title: Radiolabeling and in vivo behavior of copper-64-labeled cross-bridged cyclam ligands.
abstract: Macrocyclic chelators and their metal complexes have widespread applications in the biomedical sciences, including radiopharmaceutical chemistry. The use of copper radionuclides in radiopharmaceuticals is increasing. Macrocyclic chelators have been found to have enhanced in vivo stability over acyclic chelators such as ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA). The currently used chelators of choice for labeling copper radionuclides to biological molecules are analogues of TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid); however, recent reports have demonstrated evidence of in vivo instability of the radio-Cu(II)-TETA complexes. A new class of structurally reinforced macrocycles, the "cross-bridged" cyclam derivatives, form highly stable complexes with Cu(II) that are resistant to dissociation in strong acid. Here, we evaluate a series of (64)Cu(II) cross-bridged macrocyclic complexes for biological stability and in vivo behavior. The ligands evaluated include the parent ligand, 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (1), and three 4,11-di-pendant arm derivatives: 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (2); 4,11-bis(N,N-diethyl-amidomethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (3); and 4,11-bis(amidoethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (4). Copper-64 formed complexes with ligands 1-4 in high radiochemical yields. The (64)Cu-2 complex was neutral, while (64)Cu complexes of 1, 3, and 4 were positively charged. All complexes showed no decomposition in rat serum out to 24 h. Biodistribution experiments in Sprague-Dawley rats indicated that (64)Cu-1, -3, and -4 were taken up by the liver and kidney and cleared slowly over 24 h, whereas (64)Cu-2 cleared rapidly from all tissues. The rapid clearance of the (64)Cu-2 complex from the blood and liver, as well as liver metabolism experiments in rats, suggests that it is highly stable in vivo. A bifunctional chelator of 2 is a significant candidate for labeling copper radionuclides to biological molecules for diagnostic imaging and targeted radiotherapy.
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Xiankai
authors.initials: X
authors.lastname: Sun
authors.forename: Melinda
authors.initials: M
authors.lastname: Wuest
authors.forename: Gary R
authors.initials: GR
authors.lastname: Weisman
authors.forename: Edward H
authors.initials: EH
authors.lastname: Wong
authors.forename: David P
authors.initials: DP
authors.lastname: Reed
authors.forename: C Andrew
authors.initials: CA
authors.lastname: Boswell
authors.forename: Ramunas
authors.initials: R
authors.lastname: Motekaitis
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Martell
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welch
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Anderson
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D003301:Copper Radioisotopes; D004355:Drug Stability; D005260:Female; D006571:Heterocyclic Compounds / Q000737:chemistry*; D007553:Isotope Labeling; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008297:Male; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D011199:Potentiometry; D011522:Protons; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D002614:Chelating Agents; D003301:Copper Radioisotopes; D006571:Heterocyclic Compounds; D008024:Ligands; D009942:Organometallic Compounds; D011522:Protons; D019275:Radiopharmaceuticals; C024560:cyclam