Header

UZH-Logo

Maintenance Infos

HNODThia: A Promising Chelator for the Development of $^{64}$Cu Radiopharmaceuticals


Hierlmeier, Ina; Guillou, Amaury; Earley, Daniel F; Linden, Anthony; Holland, Jason P; Bartholomä, Mark D (2023). HNODThia: A Promising Chelator for the Development of $^{64}$Cu Radiopharmaceuticals. Inorganic Chemistry, 62(50):20537-20558.

Abstract

Herein, we present the synthesis and coordination chemistry of copper(II) and zinc(II) complexes of two novel heterocyclic triazacyclononane (tacn)-based chelators (HNODThia and NODThia-AcNHEt). The chelator HNODThia 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.

Abstract

Herein, we present the synthesis and coordination chemistry of copper(II) and zinc(II) complexes of two novel heterocyclic triazacyclononane (tacn)-based chelators (HNODThia and NODThia-AcNHEt). The chelator HNODThia 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.

Statistics

Citations

Dimensions.ai Metrics
1 citation in Web of Science®
1 citation in Scopus®
Google Scholar™

Altmetrics

Downloads

0 downloads since deposited on 20 Feb 2024
0 downloads since 12 months

Additional indexing

Other titles:HNODThia: A Promising Chelator for the Development of 64Cu Radiopharmaceuticals
Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Scopus Subject Areas:Physical Sciences > Physical and Theoretical Chemistry
Physical Sciences > Inorganic Chemistry
Uncontrolled Keywords:Inorganic Chemistry, Physical and Theoretical Chemistry
Language:English
Date:24 July 2023
Deposited On:20 Feb 2024 07:57
Last Modified:30 Jun 2024 01:37
Publisher:American Chemical Society (ACS)
ISSN:0020-1669
OA Status:Closed
Publisher DOI:https://doi.org/10.1021/acs.inorgchem.3c01616
PubMed ID:37487036
Project Information:
  • : FunderH2020
  • : Grant ID101034329
  • : Project TitleWINNINGNormandy - WelcomINg and TraiNING of international high-level post-docs in Normandy
  • : FunderH2020
  • : Grant ID676904
  • : Project TitleNanoSCAN - Developing multi-modality nanomedicines for targeted annotation of oncogenic signaling pathways
  • : FunderH2020
  • : Grant ID101001734
  • : Project TitlePhotoPHARMA - Light-induced synthesis of protein-drug conjugates for imaging and therapy