Octadentate Picolinic Acid-Based Bispidine Ligand for Radiometal Ions

The synthesis of the octadentate bispidine ligand bearing two picolinic acid pendant arms (H(2)bispa(2)), and its coordination chemistry with radionuclides relevant for nuclear medicine, namely indium(III) (In-111), lutetium(III) (Lu-177), and lanthanum(III) (as surrogate for Ac-225), are reported. The non-radioactive metal complexes of the N6O2-type bispa ligand were characterized by H-1 and (CNMR)-C-13 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 H(2)bispa(2) comparable to those of the macrocyclic ``gold standard{''} DOTA. After an incubation time of 1day, 86 and 87% of {[}Lu-177(bispa(2))](+) and {[}Lu-177(DOTA)](-), respectively, remain intact. Importantly, unlike DOTA, H(2)bispa(2) is radiolabeled quantitatively with In-111(III) and Ac-225(III) under ambient conditions, which is an essential aspect when working with heat-sensitive antibodies as targeting vectors. In the case of In-111(III), room temperature radiolabeling of H(2)bispa(2) yields molar activities as high as 70 MBq nmol(-1) within 10 minutes. These are promising results for radiopharmaceutical applications of H(2)bispa(2).