The HSmacropa Series: Increasing the Chemical Softness of Hmacropa with Sulfur Atoms to Chelate Radiometals [Bi]Bi and [Pb]Pb for Radiopharmaceutical Applications.

The effects of replacing nitrogen with sulfur atoms in the 18-membered macrocycle of the Hmacropa chelator on the binding affinity and stability of "intermediate" (radio)metal [Pb]Pb and [Bi]Bi 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 HSmacropa (NOS) and HSmacropa (NOS), respectively. Trends on the Pb- and Bi-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. H-Pb 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 Pb and Bi complexes. Conversely, DFT calculations with mock compounds dimethyl ether (DME) and dimethyl sulfide (DMS) demonstrated enhanced affinity of the S atom to both Pb and Bi with DMS compared to DME evinced by large Δ° values for both Pb and Bi complexes. The decreased stability of Pb/Bi-Smacropa ( = 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, [Pb]Pb and [Bi]Bi labeling (pH = 7, 30 min reaction time; 10-10 M chelator) resulted in both Smacropa and macropa attaining similarly high radiolabeling efficiency. Meanwhile, Smacropa only possessed the ability to complex [Bi]Bi. Both [Pb][Pb(macropa)] and [Pb][Pb(Smacropa)] 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 [Pb]Pb and [Bi]Bi radiopharmaceuticals.