title: Synthesis, Copper(II) Complexation, (64)Cu-Labeling, and Bioconjugation of a New Bis(2-pyridylmethyl) Derivative of 1,4,7-Triazacyclononane.
abstract: A new ligand derivative of 1,4,7-triazacyclononane (TACN), 2-[4,7-bis(2-pyridylmethyl)-1,4,7-triazacyclononan-1-yl]acetic acid ( 6), has been synthesized and its complexation behavior toward Cu2+ ions investigated. The ligand 6 has been characterized by spectroscopic methods, and a molecular structure of a corresponding Cu(II) complex has been elucidated by single-crystal X-ray analysis. The suitability of 6 for conjugation to peptide substrates has been shown by amide coupling of 6 to the stabilized derivative of bombesin (BN), beta Ala-beta Ala-[Cha13, Nle14]BN(7-14), to give the conjugate 8. The free ligand 6 and the bioconjugate 8 were labeled with 64Cu2+, and the resulting complexes, 64Cu subset6 and 64Cu subset8 , were found to be stable in the presence of a large excess of a competing ligand (cyclam) or copper-seeking superoxide dismutase (SOD), as well as in rat plasma. Biodistribution studies of 64Cu subset8 in Wistar rats showed a high activity uptake into the pancreas (5.76 +/- 0.25 SUV, 5 min p.i.; 3.93 +/- 0.25 SUV, 1 h p.i.), which is the organ with high levels of gastrin-releasing peptide receptor (GRPR). This receptor is overexpressed in a large number of breast and prostate carcinomas. The novel 64Cu subset6 complex had a dominating influence on the nonspecific activity biodistribution of its BN conjugate, since the distribution data of 64Cu subset6 are similar to those of 64Cu subset8 . The 64Cu complexes exhibited a low activity accumulation in the liver tissue and an extensive renal clearance, which was distinctively different to the biodistribution of 64CuCl 2, suggesting that 64Cu subset6 does not undergo significant demetalation, but rather exhibits high in vivo stability.
authors.affiliation: School of Chemistry, Monash University, Clayton, Vic 3800, Australia.
authors.forename: Gilles
authors.initials: G
authors.lastname: Gasser
authors.forename: Linda
authors.initials: L
authors.lastname: Tjioe
authors.forename: Bim
authors.initials: B
authors.lastname: Graham
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Belousoff
authors.forename: Stefanie
authors.initials: S
authors.lastname: Juran
authors.forename: Martin
authors.initials: M
authors.lastname: Walther
authors.forename: Jens-Uwe
authors.initials: JU
authors.lastname: Künstler
authors.forename: Ralf
authors.initials: R
authors.lastname: Bergmann
authors.forename: Holger
authors.initials: H
authors.lastname: Stephan
authors.forename: Leone
authors.initials: L
authors.lastname: Spiccia
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003300:Copper / Q000737:chemistry* / Q000493:pharmacokinetics; D003301:Copper Radioisotopes; D018360:Crystallography, X-Ray; D004355:Drug Stability; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000493:pharmacokinetics; D006863:Hydrogen-Ion Concentration; D007553:Isotope Labeling; D008099:Liver / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D012997:Solvents; D017550:Spectroscopy, Fourier Transform Infrared; D013482:Superoxide Dismutase / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: C529175:2-(4,7-bis(2-pyridylmethyl)-1,4,7-triazacyclononan-1-yl)acetic acid; D003301:Copper Radioisotopes; D006571:Heterocyclic Compounds; D011725:Pyridines; D019275:Radiopharmaceuticals; D012997:Solvents; C075712:1,4,7-triazacyclononane; D003300:Copper; D013482:Superoxide Dismutase