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

Journal Article · Fri May 01 00:00:00 EDT 2015 · Nuclear Medicine and Biology

DOI:https://doi.org/10.1016/j.nucmedbio.2014.12.007· OSTI ID:1193399

Wilson, Justin J. ^[1]; Ferrier, Maryline ^[1]; Radchenko, Valery ^[1]; Maassen, Joel R. ^[1]; Engle, Jonathan W. ^[1]; Batista, Enrique R. ^[1]; Martin, Richard L. ^[1]; Nortier, Francois M. ^[1]; Fassbender, Michael E. ^[1]; John, Kevin D. ^[1]; Birnbaum, Eva R. ^[1]

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1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

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. The ligands, 1,4,7,10-tetrakis(pyridin-2-ylmethyl)-1,4,7,10-tetraazacyclododecane (L^py), 1,4,7,10-tetrakis(3-pyridazylmethyl)-1,4,7,10-tetraazacyclododecane (L^pyd), 1,4,7,10-tetrakis(4-pyrimidylmethyl)-1,4,7,10-tetraazacyclododecane (L^pyr), and 1,4,7,10-tetrakis(2-pyrazinylmethyl)-1,4,7,10-tetraazacyclododecane (L^pz), 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 (t_1/2 = 32 years), 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⁺.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, L^py was found to exhibit optimal Bi³⁺-binding kinetics and complex stability. L^py 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⁺. Taken together, these data implicate L^py 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.

• Research Organization: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
• Sponsoring Organization: USDOE
• Grant/Contract Number: AC52-06NA25396
• OSTI ID: 1193399
• Alternate ID(s): OSTI ID: 1359705
• Report Number(s): LA-UR-14-28015; PII: S0969805114005721; TRN: US1600595
• Journal Information: Nuclear Medicine and Biology, Vol. 42, Issue 5; ISSN 0969-8051
• Publisher: Elsevier
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
targeted α-therapy
bismuth-213
actinium-225
radiolabeling
radio-thin-layer chromatography
macrocycles