[^natY/⁹⁰Y]Yttrium and [^natLu/¹⁷⁷Lu]Lutetium Complexation by Rigid H₄OCTAPA Derivatives. Effect of Ligand Topology

We present a detailed investigation on the coordination chemistry of [^nat/90Y]Y³⁺ and [^nat/177Lu]Lu³⁺ with the new acyclic chelator H₄CHXOITAPA. This octadentate chelator forms nine-coordinated Y³⁺ and Lu³⁺ complexes thanks to the coordination of a water molecule, as demonstrated by the X-ray structure of [Y(HCHXOITAPA)(H₂O)] and ¹H, ¹³C, and ⁸⁹Y NMR studies in solution. These complexes display slightly higher thermodynamic stabilities compared with those of the known H₄CHXOCTAPA and H₄OCTAPA chelators, reaching log K_YL and log K_LuL values of 21.24(5) and 21.96(1), respectively. Kinetic studies indicate that these complexes dissociate mainly through the spontaneous and proton-assisted pathways at pH 7.4. The chelator can be readily radiolabeled with [⁹⁰Y]Y³⁺ and [¹⁷⁷Lu]Lu³⁺ at room temperature in 10 min. The radio-complexes are stable in human serum at 37 °C, in contrast with the analogues of the known H₄CHXOCTAPA and H₄OCTAPA chelators, which experience significant dissociation under these conditions. Thus, the H₄CHXOITAPA chelator represents the most promising candidate among the H₄OCTAPA family for the development of ⁹⁰Y- and ¹⁷⁷Lu-based radiopharmaceuticals.