The H₂S<i>_x</i>macropa Series: Increasing the Chemical Softness of H₂macropa with Sulfur Atoms to Chelate Radiometals [²¹³Bi]Bi³⁺ and [²⁰³Pb]Pb²⁺ for Radiopharmaceutical App

The effects of replacing nitrogen with sulfur atoms in the 18-membered macrocycle of the H₂macropa chelator on the binding affinity and stability of "intermediate" (radio)metal [²⁰³Pb]Pb²⁺ and [²¹³Bi]Bi³⁺ complexes are investigated. The 1,4,10,13-tetraoxo-7,16-diazacyclooctadecane backbone was replaced with derivatives containing sulfur in the 1,4- or the 1,4,10,13-positions to yield the novel chelators H₂S₂macropa (N₄O₄S₂) and H₂S₄macropa (N₄O₂S₄), respectively. Trends on the ^nat/203Pb- and ^nat/213Bi-complex stability constants, coordination chemistry, radiolabeling, and kinetic inertness were assessed via potentiometric titrations, UV-vis spectroscopy, NMR spectroscopy, X-ray crystallography and density functional theory (DFT) calculations. ¹H-²⁰⁷Pb NMR spectroscopy confirmed the involvement of backbone S and/or O donors in the metal coordination sphere. Overall, the trend demonstrated that increasing the softness of the donor atoms within the ligand backbone decreased the thermodynamic stability and kinetic inertness of both the Pb²⁺ and Bi³⁺ complexes. Conversely, DFT calculations with mock compounds dimethyl ether (DME) and dimethyl sulfide (DMS) demonstrated enhanced affinity of the S atom to both Pb²⁺ and Bi³⁺ with DMS compared to DME evinced by large Δ<i>G</i>° values for both Pb²⁺ and Bi³⁺ complexes. The decreased stability of Pb/Bi-S_<i>x</i>macropa (<i>x</i> = 0, 2, 4) upon increased sulfur atom incorporation may be a result of the increased steric strain within the macrocyclic backbone upon sulfur atom introduction. Nonetheless, [²⁰³Pb]Pb²⁺ and [²¹³Bi]Bi³⁺ labeling (pH = 7, 30 min reaction time; 10^-4-10^-8 M chelator) resulted in both S₂macropa^2- and macropa^2- attaining similarly high radiolabeling efficiency. Meanwhile, S₄macropa^2- only possessed the ability to complex [²¹³Bi]Bi³⁺. Both [²⁰³Pb][Pb(macropa)] and [²⁰³Pb][Pb(S₂macropa)] remained greater than 97% intact when challenged against human serum over 72 h. The results of this study reveal the effects of incorporating sulfur donor atoms into macrocyclic chelators for [²⁰³Pb]Pb²⁺ and [²¹³Bi]Bi³⁺ radiopharmaceuticals.