Evaluation of the Effect of Macrocyclic Ring Size on [²⁰³Pb]Pb(II) Complex Stability in Pyridyl-Containing Chelators

As an element-equivalent theranostic pair, lead-203 (²⁰³Pb, 100% EC, half-life = 51.92 h) and lead-212 (²¹²Pb, 100% β^-, half-life = 10.64 h), through the emission of γ rays and an α particle in its decay chain, respectively, can aid in the development of personalized targeted radionuclide treatment for advanced and currently untreatable cancers. With these isotopes currently being used in clinical trials, an understanding of the relationship between the chelator structure, ability to incorporate the radiometal, and metal-complex stability is needed to help design appropriate chelators for clinical use. Herein, we report an investigation into the effect of ring size in macrocyclic chelators where pyridine, an intermediate Lewis base, acts as an electron donor toward lead. Crown-4Py (4,7,13,16-tetrakis(pyridin-2-ylmethyl)-1,10-dioxa-4,7,13,16-tetraazacyclooctadecane), cyclen-4Py (1,4,7,10-tetrakis(pyridin-2-ylmethyl)-1,4,7,10-tetraazacyclododecane), and NOON-2Py (7,16-bis(pyridin-2-ylmethyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane) were synthesized and analyzed for their ability to coordinate Pb²⁺. Metal complex stability was investigated via [²⁰³Pb]Pb²⁺ radiolabeling studies, ¹H NMR spectroscopy, X-ray crystallography, and potentiometry. With the smallest macrocyclic backbone, cyclen-4Py had the highest radiochemical yield, while, in descending order, crown-4Py and NOON-2Py had the lowest. Thermodynamic stability constants (log K_ML) of 19.95(3), 13.29(5), and 11.67 for [Pb(Cyclen-4Py)]²⁺, [Pb(Crown-4Py)]²⁺, and [Pb(NOON-2Py)]²⁺, respectively, correlated with their radiochemical yields. The X-ray crystal structure of the least stable complexes [Pb(NOON-2Py)]²⁺ revealed a hemidirected Pb²⁺ center, as reflected by a void within the coordination sphere, and [Pb(Crown-4Py)]²⁺ showed an average Pb-N pyridine interatomic distance of >3 Å. By contrast, the crystal structure of [Pb(Cyclen-4Py)]²⁺ showed shorter Pb-N pyridine interactions, and in solution, only one highly symmetric isomer existed for this complex, whereas conformational flexibility was observed for both [Pb(Crown-4Py)]²⁺ and [Pb(NOON-2Py)]²⁺ at the NMR timescale. This study illustrates the importance of the macrocyclic backbone size when incorporating bulky electron-donor groups into the design of a macrocyclic chelator as it affects the accessibility of lead to the donor arms. Our results show that cyclen-4Py is a promising chelator for future studies with this theranostic pair.