title: A dual radiolabelling approach for tracking metal complexes: investigating the speciation of copper bis(thiosemicarbazonates) in vitro and in vivo.
abstract: Copper(II)bis(thiosemicarbazonato) complexes such as [(64)Cu]Cu-ATSM continue to be investigated for positron emission tomography (PET) imaging of tumour hypoxia. However, the currently proposed mechanisms for the mode of action of these complexes are unable to account fully for their observed biological behaviour. In order to examine the roles of the copper metal and the ligand, we designed a pair of (123)I/(64)Cu-copper bis(thiosemicarbazonates), radiolabelled at either the metal or at the ligand. In vitro cellular retention studies of the orthogonal pair demonstrate for the first time that retention under hypoxia involves dissociation of the copper bis(thiosemicarbazone) complex, consistent with the previously suggested mechanism of reductive trapping of copper. In contrast, in vivo biodistribution and dynamic PET/SPECT imaging of the orthogonally labelled complexes underline our previous findings for [(64)Cu]Cu-ATSM and [(64)Cu]Cu-acetate, providing further support for the important contribution of copper metabolism in the in vivo hypoxia selectivity of Cu-ATSM. This dual radiolabelling approach may find applications for determining the speciation of other metal complexes in vitro and in vivo.
authors.affiliation: Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Rd, Oxford, OX1 3TA, UK. jon.dilworth@chem.ox.ac.uk.
authors.forename: Rebekka
authors.initials: R
authors.lastname: Hueting
authors.forename: Veerle
authors.initials: V
authors.lastname: Kersemans
authors.forename: Matthew
authors.initials: M
authors.lastname: Tredwell
authors.forename: Bart
authors.initials: B
authors.lastname: Cornelissen
authors.forename: Martin
authors.initials: M
authors.lastname: Christlieb
authors.forename: Antony D
authors.initials: AD
authors.lastname: Gee
authors.forename: Jan
authors.initials: J
authors.lastname: Passchier
authors.forename: Sean C
authors.initials: SC
authors.lastname: Smart
authors.forename: Véronique
authors.initials: V
authors.lastname: Gouverneur
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Muschel
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Dilworth
mesh_terms: D000818:Animals; D002460:Cell Line; D056831:Coordination Complexes; D003301:Copper Radioisotopes / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000150:complications / Q000175:diagnosis* / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000150:complications / Q000175:diagnosis* / Q000378:metabolism; D009942:Organometallic Compounds / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D013882:Thiosemicarbazones / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D056831:Coordination Complexes; D003301:Copper Radioisotopes; D009942:Organometallic Compounds; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone)