H 3 trica: Versatile Macrocyclic Chelator for [ 225 Ac]Ac 3+ and [ 155/161 Tb]Tb 3+ Theranostics.

H 3 trica is a nonadentate chelating ligand intended for coordinating large radiometal ions, such as those used in nuclear medicine. This chelator, featuring a triaza-18-crown-6 macrocycle with three pendant carboxylic acid functional groups, was synthesized and characterized. Complementary nuclear magnetic resonance (NMR) spectroscopy and high-resolution electrospray-ionization mass spectroscopy (HR-ESI-MS) studies were used to explore the coordination of H 3 trica with metal ions such as La 3+ , Y 3+ (as a model for Tb 3+) , and Lu 3+ at the bulk scale. Thermodynamic solution studies provided valuable insights, highlighting robust metal complexation of H 3 trica with La 3+ , Tb 3+ , and Lu 3+ , with the most noteworthy log K ML value observed for Tb 3+ (log K TbL = 17.08), followed by La 3+ (log K LaL = 16.64) and Lu 3+ (log K LuL = 16.25). Concentration-dependent radiolabeling studies with [ 225 Ac]Ac 3+ , [ 155 Tb]Tb 3+ , and [ 161 Tb]Tb 3+ demonstrated rapid complexation (5-30 min) under mild conditions (pH 6-7, 25 °C). Importantly, the radiolabeled complexes exhibited stability during incubation in human serum for one-half-life of the corresponding radiometal. Thus, H 3 trica emerges as a valuable chelator, demonstrating its potential to coordinate the theranostic couple [ 225 Ac]Ac 3+ /[ 155 Tb]Tb 3+ as well as the powerful terbium quartet ([ 149/152/155/161 Tb]Tb 3+ ) with efficiency and stability.