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Tuning Tetrazole Photochemistry for Protein Ligation and Molecular Imaging


Fay, Rachael; Holland, Jason P (2021). Tuning Tetrazole Photochemistry for Protein Ligation and Molecular Imaging. Chemistry - A European Journal, 27(15):4893-4897.

Abstract

Photochemistry provides a wide range of alternative reagents that hold potential for use in bimolecular functionalisation of proteins. Here, we report the synthesis and characterisation of metal ion binding chelates derivatised with disubstituted tetrazoles for the photoradiochemical labelling of monoclonal antibodies (mAbs). The photophysical properties of tetrazoles featuring extended aromatic systems and auxochromic substituents to tune excitation toward longer wavelengths (365 and 395 nm) were studied. Two photoactivatable chelates based on desferrioxamine B (DFO) and the aza-macrocycle NODAGA were functionalised with a tetrazole and developed for protein labelling with 89Zr, 64Cu and 68Ga radionuclides. DFO-tetrazole (1) was assessed by direct conjugation to formulated trastuzumab and subsequent radiolabelling with 89Zr. Radiochemical studies and cellular-based binding assays demonstrated that the radiotracer remained stable in vitro retained high immunoreactivity. Positron emission tomography (PET) imaging and biodistribution studies were used to measure the tumour specific uptake and pharmacokinetic profile in mice bearing SK-OV-3 xenografts. Experiments demonstrate that tetrazole-based photochemistry is a viable approach for the light-induced synthesis of PET radiotracers.

Abstract

Photochemistry provides a wide range of alternative reagents that hold potential for use in bimolecular functionalisation of proteins. Here, we report the synthesis and characterisation of metal ion binding chelates derivatised with disubstituted tetrazoles for the photoradiochemical labelling of monoclonal antibodies (mAbs). The photophysical properties of tetrazoles featuring extended aromatic systems and auxochromic substituents to tune excitation toward longer wavelengths (365 and 395 nm) were studied. Two photoactivatable chelates based on desferrioxamine B (DFO) and the aza-macrocycle NODAGA were functionalised with a tetrazole and developed for protein labelling with 89Zr, 64Cu and 68Ga radionuclides. DFO-tetrazole (1) was assessed by direct conjugation to formulated trastuzumab and subsequent radiolabelling with 89Zr. Radiochemical studies and cellular-based binding assays demonstrated that the radiotracer remained stable in vitro retained high immunoreactivity. Positron emission tomography (PET) imaging and biodistribution studies were used to measure the tumour specific uptake and pharmacokinetic profile in mice bearing SK-OV-3 xenografts. Experiments demonstrate that tetrazole-based photochemistry is a viable approach for the light-induced synthesis of PET radiotracers.

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Additional indexing

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 > Catalysis
Physical Sciences > Organic Chemistry
Uncontrolled Keywords:General Chemistry, Catalysis, Organic Chemistry
Language:English
Date:12 March 2021
Deposited On:21 Jan 2022 06:00
Last Modified:26 Feb 2024 02:44
Publisher:Wiley-VCH Verlag
ISSN:0947-6539
OA Status:Green
Publisher DOI:https://doi.org/10.1002/chem.202100061
Project Information:
  • : FunderSNSF
  • : Grant IDPP00P2_163683
  • : Project TitleAdvanced radiochemical methods for multi-modal imaging with nanomedicines
  • : FunderSNSF
  • : Grant IDPP00P2_190093
  • : Project TitleRadiochemistry in a Flash: Advanced methods for the synthesis of multi-modal imaging agents
  • : FunderKrebsliga
  • : Grant IDKLS-4257-08-2017
  • : Project Title
  • Content: Accepted Version