A pH-dependant structural study on Ga3+complexes with monoamide derivatives of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) for PET applications

Abstract

All reported 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) derivatives for 68Ga labeling include a branched linker or an extra acetic acid, which require time-consuming multi-step syntheses. We synthesized two monoamide derivatives of NOTA conjugated with methylamine or benzylamine to see the possibility of stable Ga3+ complex formation. Ga3+ complexes were synthesized at different chelating pH values (3 and 5) and characterized by single crystal X-ray diffraction and multinuclear nuclear magnetic resonance (NMR) spectroscopy. Crystals were obtained by slow evaporation of ethanol and water solution. X-ray crystal analysis showed the metal coordination to either nitrogen or oxygen atom of the amide bond at different chelation pH to form stable hexadentate complex. At pH 5, both ligands showed coordination to amide nitrogen. However, at pH 3, oxygen atom of amide bond was coordinated with gallium in case of benzylamine derivative, while methylamine derivative always showed nitrogen coordination. In solution chemistry, 71Ga NMR at range of pH showed possibility of two different coordination. Variable temperature 1H NMR spectroscopy showed the rigidity of these complexes. This finding could open up a wide range of applications for NOTA type bifunctional chelating agents by eliminating the multi-step synthesis required to introduce extra linkers.