title: Synthesis of a cross-bridged cyclam derivative for peptide conjugation and 64Cu radiolabeling.
abstract: The increased use of copper radioisotopes in radiopharmaceutical applications has created a need for bifunctional chelators (BFCs) that form stable radiocopper complexes and allow covalent attachment to biological molecules. Previous studies have established that 4,11-bis-(carbo- tert-butoxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (H 2CB-TE2A), a member of the ethylene "cross-bridged" cyclam (CB-cyclam) class of bicyclic tetraaza macrocycles, forms highly kinetically stable complexes with Cu(II) and is less susceptible to in vivo transchelation than its nonbridged analogue, 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA). Herein, we report a convenient synthesis of a novel cross-bridged BFC that is structurally analogous to CB-TE2A in that it possesses two coordinating acetate arms, but in addition possesses a third orthogonally protected arm for conjugation to peptides and other targeting agents. Application of this strategy to cross-bridged chelators may also enable the development of even further improved agents for (64)Cu-mediated diagnostic positron emission tomography (PET) imaging as well as for targeted radiotherapeutic applications.
authors.affiliation: Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892-1088, UAS.
authors.forename: C Andrew
authors.initials: CA
authors.lastname: Boswell
authors.forename: Celeste A S
authors.initials: CA
authors.lastname: Regino
authors.forename: Kwamena E
authors.initials: KE
authors.lastname: Baidoo
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Wong
authors.forename: Ambika
authors.initials: A
authors.lastname: Bumb
authors.forename: Heng
authors.initials: H
authors.lastname: Xu
authors.forename: Diane E
authors.initials: DE
authors.lastname: Milenic
authors.forename: James A
authors.initials: JA
authors.lastname: Kelley
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Lai
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
mesh_terms: D000588:Amines / Q000737:chemistry; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry; D003301:Copper Radioisotopes; D003432:Cross-Linking Reagents / Q000138:chemical synthesis* / Q000737:chemistry; D047029:Lactams, Macrocyclic / Q000138:chemical synthesis* / Q000737:chemistry; D008024:Ligands; D010455:Peptides / Q000737:chemistry* / Q000627:therapeutic use; D013194:Staining and Labeling / Q000379:methods*
chemical_list: D000588:Amines; D002614:Chelating Agents; D003301:Copper Radioisotopes; D003432:Cross-Linking Reagents; D047029:Lactams, Macrocyclic; D008024:Ligands; D010455:Peptides