HNODThia: A Promising Chelator for the Development of 64 Cu Radiopharmaceuticals.

Herein, we present the synthesis and coordination chemistry of copper(II) and zinc(II) complexes of two novel heterocyclic triazacyclononane (tacn)-based chelators (H NODThia and NODThia-AcNHEt ). The chelator H NODThia was further derivatized to obtain a novel PSMA-based bioconjugate ( NODThia-PSMA ) and a bifunctional photoactivatable azamacrocyclic analogue, NODThia-PEG 3 -ArN 3 , for the development of copper-64 radiopharmaceuticals. 64 Cu radiolabeling experiments were performed on the different metal-binding chelates, whereby quantitative radiochemical conversion (RCC) was obtained in less than 10 min at room temperature. The in vitro stability of NODThia-PSMA in human plasma was assessed by ligand-challenge and copper-exchange experiments. Next, we investigated the viability of the photoactivatable analog ( NODThia-PEG 3 -ArN 3 ) for the light-induced photoradiosynthesis of radiolabeled proteins. One-pot photoconjugation reactions to human serum albumin (HSA) as a model protein and the clinically relevant monoclonal antibody formulation MetMAb were performed. [ 64 Cu]Cu- 7 -azepin-HSA and [ 64 Cu]Cu- 7 -azepin-onartuzumab were prepared in less than 15 min by irradiation at 395 nm, with radiochemical purities (RCP) of >95% and radiochemical yields (RCYs) of 42.7 ± 5.3 and 49.6%, respectively. Together, the results obtained here open the way for the development of highly stable 64 Cu-radiopharmaceuticals by using aza -heterocyclic tacn-based chelators, and the method can easily be extended to the development of 67 Cu radiopharmaceuticals for future applications in molecularly targeted radio(immuno)therapy.