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

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 Tc-99m-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 Tc-99m-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 Tc-99m-counterparts that reacted with trans-cyclooctene modified-bevacizumab and recognized cells that overexpress vascular endothelial growth factor (VEGF). Additionally, the in vivo Tc-99m-counterparts-biodistributions were studied, on the desired organs, and they resulted dependent of lipophilicity.