Looking for New [1,2,4,5]Tetrazines to Produce ^99mTc‐Labelled Derivatives, with a Suitable Lipophilicity Balance for Use in Bioorthogonal Reactions

Abstract

The reaction between [1,2,4,5]tetrazines with trans‐cyclooctene through the cycloaddition process has been described as a powerful tool in bioorthogonal processes. Specifically the diagnostic with fluorescent‐ and radio‐labelled [1,2,4,5]tetrazines and pre‐targeted trans‐cyclooctene modified‐antibody has been used by us for this purpose. Our previously developed 99mTc‐radiolabelled [1,2,4,5]tetrazine‐derivatives porting 6‐hydrazinonicotinyl‐chelator displayed some limitations related to its unappropriated biodisposal. Herein, we explored [1,2,4,5]tetrazines porting other 99mTc‐coordination‐moieties, 1,4,8,11‐tetrazacyclotetradecanyl and diethylenetriaminepentaacetyl, as potential hydrophilic functions. Some of the new modified [1,2,4,5]tetrazines were able to coordinate efficiently the radionuclide generating 99mTc‐counterparts that reacted with trans‐cyclooctene modified‐bevacizumab and recognized cells that overexpress vascular endothelial growth factor (VEGF). Additionally, the in vivo 99mTc‐counterparts‐biodistributions were studied, on the desired organs, and they resulted dependent of lipophilicity.