Versatile Macrocyclic Platform for the Complexation of [^natY/⁹⁰Y]Yttrium and Lanthanide Ions

We report a macrocyclic ligand (H₃L) based on a 3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane platform containing three acetate pendant arms and a benzyl group attached to the fourth nitrogen atom of the macrocycle. The X-ray structures of the YL and TbL complexes reveal nine coordination of the ligand to the metal ions through the six nitrogen atoms of the macrocycle and three oxygen atoms of the carboxylate pendants. A combination of NMR spectroscopic studies (¹H, ¹³C, and ⁸⁹Y) and DFT calculations indicated that the structure of the YL complex in the solid state is maintained in an aqueous solution. The detailed study of the emission spectra of the EuL and TbL complexes revealed Ln³⁺-centered emission with quantum yields of 7.0 and 60%, respectively. Emission lifetime measurements indicate that the ligand offers good protection of the metal ions from surrounding water molecules, preventing the coordination of water molecules. The YL complex is remarkably inert with respect to complex dissociation, with a lifetime of 1.7 h in 1 M HCl. On the other hand, complex formation is fast (∼1 min at pH 5.4, 2 × 10^-5 M). Studies using the ⁹⁰Y-nuclide confirmed fast radiolabeling since [⁹⁰Y]YL is nearly quantitatively formed (radiochemical yield (RCY) > 95) in a short time over a broad range of pH values from ca. 2.4 to 9.0. Challenging experiments in the presence of excess ethylenediaminetetraacetic acid (EDTA) and in human serum revealed good stability of the [⁹⁰Y]YL complex. All of these experiments combined suggest the potential application of H₃L derivatives as Y-based radiopharmaceuticals.