title: Synthesis, characterisation and evaluation of a novel copper-64 complex with selective uptake in EMT-6 cells under hypoxic conditions.
abstract: The radiometal (64)Cu is now widely used in the development of diagnostic imaging agents for positron emission tomography (PET). The present study has led to the development and evaluation of a novel chelating agent for (64)Cu: the new monothiourea tripodal ligand 1-benzoyl-3-{6-[(bis-pyridin-2-ylmethyl-amino)-methyl]-pyridin-2-yl}-thiourea (MTUBo). X-ray crystallographic analysis has shown this ligand forms a mononuclear complex with copper(II) and co-ordinates via a trigonal bipyramidal N4S array of donor atoms. Promisingly, cell uptake studies revealed that (64)Cu-MTUBo selectively accumulates in EMT-6 cells incubated under hypoxic conditions which may result from its relatively high Cu(II/I) redox potential. Small-animal PET imaging and ex vivo biodistribution studies in EMT-6 tumor bearing BALB/c mice revealed significant tumor uptake after 1 h p.i., yielding tumor-to-muscle (T/M) and tumor-to-blood (T/B) ratios of 8.1 and 1.1, respectively. However, injection of (64)Cu-acetate resulted in similar uptake indicating that the observed uptake was most likely non-specific. Despite showing high in vitro stability, it is likely that in vivo the complex undergoes transchelation to proteins within the blood in a relatively short timeframe. For comparison, the hypoxia imaging agent (64)Cu-ATSM was also evaluated in the same murine tumor model and showed about 60% higher tumor uptake than (64)Cu-MTUBo.
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada.
authors.forename: James C
authors.initials: JC
authors.lastname: Knight
authors.forename: Melinda
authors.initials: M
authors.lastname: Wuest
authors.forename: Fawaz A
authors.initials: FA
authors.lastname: Saad
authors.forename: Monica
authors.initials: M
authors.lastname: Wang
authors.forename: David W
authors.initials: DW
authors.lastname: Chapman
authors.forename: Hans-Soenke
authors.initials: HS
authors.lastname: Jans
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Lapi
authors.forename: Benson M
authors.initials: BM
authors.lastname: Kariuki
authors.forename: Angelo J
authors.initials: AJ
authors.lastname: Amoroso
authors.forename: Frank
authors.initials: F
authors.lastname: Wuest
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D003301:Copper Radioisotopes / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000378:metabolism / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D012513:Sarcoma, Experimental / Q000175:diagnosis / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D003301:Copper Radioisotopes; D009942:Organometallic Compounds