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

TitleEvaluation of nitrogen-rich macrocyclic ligands for the chelation of therapeutic bismuth radioisotopes
Publication TypeJournal Article
Year of Publication2015
AuthorsWilson, JJ, Ferrier, M, Radchenko, V, Maassen, JR, Engle, JW, Batista, ER, Martin, RL, Nortier, FM, Fassbender, ME, John, KD, Birnbaum, ER
JournalNuclear Medicine and Biology
Pagination428 - 438
KeywordsActinium-225, Bismuth-213, macrocycles, Radio-thin-layer chromatography, radiolabeling, Targeted α-therapy

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.