title: (11)C- and (18)F-Labeled Radioligands for P-Glycoprotein Imaging by Positron Emission Tomography.
abstract: P-Glycoprotein (P-gp) is an efflux transporter widely expressed at the human blood-brain barrier. It is involved in xenobiotics efflux and in onset and progression of neurodegenerative disorders. For these reasons, there is great interest in the assessment of P-gp expression and function by noninvasive techniques such as positron emission tomography (PET). Three radiolabeled aryloxazole derivatives: 2-[2-(2-methyl-((11)C)-5-methoxyphenyl)oxazol-4-ylmethyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ([(11)C]-5); 2-[2-(2-fluoromethyl-((18)F)-5-methoxyphenyl)oxazol-4-ylmethyl]-6,7-dimethoxy-1,2,3,4-tetra-hydroisoquinoline ([(18)F]-6); and 2-[2-(2-fluoroethyl-((18)F)-5-methoxyphenyl)oxazol-4-ylmethyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ([(18)F]-7), were tested in several in vitro biological assays to assess the effect of the aryl substituent in terms of potency and mechanism of action toward P-gp. Methyl derivative [(11)C]-5 is a potent P-gp substrate, whereas the corresponding fluoroethyl derivative [(18)F]-7 is a P-gp inhibitor. Fluoromethyl compound [(18)F]-6 is classified as a non-transported P-gp substrate, because its efflux increases after cyclosporine A modulation. These studies revealed a promising substrate and inhibitor, [(11)C]-5 and [(18)F]-7, respectively, for in vivo imaging of P-gp by using PET.
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. mariangelacantore@gmail.com.|Biofordrug s.r.l., Spin-off dell'Università degli Studi di Bari "A. Moro", via Orabona 4, 70125, Bari, Italy. mariangelacantore@gmail.com.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Cantore
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Benadiba
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Elsinga
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Chantal
authors.initials: C
authors.lastname: Kwizera
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Rudi A J O
authors.initials: RA
authors.lastname: Dierckx
authors.affiliation: Biofordrug s.r.l., Spin-off dell'Università degli Studi di Bari "A. Moro", via Orabona 4, 70125, Bari, Italy.|Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "A. Moro", via Orabona 4, 70125, Bari, Italy.
authors.forename: Nicola Antonio
authors.initials: NA
authors.lastname: Colabufo
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Luurtsema
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018938:Caco-2 Cells; D002250:Carbon Radioisotopes; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005462:Fluorine Radioisotopes; D006801:Humans; D007553:Isotope Labeling; D008024:Ligands; D057054:Molecular Imaging; D015394:Molecular Structure; D049268:Positron-Emission Tomography; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D008024:Ligands
keywords: glycoproteins; inhibitors; isotope labeling; positron emission tomography; radioligands