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 K_ML value observed for Tb³⁺ (log K_TbL = 17.08), followed by La³⁺ (log K_LaL = 16.64) and Lu³⁺ (log K_LuL = 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 ([^{149/152/155/161}Tb]Tb³⁺) with efficiency and stability.