Trans-Picolinate Functionalization of a Cyclen-Based Chelator Enables Complexation of Large Radiometals for Cancer Theranostics

Abstract The development of chelators with diverse coordination properties is essential for expanding the radiometals available for imaging and targeted therapy. We investigate the metal-binding behavior of DO2A-2PA, a trans-picolinic acid-functionalized cyclen chelator, with isotopes of lanthanum (133/155La/natLa), actinium (225Ac), lead (203Pb/212Pb/natPb), and lutetium (117Lu/natLu). Metal complexes were characterized in solution by 1H NMR spectroscopy (natLa3+, natPb2+, and natLu3+) and in the solid state by X-ray crystallography (natLa3+, natPb2+). The solid-state structures revealed a 10-coordinate La3+ complex, whereas Pb2+ engaged only six donor atoms and resided deeper within the cyclen cavity, consistent with shorter M-NDO2A distances in [Pb(H4DO2A-2PA)]2+. Solution-state NMR studies showed fluxional behavior for La3+, Pb2+, and Lu3+ complexes, supported by variable-temperature experiments. Radiolabeling studies demonstrated efficient, quantitative, and ambient-temperature incorporation of [225Ac]Ac3+ and [133/135La]La3+, with the resulting radiocomplexes exhibiting high kinetic inertness in vitro. Although quantitative [203Pb]/[212Pb]Pb2+ labeling was achieved with DO2A-2PA, performance did not exceed DOTAM, and incorporation of [177Lu]Lu3+ remained inefficient even at elevated temperatures. Overall, these results identify DO2A-2PA as a promising chelator for large, hard radiometals particularly [225Ac]Ac3+ and [133/135La]La3+ while underscoring that increased donor-atom density does not universally enhance coordination performance for softer radiometals such as [203Pb]/[212Pb]Pb2+.