Cu-PSMA-Targeted PET for Prostate Cancer: From Radiotracer Development to First-in-Human Imaging.

The demand for PET tracers that target prostate-specific membrane antigen (PSMA) continues to increase. Meeting this demand with approved Ga- and F-labeled PSMA tracers is challenging outside of major urban centers. This is because the short physical half-life of these radionuclides makes it necessary to produce them near their sites of usage. To overcome this challenge, we propose cyclotron-produced Cu for labeling PSMA PET tracers. Cu can be produced on a large scale, and its 3.33-h half-life allows shipping over considerably longer distances than possible for Ga and F. Production of true theranostic twins using Cu and the β-emitter Cu is also feasible. PSMA-I&T (DOTAGA-(l-y)fk(sub-KuE)) and its derivative in which the DOTAGA chelator was replaced by NODAGA (NODAGA-(l-y)fk(sub-KuE)), herein reported as DOTAGA-PSMA-I&T and NODAGA-PSMA-I&T, respectively, were labeled with Cu and compared with [Ga]Ga-DOTAGA-PSMA-I&T, [Ga]Ga-NODAGA-PSMA-I&T, [Ga]Ga-PSMA-11, and [F]PSMA-1007. In vitro (lipophilicity, affinity, cellular uptake, and distribution) and in vivo (PET/CT, biodistribution, and stability) studies were performed in LNCaP cells and xenografts. Human dosimetry estimates were calculated for [Cu]Cu-NODAGA-PSMA-I&T. First-in-human imaging with [Cu]Cu-NODAGA-PSMA-I&T was performed in a patient with metastatic prostate cancer. [Cu]Cu-DOTAGA-PSMA-I&T and [Cu]Cu-NODAGA-PSMA-I&T were synthesized with radiochemical purity of more than 97%, at an apparent molar activity of 24 MBq/nmol, without purification after labeling. In vitro, natural Cu (Cu)-DOTAGA-PSMA-I&T and Cu-NODAGA-PSMA-I&T showed high affinity for PSMA (inhibitory concentration of 50%, 11.2 ± 2.3 and 9.3 ± 1.8 nM, respectively), although lower than the reference Ga-PSMA-11 (inhibitory concentration of 50%, 2.4 ± 0.4 nM). Their cellular uptake and distribution were comparable to those of [Ga]Ga-PSMA-11. In vivo, [Cu]Cu-NODAGA-PSMA-I&T showed significantly lower uptake in nontargeted tissues than [Cu]Cu-DOTAGA-PSMA-I&T and higher tumor uptake (14.0 ± 5.0 percentage injected activity per gram of tissue [%IA/g]) than [Cu]Cu-DOTAGA-PSMA-I&T (6.06 ± 0.25 %IA/g, = 0.0059), [Ga]Ga-PSMA-11 (10.2 ± 1.5 %IA/g, = 0.0972), and [F]PSMA-1007 (9.70 ± 2.57 %IA/g, = 0.080) at 1 h after injection. Tumor uptake was also higher for [Cu]Cu-NODAGA-PSMA-I&T at 4 h after injection (10.7 ± 3.3 %IA/g) than for [Cu]Cu-DOTAGA-PSMA-I&T (4.88 ± 0.63 %IA/g, = 0.0014) and [F]PSMA-1007 (6.28 ± 2.19 %IA/g, = 0.0145). Tumor-to-nontumor ratios of [Cu]Cu-NODAGA-PSMA-I&T were superior to those of [Cu]Cu-DOTAGA-PSMA-I&T and comparable to those of [Ga]Ga-PSMA-11 and [F]PSMA-1007 at 1 h after injection and increased significantly between 1 and 4 h after injection in most cases. Human dosimetry estimates for [Cu]Cu-NODAGA-PSMA-I&T were similar to the ones reported for F-PSMA ligands. First-in-human imaging demonstrated multifocal osseous and hepatic metastases. [Cu]Cu-NODAGA-PSMA-I&T is a promising PSMA radiotracer that compares favorably with [Ga]Ga-PSMA-11 and [F]PSMA-1007, while allowing delayed imaging.