title: Synthesis and in vivo evaluation of [11C]tariquidar, a positron emission tomography radiotracer based on a third-generation P-glycoprotein inhibitor.
abstract: The aim of this study was to develop a positron emission tomography (PET) tracer based on the dual P-glycoprotein (P-gp) breast cancer resistance protein (BCRP) inhibitor tariquidar (1) to study the interaction of 1 with P-gp and BCRP in the blood-brain barrier (BBB) in vivo. O-Desmethyl-1 was synthesized and reacted with [(11)C]methyl triflate to afford [(11)C]-1. Small-animal PET imaging of [(11)C]-1 was performed in naïve rats, before and after administration of unlabeled 1 (15 mg/kg, n=3) or the dual P-gp/BCRP inhibitor elacridar (5mg/kg, n=2), as well as in wild-type, Mdr1a/b((-/-)), Bcrp1((-/-)) and Mdr1a/b((-/-))Bcrp1((-/-)) mice (n=3). In vitro autoradiography was performed with [(11)C]-1 using brain sections of all four mouse types, with and without co-incubation with unlabeled 1 or elacridar (1 microM). In PET experiments in rats, administration of unlabeled 1 or elacridar increased brain activity uptake by a factor of 3-4, whereas blood activity levels remained unchanged. In Mdr1a/b((-/-)), Bcrp1((-/-)) and Mdr1a/b((-/-))Bcrp1((-/-)) mice, brain-to-blood ratios of activity at 25 min after tracer injection were 3.4, 1.8 and 14.5 times higher, respectively, as compared to wild-type animals. Autoradiography showed approximately 50% less [(11)C]-1 binding in transporter knockout mice compared to wild-type mice and significant displacement by unlabeled elacridar in wild-type and Mdr1a/b((-/-)) mouse brains. Our data suggest that [(11)C]-1 interacts specifically with P-gp and BCRP in the BBB. However, further investigations are needed to assess if [(11)C]-1 behaves in vivo as a transported or a non-transported inhibitor.
authors.affiliation: Department of Medicinal Chemistry, University of Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Bauer
authors.forename: Claudia
authors.initials: C
authors.lastname: Kuntner
authors.forename: Jens P
authors.initials: JP
authors.lastname: Bankstahl
authors.forename: Thomas
authors.initials: T
authors.lastname: Wanek
authors.forename: Marion
authors.initials: M
authors.lastname: Bankstahl
authors.forename: Johann
authors.initials: J
authors.lastname: Stanek
authors.forename: Severin
authors.initials: S
authors.lastname: Mairinger
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörner
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Löscher
authors.forename: Markus
authors.initials: M
authors.lastname: Müller
authors.forename: Thomas
authors.initials: T
authors.lastname: Erker
authors.forename: Oliver
authors.initials: O
authors.lastname: Langer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001812:Blood-Brain Barrier / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000737:chemistry; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D049268:Positron-Emission Tomography; D011804:Quinolines / Q000737:chemistry*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D002250:Carbon Radioisotopes; D011804:Quinolines; D019275:Radiopharmaceuticals; C402343:tariquidar