H3trica: Versatile Macrocyclic Chelator for [225Ac]Ac3+ and [155/161Tb]Tb3+ Theranostics

H3trica 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 H3trica with metal ions such as La3+, Y3+ (as a model for Tb3+), and Lu3+ at the bulk scale. Thermodynamic solution studies provided valuable insights, highlighting robust metal complexation of H3trica with La3+, Tb3+, and Lu3+, with the most noteworthy log KML value observed for Tb3+ (log KTbL = 17.08), followed by La3+ (log KLaL = 16.64) and Lu3+ (log KLuL = 16.25). Concentration-dependent radiolabeling studies with [225Ac]Ac3+, [155Tb]Tb3+, and [161Tb]Tb3+ 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, H3trica emerges as a valuable chelator, demonstrating its potential to coordinate the theranostic couple [225Ac]Ac3+/[155Tb]Tb3+ as well as the powerful terbium quartet ([149/152/155/161Tb]Tb3+) with efficiency and stability.