11C‐ and 18F‐Labeled Radioligands for P‐Glycoprotein Imaging by Positron Emission Tomography |
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Authors: | Dr. Mariangela Cantore Marcel Benadiba Philip H. Elsinga Chantal Kwizera Rudi A. J. O. Dierckx Nicola Antonio Colabufo Gert Luurtsema |
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Affiliation: | 1. (+39)?0805442231;2. Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;3. Biofordrug s.r.l., Spin-off dell'Università degli Studi di Bari “A. Moro”, Bari, Italy;4. Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari “A. Moro”, Bari, Italy |
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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‐(11C)‐5‐methoxyphenyl)oxazol‐4‐ylmethyl]‐6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline ([11C]‐ 5 ); 2‐[2‐(2‐fluoromethyl‐(18F)‐5‐methoxyphenyl)oxazol‐4‐ylmethyl]‐6,7‐dimethoxy‐1,2,3,4‐tetra‐hydroisoquinoline ([18F]‐ 6 ); and 2‐[2‐(2‐fluoroethyl‐(18F)‐5‐methoxyphenyl)oxazol‐4‐ylmethyl]‐6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline ([18F]‐ 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 [11C]‐ 5 is a potent P‐gp substrate, whereas the corresponding fluoroethyl derivative [18F]‐ 7 is a P‐gp inhibitor. Fluoromethyl compound [18F]‐ 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, [11C]‐ 5 and [18F]‐ 7 , respectively, for in vivo imaging of P‐gp by using PET. |
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Keywords: | glycoproteins inhibitors isotope labeling positron emission tomography radioligands |
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