Double-Armed\n18- and 21-Membered Macrocycles as Potential Chelators for Lead and\nBismuth Radiopharmaceuticals

With increasing clinical applications and interest in\ntargeted\nalpha therapy, there is growing interest in developing alternative\nchelating agents for [<sup>212</sup>Pb]Pb<sup>2+</sup> and [<sup>212/213</sup>Bi]Bi<sup>3+</sup> that exhibit rapid radiolabeling kinetics and\nkinetic inertness. Herein we report the synthesis and detailed investigation\nof diacetate and dipicolinate 18- and 21-membered macrocyclic chelators\nBADA-18, BADA-21, BADPA-18, and BADPA-21 for the complexation of Pb<sup>2+</sup> and Bi<sup>3+</sup> ions with potential use in the preparation\nof radiopharmaceuticals. The formation of mononuclear complexes was\nestablished by using ESI-mass spectrometry, and their stability constants\nwere determined by potentiometric titration. A thorough study of the\nstructure of the metal complexes was carried out by using X-ray diffraction\nand NMR spectroscopy. It was shown how the stability of the complex\nis influenced by an increase in the size of the macrocycle, the replacement\nof acetate arms with picolinate ones, the rigidity of the ligand,\nas well as the type of conformation (<i>syn</i>- or <i>anti</i>-) of the metal complex. The new ligands were radiolabeled\nwith [<sup>210</sup>Pb]Pb<sup>2+</sup> and [<sup>207</sup>Bi]Bi<sup>3+</sup>, and the in vitro stability of the resulting complexes in\na competitive environment of serum and biologically significant metal\nions was assessed. Rapid complex formation in 1–2 min at room\ntemperature, as well as the high kinetic inertness of the complexes\nPb(BADPA-18) and Bi(BADPA-18) in biological media, demonstrate its\npotential for use in targeted radionuclide therapy.