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Tuning Tetrazole Photochemistry for Protein Ligation and Molecular Imaging
Author(s) -
Fay Rachael,
Holland Jason P.
Publication year - 2021
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202100061
Subject(s) - tetrazole , chemistry , biodistribution , labelling , chelation , reagent , combinatorial chemistry , radiochemistry , ligand (biochemistry) , in vitro , photochemistry , stereochemistry , receptor , organic chemistry , biochemistry
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 89 Zr, 64 Cu and 68 Ga radionuclides. DFO‐tetrazole ( 1 ) was assessed by direct conjugation to formulated trastuzumab and subsequent radiolabelling with 89 Zr. 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.