title: Synthesis, Cu(II) complexation, 64Cu-labeling and biological evaluation of cross-bridged cyclam chelators with phosphonate pendant arms.
abstract: A new class of cross-bridged cyclam-based macrocycles featuring phosphonate pendant groups has been developed. 1,4,8,11-tetraazacyclotetradecane-1,8-di(methanephosphonic acid) (CB-TE2P, 1) and 1,4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8-(methanecarboxylic acid) (CB-TE1A1P, 2) have been synthesized and have been shown to readily form neutral copper(II) complexes at room temperature as the corresponding dianions. Both complexes showed high kinetic inertness to demetallation and crystal structures confirmed complete encapsulation of copper(II) ion within each macrocycle's cleft-like structure. Unprecedented for cross-bridged cyclam derivatives, both CB-TE2P (1) and CB-TE1A1P (2) can be radiolabeled with (64)Cu at room temperature in less than 1 h with specific activities >1 mCi μg(-1). The in vivo behavior of both (64)Cu-CB-TE2P and (64)Cu-CB-TE1A1P were investigated through biodistribution studies using healthy male Lewis rats. Both new compounds showed rapid clearance with similar or lower accumulation in non-target organs/tissues when compared to other copper chelators including CB-TE2A, NOTA and Diamsar.
authors.affiliation: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ferdani
authors.forename: Dannon J
authors.initials: DJ
authors.lastname: Stigers
authors.forename: Ashley L
authors.initials: AL
authors.lastname: Fiamengo
authors.forename: Lihui
authors.initials: L
authors.lastname: Wei
authors.forename: Barbara T Y
authors.initials: BT
authors.lastname: Li
authors.forename: James A
authors.initials: JA
authors.lastname: Golen
authors.forename: Arnold L
authors.initials: AL
authors.lastname: Rheingold
authors.forename: Gary R
authors.initials: GR
authors.lastname: Weisman
authors.forename: Edward H
authors.initials: EH
authors.lastname: Wong
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Anderson
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry; D002614:Chelating Agents / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D003301:Copper Radioisotopes / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006571:Heterocyclic Compounds / Q000737:chemistry*; D007553:Isotope Labeling; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D063065:Organophosphonates / Q000737:chemistry*; D011789:Quantum Theory; D051381:Rats
chemical_list: D002264:Carboxylic Acids; D002614:Chelating Agents; D003301:Copper Radioisotopes; D006571:Heterocyclic Compounds; D008024:Ligands; D009942:Organometallic Compounds; D063065:Organophosphonates; C024560:cyclam; D003300:Copper