Evaluation of nitrogen-rich macrocyclic ligands for the chelation of therapeutic bismuth radioisotopes

Introduction The use of α-emitting isotopes for radionuclide therapy is a promising treatment strategy for small micro-metastatic disease. The radioisotope 213Bi is a nuclide that has found substantial use for targeted α-therapy (TAT). The relatively unexplored aqueous chemistry of Bi3+, however, hinders the development of bifunctional chelating agents that can successfully deliver these Bi radioisotopes to the tumor cells. Here, a novel series of nitrogen-rich macrocyclic ligands is explored for their potential use as Bi-selective chelating agents. Methods The ligands, 1,4,7,10-tetrakis(pyridin-2-ylmethyl)-1,4,7,10-tetraazacyclododecane (Lpy), 1,4,7,10-tetrakis(3-pyridazylmethyl)-1,4,7,10-tetraazacyclododecane (Lpyd), 1,4,7,10-tetrakis(4-pyrimidylmethyl)-1,4,7,10-tetraazacyclododecane (Lpyr), and 1,4,7,10-tetrakis(2-pyrazinylmethyl)-1,4,7,10-tetraazacyclododecane (Lpz), were prepared by a previously reported method and investigated here for their abilities to bind Bi radioisotopes. The commercially available and commonly used ligands 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and N-[(R)-2-amino-3-(p-isothiocyanato-phenyl)propyl]-trans-(S,S)- cyclohexane-1,2-diamine-N,N,N',N",N"-pentaacetic acid (CHX-A′′-DTPA) were also explored for comparative purposes. Radio-thin-layer chromatography (TLC) was used to measure the binding kinetics and stabilities of the complexes formed. The long-lived isotope, 207Bi (t1/2=32years), was used for these studies. Density functional theory (DFT) calculations were also employed to probe the ligand interactions with Bi3+ and the generator parent ion Ac3+. Results In contrast to DOTA and CHX-A′′-DTPA, these nitrogen-rich macrocycles selectively chelate Bi3+ in the presence of the parent isotope Ac3+. Among the four tested, Lpy was found to exhibit optimal Bi3+-binding kinetics and complex stability. Lpy complexes Bi3+ more rapidly than DOTA, yet the resulting complexes are of similar stability. DFT calculations corroborate the experimentally observed selectivity of these ligands for Bi3+ over Ac3+. Conclusion Taken together, these data implicate Lpy as a valuable chelating agent for the delivery of 213Bi. Its selectivity for Bi3+ and rapid and stable labeling properties warrant further investigation and biological studies.