Header

UZH-Logo

Maintenance Infos

Synthesis and Photochemical Studies on Gallium and Indium Complexes of DTPA-PEG3-ArN3 for Radiolabeling Antibodies


Gut, Melanie; Holland, Jason P (2019). Synthesis and Photochemical Studies on Gallium and Indium Complexes of DTPA-PEG3-ArN3 for Radiolabeling Antibodies. Inorganic Chemistry, 58(18):12302-12310.

Abstract

Photochemistry is a rich source of inspiration for developing alternative methods to functionalize proteins with drug molecules, fluorophores, and radioactive probes. Here, we report the synthesis and photochemical reactivity of a modified diethylenediamine pentaacetic acid chelate that was derivatized with a light-responsive aryl azide group (DTPA-PEG3-ArN3, compound 1). The corresponding nonradioactive and radioactive nat/68Ga3+ and nat/111In3+ complexes of DTPA-PEG3-ArN3 were synthesized and their physical and photochemical properties were studied to evaluate the potential of employing this ligand system in the photochemical synthesis of radiolabeled antibodies. Photodegradation kinetics revealed that irradiation with ultraviolet light (365 nm) induced rapid photoactivation of compound 1 and the metal complexes nat/68Ga-1– and nat/111In-1–. Light-induced reactions were complete in <100 s, with measured first-order rate constants of 0.078 ± 0.045 s–1, 0.093 ± 0.009 s–1, and 0.117 ± 0.054 s–1 (n = 2, per species) for compound 1, natGa-1–, and natIn-1–, respectively. Photochemically induced bioconjugation reactions between DTPA-PEG3-ArN3 and the monoclonal antibody trastuzumab, as well as pre- and postconjugation 68Ga- and 111In-radiolabeling experiments, were performed using either a one-pot or two-step strategy. Both approaches yielded radiolabeled trastuzumab ([68Ga]GaDTPA-azepin-trastuzumab) with average radiochemical conversions of 3.9 ± 1.0% (n = 4, one-pot), and 10.0 ± 1.0% (n = 3, two-step). One-pot radiolabeling reactions with [111In]InCl3 produced the corresponding [111In]InDTPA-azepin-trastuzumab radiotracer in a similar radiochemical conversion of 5.4 ± 0.8% (n = 3). Radiochemical conversions for the desired bimolecular coupling between the chelate and the protein were comparatively low. This observation is likely caused by the high photoinduced reactivity of the compounds and subsequent competition with background reactions. Nevertheless, access to DTPA-PEG3-ArN3 increases the scope of photoradiochemical methods to include metal ions like In3+ that form complexes with higher coordination numbers.

Abstract

Photochemistry is a rich source of inspiration for developing alternative methods to functionalize proteins with drug molecules, fluorophores, and radioactive probes. Here, we report the synthesis and photochemical reactivity of a modified diethylenediamine pentaacetic acid chelate that was derivatized with a light-responsive aryl azide group (DTPA-PEG3-ArN3, compound 1). The corresponding nonradioactive and radioactive nat/68Ga3+ and nat/111In3+ complexes of DTPA-PEG3-ArN3 were synthesized and their physical and photochemical properties were studied to evaluate the potential of employing this ligand system in the photochemical synthesis of radiolabeled antibodies. Photodegradation kinetics revealed that irradiation with ultraviolet light (365 nm) induced rapid photoactivation of compound 1 and the metal complexes nat/68Ga-1– and nat/111In-1–. Light-induced reactions were complete in <100 s, with measured first-order rate constants of 0.078 ± 0.045 s–1, 0.093 ± 0.009 s–1, and 0.117 ± 0.054 s–1 (n = 2, per species) for compound 1, natGa-1–, and natIn-1–, respectively. Photochemically induced bioconjugation reactions between DTPA-PEG3-ArN3 and the monoclonal antibody trastuzumab, as well as pre- and postconjugation 68Ga- and 111In-radiolabeling experiments, were performed using either a one-pot or two-step strategy. Both approaches yielded radiolabeled trastuzumab ([68Ga]GaDTPA-azepin-trastuzumab) with average radiochemical conversions of 3.9 ± 1.0% (n = 4, one-pot), and 10.0 ± 1.0% (n = 3, two-step). One-pot radiolabeling reactions with [111In]InCl3 produced the corresponding [111In]InDTPA-azepin-trastuzumab radiotracer in a similar radiochemical conversion of 5.4 ± 0.8% (n = 3). Radiochemical conversions for the desired bimolecular coupling between the chelate and the protein were comparatively low. This observation is likely caused by the high photoinduced reactivity of the compounds and subsequent competition with background reactions. Nevertheless, access to DTPA-PEG3-ArN3 increases the scope of photoradiochemical methods to include metal ions like In3+ that form complexes with higher coordination numbers.

Statistics

Citations

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

Altmetrics

Downloads

2 downloads since deposited on 07 Feb 2020
2 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Uncontrolled Keywords:Physical and Theoretical Chemistry, Inorganic Chemistry
Language:English
Date:16 September 2019
Deposited On:07 Feb 2020 15:36
Last Modified:07 Feb 2020 15:37
Publisher:American Chemical Society (ACS)
ISSN:0020-1669
OA Status:Closed
Publisher DOI:https://doi.org/10.1021/acs.inorgchem.9b01802
Project Information:
  • : FunderSNSF
  • : Grant IDPP00P2_163683
  • : Project TitleAdvanced radiochemical methods for multi-modal imaging with nanomedicines
  • : FunderH2020
  • : Grant ID676904
  • : Project TitleNanoSCAN - Developing multi-modality nanomedicines for targeted annotation of oncogenic signaling pathways
  • : FunderKrebsliga
  • : Grant IDKLS-4257-08-2017
  • : Project Title

Download

Closed Access: Download allowed only for UZH members