title: Enhancing PET Signal at Target Tissue in Vivo: Dendritic and Multimeric Tris(hydroxypyridinone) Conjugates for Molecular Imaging of αvβ3Integrin Expression with Gallium-68.
abstract: Tris(hydroxypyridinone) chelators conjugated to peptides can rapidly complex the positron-emitting isotope gallium-68 (68Ga) under mild conditions, and the resulting radiotracers can delineate peptide receptor expression at sites of diseased tissue in vivo. We have synthesized a dendritic bifunctional chelator containing nine 1,6-dimethyl-3-hydroxypyridin-4-one groups (SCN-HP9) that can coordinate up to three Ga3+ions. This derivative has been conjugated to a trimeric peptide (RGD3) containing three peptide groups that target the αvβ3integrin receptor. The resulting dendritic compound, HP9-RGD3, can be radiolabeled in 97% radiochemical yield at a 3-fold higher specific activity than its homologues HP3-RGD and HP3-RGD3that contain only a single metal binding site. PET scanning and biodistribution studies show that [68Ga(HP9-RGD3)] demonstrates higher receptor-mediated tumor uptake in animals bearing U87MG tumors that overexpress αvβ3integrin than [68Ga(HP3-RGD)] and [68Ga(HP3-RGD3)]. However, concomitant nontarget organ retention of [68Ga(HP9-RGD3)] results in low tumor to nontarget organ contrast in PET images. On the other hand, the trimeric peptide homologue containing a single tris(hydroxypyridinone) chelator, [68Ga(HP3-RGD3)], clears nontarget organs and exhibits receptor-mediated uptake in mice bearing tumors and in mice with induced rheumatoid arthritis. PET imaging with [68Ga(HP3-RGD3)] enables clear delineation of αvβ3integrin receptor expression in vivo.
authors.affiliation: King's College London , Division of Imaging Sciences and Biomedical Engineering, Fourth Floor Lambeth Wing, St Thomas' Hospital, London SE1 7EH, United Kingdom.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Imberti
authors.affiliation: King's College London , Division of Imaging Sciences and Biomedical Engineering, Fourth Floor Lambeth Wing, St Thomas' Hospital, London SE1 7EH, United Kingdom.
authors.forename: Samantha Y A
authors.initials: SY
authors.lastname: Terry
authors.affiliation: Peter MacCallum Cancer Centre , Melbourne, Victoria 3000, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne , Parkville, Victoria 3010, Australia.
authors.forename: Carleen
authors.initials: C
authors.lastname: Cullinane
authors.affiliation: King's College London , Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, Faculty of Life Sciences and Medicine, London SE1 1UL, United Kingdom.
authors.forename: Fiona
authors.initials: F
authors.lastname: Clarke
authors.affiliation: King's College London , Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, Faculty of Life Sciences and Medicine, London SE1 1UL, United Kingdom.
authors.forename: Georgina H
authors.initials: GH
authors.lastname: Cornish
authors.affiliation: King's College London , Division of Imaging Sciences and Biomedical Engineering, Fourth Floor Lambeth Wing, St Thomas' Hospital, London SE1 7EH, United Kingdom.
authors.forename: Nisha K
authors.initials: NK
authors.lastname: Ramakrishnan
authors.affiliation: Peter MacCallum Cancer Centre , Melbourne, Victoria 3000, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Roselt
authors.affiliation: King's College London , Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, Faculty of Life Sciences and Medicine, London SE1 1UL, United Kingdom.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Cope
authors.affiliation: Peter MacCallum Cancer Centre , Melbourne, Victoria 3000, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne , Parkville, Victoria 3010, Australia.
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Hicks
authors.affiliation: King's College London , Division of Imaging Sciences and Biomedical Engineering, Fourth Floor Lambeth Wing, St Thomas' Hospital, London SE1 7EH, United Kingdom.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Blower
authors.affiliation: King's College London , Division of Imaging Sciences and Biomedical Engineering, Fourth Floor Lambeth Wing, St Thomas' Hospital, London SE1 7EH, United Kingdom.
authors.forename: Michelle T
authors.identifier: 0000-0002-3349-7346
authors.initials: MT
authors.lastname: Ma
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging; D002614:Chelating Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D005260:Female; D005710:Gallium Radioisotopes / Q000737:chemistry* / Q000493:pharmacokinetics; D039302:Integrin alphaVbeta3 / Q000032:analysis*; D007596:Joints / Q000000981:diagnostic imaging; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000000981:diagnostic imaging; D009842:Oligopeptides / Q000737:chemistry* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: C121031:3-hydroxypyridin-4-one; D002614:Chelating Agents; D005710:Gallium Radioisotopes; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D011725:Pyridines; C047981:arginyl-glycyl-aspartic acid