The H2Sxmacropa Series: Increasing the Chemical Softness of H2macropa with Sulfur Atoms to Chelate Radiometals [213Bi]Bi3+ and [203Pb]Pb2+ for Radiopharmaceutical Applications.

Abstract

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 ΔG° values for both Pb2+ and Bi3+ complexes. The decreased stability of Pb/Bi-Sxmacropa (x = 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 S2macropa2- and macropa2- attaining similarly high radiolabeling efficiency. Meanwhile, S4macropa2- 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.