title: Synthesis of multi-galactose-conjugated 2'-O-methyl oligoribonucleotides and their in vivo imaging with positron emission tomography.
abstract: (68)Ga labelled 2'-O-methyl oligoribonucleotides (anti-miR-15b) bearing one, three or seven d-galactopyranoside residues have been prepared and their distribution in healthy rats has been studied by positron emission tomography (PET). To obtain the heptavalent conjugate, an appropriately protected 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) precursor bearing a 4-[4-(4,4'-dimethoxytrityloxy)butoxy]phenyl side arm was first immobilized via a base labile linker to the support and the oligonucleotide was assembled on the detritylated hydroxyl function of this handle. A phosphoramidite building block bearing two phthaloyl protected aminooxy groups and one protected hydroxyl function was introduced into the 5'-terminus. One acetylated galactopyranoside was coupled as a phosphoramidite to the hydroxyl function, the phthaloyl protections were removed on-support and two trivalent galactopyranoside clusters were attached as aldehydes by on-support oximation. A two-step cleavage with aqueous alkali and ammonia released the conjugate in a fully deprotected form, allowing radiolabelling with (68)Ga in solution. The mono- and tri-galactose conjugates were obtained in a closely related manner. In vivo imaging in rats with PET showed remarkable galactose-dependent liver targeting of the conjugates.
authors.affiliation: Skeletal Biology Consortium, Department of Cell Biology and Anatomy, University of Turku, FI-20520 Turku, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Mäkilä
authors.affiliation: Department of Chemistry, University of Turku, FI-20014 Turku, Finland.
authors.forename: Satish
authors.initials: S
authors.lastname: Jadhav
authors.affiliation: Department of Chemistry, University of Turku, FI-20014 Turku, Finland.
authors.forename: Anu
authors.initials: A
authors.lastname: Kiviniemi
authors.affiliation: Turku PET Centre, University of Turku and Turku University Hospital, FI-20520 Turku, Finland.
authors.forename: Meeri
authors.initials: M
authors.lastname: Käkelä
authors.affiliation: Turku PET Centre, University of Turku and Turku University Hospital, FI-20520 Turku, Finland; Turku Center for Disease Modelling, University of Turku, FI-20520 Turku, Finland.
authors.forename: Heidi
authors.initials: H
authors.lastname: Liljenbäck
authors.affiliation: Department of Chemistry, University of Turku, FI-20014 Turku, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Poijärvi-Virta
authors.affiliation: Skeletal Biology Consortium, Department of Cell Biology and Anatomy, University of Turku, FI-20520 Turku, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Laitala-Leinonen
authors.affiliation: Department of Chemistry, University of Turku, FI-20014 Turku, Finland.
authors.forename: Harri
authors.initials: H
authors.lastname: Lönnberg
authors.affiliation: Turku PET Centre, University of Turku and Turku University Hospital, FI-20520 Turku, Finland; Turku Center for Disease Modelling, University of Turku, FI-20520 Turku, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Roivainen
authors.affiliation: Department of Chemistry, University of Turku, FI-20014 Turku, Finland. Electronic address: pamavi@utu.fi.
authors.forename: Pasi
authors.initials: P
authors.lastname: Virta
mesh_terms: D000818:Animals; D005260:Female; D005690:Galactose / Q000737:chemistry; D005710:Gallium Radioisotopes / Q000737:chemistry; D006571:Heterocyclic Compounds / Q000737:chemistry; D007668:Kidney / Q000378:metabolism; D008107:Liver Diseases / Q000175:diagnosis / Q000378:metabolism; D008297:Male; D009843:Oligoribonucleotides / Q000737:chemistry* / Q000652:urine; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005710:Gallium Radioisotopes; D006571:Heterocyclic Compounds; D009843:Oligoribonucleotides; D019275:Radiopharmaceuticals; C075712:1,4,7-triazacyclononane; D005690:Galactose
keywords: (68)Ga-labelled oligonucleotides; Liver targeting; Oligonucleotide-glyco-conjugates; PET-imaging; Solid-phase synthesis