Octadentate Picolinic Acid‐Based Bispidine Ligand for Radiometal Ions

Abstract

The synthesis of the octadentate bispidine ligand bearing two picolinic acid pendant arms (H₂ bispa² ), and its coordination chemistry with radionuclides relevant for nuclear medicine, namely indium(III) (¹¹¹ In), lutetium(III) (¹⁷⁷ Lu), and lanthanum(III) (as surrogate for ²²⁵ Ac), are reported. The non-radioactive metal complexes of the N₆ O₂ -type bispa ligand were characterized by ¹ H and ¹³ C NMR spectroscopy, elemental analysis, mass spectrometry and single-crystal X-ray analysis. Experimental structural data, computational analysis, complex stabilities determined by potentiometric titration, and "radiostabilities" determined by competition studies in the presence of human serum reveal complex stabilities of H₂ bispa² comparable to those of the macrocyclic "gold standard" DOTA. After an incubation time of 1 day, 86 and 87 % of [¹⁷⁷ Lu(bispa² )]⁺ and [¹⁷⁷ Lu(DOTA)]^- , respectively, remain intact. Importantly, unlike DOTA, H₂ bispa² is radiolabeled quantitatively with ¹¹¹ In^III and ²²⁵ Ac^III under ambient conditions, which is an essential aspect when working with heat-sensitive antibodies as targeting vectors. In the case of ¹¹¹ In^III , room temperature radiolabeling of H₂ bispa² yields molar activities as high as 70 MBq nmol^-1 within 10 minutes. These are promising results for radiopharmaceutical applications of H₂ bispa² .