title: Synthesis and Preclinical Evaluation of Three Novel Fluorine-18 Labeled Radiopharmaceuticals for P-Glycoprotein PET Imaging at the Blood-Brain Barrier.
abstract: P-Glycoprotein (P-gp), along with other transporter proteins at the blood-brain barrier (BBB), limits the entry of many pharmaceuticals into the brain. Altered P-gp function has been found in several neurological diseases. To study the P-gp function, many positron emission tomography (PET) radiopharmaceuticals have been developed. Most P-gp radiopharmaceuticals are labeled with carbon-11, while labeling with fluorine-18 would increase their applicability due to longer half-life. Here we present the synthesis and in vivo evaluation of three novel fluorine-18 labeled radiopharmaceuticals: 4-((6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-2-(4-fluorophenyl)oxazole (1a), 2-biphenyl-4-yl-2-fluoroethoxy-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline (2), and 5-(1-(2-fluoroethoxy))-[3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-5,6,7,8-tetrahydronaphthalen (3). Compounds were characterized as P-gp substrates in vitro, and Mdr1a/b((-/-))Bcrp1((-/-)) and wild-type mice were used to assess the substrate potential in vivo. Comparison was made to (R)-[(11)C]verapamil, which is currently the most frequently used P-gp substrate. Compound [(18)F]3 was performing the best out of the new radiopharmaceuticals; it had 2-fold higher brain uptake in the Mdr1a/b((-/-))Bcrp1((-/-)) mice compared to wild-type and was metabolically quite stable. In the plasma, 69% of the parent compound was intact after 45 min and 96% in the brain. Selectivity of [(18)F]3 to P-gp was tested by comparing the uptake in Mdr1a/b((-/-)) mice to uptake in Mdr1a/b((-/-))Bcrp1((-/-)) mice, which was statistically not significantly different. Hence, [(18)F]3 was found to be selective for P-gp and is a promising new radiopharmaceutical for P-gp PET imaging at the BBB.
authors.affiliation: †Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands.
authors.forename: Heli
authors.initials: H
authors.lastname: Savolainen
authors.affiliation: ‡Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari, via Orabona 4, 70125 Bari, Italy.|§Biofordrug slr, via Orabona 4, 70125 Bari, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Cantore
authors.affiliation: ‡Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari, via Orabona 4, 70125 Bari, Italy.|§Biofordrug slr, via Orabona 4, 70125 Bari, Italy.
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Colabufo
authors.affiliation: †Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Elsinga
authors.affiliation: ∥Department of Radiology and Nuclear Medicine, VU University Medical Center Amsterdam, De Boelelaan 1085 C, 1081 HV Amsterdam, Netherlands.
authors.forename: Albert D
authors.initials: AD
authors.lastname: Windhorst
authors.affiliation: †Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Luurtsema
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D018938:Caco-2 Cells; D002250:Carbon Radioisotopes / Q000737:chemistry; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D006207:Half-Life; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000737:chemistry*; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals
keywords: 18F; BCRP; P-glycoprotein; PET; blood−brain barrier; radiopharmaceutical