title: Novel "bi-modal" H2dedpa derivatives for radio- and fluorescence imaging.
abstract: A novel pyridyl functionalized analog of the promising hexadentate68Ga3+chelate H2dedpa (N4O2, 1,2-[[6-carboxy-pyridin-2-yl]-methylamine]ethane) was successfully synthesized and characterized. This new bifunctional chelate (BFC) was used to prepare the first proof-of-principle bi-modal H2dedpa derivative for fluorescence and nuclear imaging. Two bi-modal H2dedpa derivatives were prepared: H2dedpa-propylpyr-FITC and H2dedpa-propylpyr-FITC-(N,N'-propyl-2-NI) (FITC=fluorescein, pyr=pyridyl functionalized, NI=nitroimidazole). The ligands possess the strong gallium-coordinating atoms contained within dedpa2-that are ideal for radiolabeling with68Ga3+for positron-emission tomography (PET) imaging, and two fluorophores for optical imaging. In addition, one analog contains two NI moieties for specific entrapment of the tracer in hypoxic cells. These new bi-modal analogs were compared to the native unfunctionalized H2dedpa scaffold to determine the extent to which the addition of pyridyl functionalization would affect metal coordination, and complex stability. The non-radioactive gallium complexes were tested in a 3D tumor spheroid model. The novel pyridyl bis-functionalized H2dedpa ligand, H2dedpa-propylpyr-NH2, was quantitatively radiolabeled with67Ga (RCY>99%) under reaction conditions commensurate with unfunctionalized H2dedpa (10min at room temperature) at ligand concentrations as low as 10-5M. The resultant67Ga-complex withstood transchelation to the in vivo metal-binding competitor apo-transferrin (2h at 37°C, 93% intact), signifying that [Ga(dedpa-propylpyr-NH2)]+is a kinetically inert complex suitable for in vivo use, but exhibited slightly reduced stability compared to the native [67Ga(dedpa)] scaffold (>99% intact). Finally, bi-model fluorescent Ga-dedpa compounds were successfully imaged in a 3D tumor spheroid model. The Ga-dedpa-FITC-NI derivative was specifically localized in the central hypoxic core of the spheroid.
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada; TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada.
authors.forename: Caterina F
authors.initials: CF
authors.lastname: Ramogida
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: Lisa
authors.initials: L
authors.lastname: Murphy
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Cawthray
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
authors.forename: James D
authors.initials: JD
authors.lastname: Ross
authors.affiliation: TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Adam
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada. Electronic address: orvig@chem.ubc.ca.
authors.forename: Chris
authors.initials: C
authors.lastname: Orvig
mesh_terms: D001059:Apoproteins / Q000737:chemistry; D015687:Cell Hypoxia; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D004355:Drug Stability; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D005021:Ethylamines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D005710:Gallium Radioisotopes / Q000737:chemistry*; D006801:Humans; D009593:Nitroimidazoles / Q000737:chemistry; D061848:Optical Imaging / Q000379:methods; D049268:Positron-Emission Tomography / Q000379:methods; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D014168:Transferrin / Q000737:chemistry
chemical_list: D001059:Apoproteins; D002614:Chelating Agents; D056831:Coordination Complexes; D005021:Ethylamines; D005710:Gallium Radioisotopes; C000596869:N,N'-((6-carboxylato)pyridin-2-yl)methyl)-1,2-diaminoethane; D009593:Nitroimidazoles; D011725:Pyridines; D019275:Radiopharmaceuticals; D014168:Transferrin; C028284:apotransferrin; D016650:Fluorescein-5-isothiocyanate
keywords: Bifunctional chelates; Fluorescence imaging; Gallium-68; Nitroimidazole; Positron-emission tomography; Spheroids