and targeted radioligand therapy (TRT) of prostate cancer continues to increase. Radiocopper (Cu)-labeled radiopharmaceuticals offer advantages over established 18 F- and 68 Ga-labeled compounds, enabling a chemically identical theranostic approach with PET imaging using 61 Cu and 64 Cu, patient-specific dosimetry, and TRT with 67 Cu. The longer physical half-life of 64 Cu also allows wider geographical distribution and delayed PET imaging. Methods This initial clinical evaluation assessed the feasibility of [ 64 Cu]Cu-NODAGA-PSMA-617-PET for prostate cancer imaging, encompassing radiopharmaceutical development, preclinical characterization, and clinical application. NODAGA-PSMA-617 was synthesized and radiolabeled with 64 Cu, followed by in vitro characterization of binding specificity, affinity, and internalization using PSMA-expressing LNCaP cells. Early (3 h p. i.) and late [ 64 Cu]Cu-NODAGA-PSMA-617-PET/CT (24 h p. i.) was performed in a patient with biochemical recurrence of prostate cancer after R1 radical prostatectomy and an unremarkable reference [ 68 Ga]Ga-PSMA-11-PET/CT. Results In vitro studies demonstrated high specific binding and internalization of [ 64 Cu]Cu-NODAGA-PSMA-617, with binding affinity and internalization characteristics comparable to similar monovalent PSMA ligands. Radiolabeling of NODAGA-PSMA-617 with 64 Cu was achieved with high yield (>98 %) and molar activity (27.8 - 45.4 MBq/nmol). The radiotracer showed stable in vivo and target-typical biodistribution. The physical half-life of 64 Cu enabled PET imaging up to 24 h after intravenous bolus injection, revealing focal tracer uptake in the former prostate region that was not clearly detectable on early 64 Cu-PET/CT at 3 h post-injection or on a previous reference [ 68 Ga]Ga-PSMA-11-PET/CT. Conclusion This study demonstrated the successful development, radiolabeling, in vitro characterization, and initial clinical evaluation of [ 64 Cu]Cu-NODAGA-PSMA-617 for early and late PSMA-PET/CT imaging. Late 64 Cu-PET imaging may provide an extended imaging window for PSMA-targeting radiopharmaceuticals. The observed delayed tracer uptake represents a proof-of-concept finding requiring systematic evaluation in a larger cohort. These preliminary findings supports further clinical investigation of [ 64 Cu]Cu-NODAGA-PSMA-617 within a theranostic radiocopper-based framework.