Equilibrium Thermodynamics of Macropa Complexes with Selected Metal Isotopes of Radiopharmaceutical Interest

To follow the design of in vivo stable chelating systems for radiometals, a concise and straightforward method toolbox was developed combining NMR, ITC, and Eu-TRLFS. For this purpose, the macropa chelator was chosen and Lu3+, La3+, Pb2+, Ra2+, and Ba2+ as radiopharmaceutically relevant metal ions. They differ in charge (+2, +3) and coordination properties (main group vs. lanthanides). 1H NMR was used to determine four pKa values (carboxylate functions: 2.40 and 3.13; amine functions: 6.80 and 7.73). Eu-TRLFS was used to validate the exclusive existence of the Mn+:ligand 1:1 complex in the chosen pH range. ITC measurements were accomplished to determine the resulting stability constants of the desired complexes with log K values ranging from 18.5 for the Pb-mcp complex to 7.3 for the Lu-mcp complex. DFT-calculated structures nicely mirror the complexes’ order of stabilities by bonding features. Radiolabeling with macropa using ligand concentrations from 10–3 M to 10–6 M pointed out the complex stability (133La > 131Ba > 177Lu).