The influence of the combination of carboxylate and phosphinate pendant arms in 1,4,7-triazacyclononane-based chelators on their ⁶⁸Ga labelling properties

In order to compare the coordination properties of 1,4,7-triazacyclononane (tacn) derivatives bearing varying numbers of phosphinic/carboxylic acid pendant groups towards ⁶⁸Ga, 1,4,7-triazacyclononane-7-acetic-1,4-bis(methylenephosphinic) acid (NOPA) and 1,4,7-triazacyclononane-4,7-diacetic-1-[methylene(2-carboxyethyl)phosphinic] acid (NO2AP) were synthesized using Mannich reactions with trivalent or pentavalent forms of H-phosphinic acids as phosphorus components. Stepwise protonation constants logK_1-3 12.06, 3.90 and 1.95, and stability constants with Ga^III and Cu^II, logK_GaL 24.01 and logK_CuL 16.66, were potentiometrically determined for NOPA. Both ligands were labelled with ⁶⁸Ga and compared with NOTA (tacn-N,N′,N″-triacetic acid) and NOPO, a TRAP-type [tacn-N,N′,N″- tris(methylenephosphinic acid)] chelator. At pH 3, NOPO and NOPA showed higher labelling efficiency (binding with lower ligand excess) at both room temperature and 95°C, compared to NO2AP and NOTA. Labelling efficiency at pH = 0-3 correlated with a number of phosphinic acid pendants: NOPO >> NOPA > NO2AP >> NOTA; however, it was more apparent at 95°C than at room temperature. By contrast, NOTA was found to be labelled more efficiently at pH > 4 compared to the ligands with phosphinic acids. Overall, replacement of a single phosphinate donor with a carboxylate does not challenge ⁶⁸Ga labelling of TRAP-type chelators. However, the presence of carboxylates facilitates labelling at neutral or weakly acidic pH.