A UV-Vis method for investigation of gallium(iii) complexation kinetics with NOTA and TRAP chelators: advantages, limitations and comparison with radiolabelling

An easy and cheap method for measurement of Ga^III complexation kinetics was developed. The method is based on UV-Vis quantification of non-complexed chelators after the addition of Cu^II ions at individual time points. The method was evaluated using established ligands, H₃nota and H₆notP^Pr, and was utilized to study the kinetics of Ga^III complexation with four new symmetric derivatives of 1,4,7-triazacyclononane bearing methylphosphonate/phosphinate pendant arms - TRAP ligands. Chelators bearing ethoxy groups (H₃L1) or 2,2,2-trifluoroethyl groups (H₃L2) on the phosphorus atoms showed fast formation (t_99% = 21 and 10 min, respectively, at pH 2.0) and efficient radiolabelling which were comparable to the previously reported chelators bearing the 2-carboxyethyl group (H₆notP^Pr). Chelators bearing (N,N-dibenzyl-amino)methyl (H₃L3) and aminomethyl (H₃L4) substituents showed a significantly slower complexation (t_99% = 4.4 and 3.6 h, respectively, at pH 2.0) and inefficient radiolabelling, mainly at room temperature or low pH. This was caused by protonation of the amino groups of the pendant arms leading to coulombic repulsion between the Ga^III ion and the positively charged protonated amines. The trends in complexation rates determined by the UV-Vis method correlated well with the results of the ⁶⁸Ga radiolabelling study.