title: Evaluation of nitrogen-rich macrocyclic ligands for the chelation of therapeutic bismuth radioisotopes.
abstract: BACKGROUND
  The use of α-emitting isotopes for radionuclide therapy is a promising treatment strategy for small micro-metastatic disease. The radioisotope (213)Bi is a nuclide that has found substantial use for targeted α-therapy (TAT). The relatively unexplored aqueous chemistry of Bi(3+), 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 (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, (207)Bi (t(1/2)=32 years), was used for these studies. Density functional theory (DFT) calculations were also employed to probe the ligand interactions with Bi(3+) and the generator parent ion Ac(3+).
  
  
  RESULTS
  In contrast to DOTA and CHX-A''-DTPA, these nitrogen-rich macrocycles selectively chelate Bi(3+) in the presence of the parent isotope Ac(3+). Among the four tested, L(py) was found to exhibit optimal Bi(3+)-binding kinetics and complex stability. L(py) complexes Bi(3+) more rapidly than DOTA, yet the resulting complexes are of similar stability. DFT calculations corroborate the experimentally observed selectivity of these ligands for Bi(3+) over Ac(3+).
  
  
  CONCLUSIONS
  Taken together, these data implicate L(py) as a valuable chelating agent for the delivery of (213)Bi. Its selectivity for Bi(3+) and rapid and stable labeling properties warrant further investigation and biological studies.
authors: Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, NM, 87545, USA. Electronic address: jjwilson@lanl.gov.
authors: Justin J
authors: JJ
authors: Wilson
authors: Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, NM, 87545, USA.
authors: Maryline
authors: M
authors: Ferrier
authors: Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, NM, 87545, USA.
authors: Valery
authors: V
authors: Radchenko
authors: Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, NM, 87545, USA.
authors: Joel R
authors: JR
authors: Maassen
authors: Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, NM, 87545, USA.
authors: Jonathan W
authors: JW
authors: Engle
authors: Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, NM, 87545, USA.
authors: Enrique R
authors: ER
authors: Batista
authors: Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, NM, 87545, USA.
authors: Richard L
authors: RL
authors: Martin
authors: Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, NM, 87545, USA.
authors: Francois M
authors: FM
authors: Nortier
authors: Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, NM, 87545, USA.
authors: Michael E
authors: ME
authors: Fassbender
authors: Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, NM, 87545, USA.
authors: Kevin D
authors: KD
authors: John
authors: Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, NM, 87545, USA. Electronic address: eva@lanl.gov.
authors: Eva R
authors: ER
authors: Birnbaum
mesh_terms: D000186:Actinium / Q000737:chemistry; D000512:Alpha Particles / Q000627:therapeutic use; D001667:Binding, Competitive; D001729:Bismuth / Q000737:chemistry* / Q000627:therapeutic use*; D002614:Chelating Agents / Q000737:chemistry*; D004492:Edetic Acid / Q000737:chemistry; D007553:Isotope Labeling; D007700:Kinetics; D008024:Ligands; D047028:Macrocyclic Compounds / Q000737:chemistry*; D009584:Nitrogen / Q000737:chemistry*; D011789:Quantum Theory; D011868:Radioisotopes
chemical_list: D002614:Chelating Agents; D008024:Ligands; D047028:Macrocyclic Compounds; D011868:Radioisotopes; D004492:Edetic Acid; D009584:Nitrogen; D000186:Actinium; D001729:Bismuth
keywords: Actinium-225; Bismuth-213; Macrocycles; Radio-thin-layer chromatography; Radiolabeling; Targeted α-therapy