title: A novel PET protocol for visualization of breast cancer resistance protein function at the blood-brain barrier.
abstract: Breast cancer resistance protein (BCRP) is the most abundant multidrug efflux transporter at the human blood-brain barrier (BBB), restricting brain distribution of various drugs. In this study, we developed a positron emission tomography (PET) protocol to visualize Bcrp function at the murine BBB, based on the dual P-glycoprotein (P-gp)/Bcrp substrate radiotracer [(11)C]tariquidar in combination with the Bcrp inhibitor Ko143. To eliminate the contribution of P-gp efflux to [(11)C]tariquidar brain distribution, we studied mice in which P-gp was genetically knocked out (Mdr1a/b((-/-)) mice) or chemically knocked out by pretreatment with cold tariquidar. We found that [(11)C]tariquidar brain uptake increased dose dependently after administration of escalating doses of Ko143, both in Mdr1a/b((-/-)) mice and in tariquidar pretreated wild-type mice. After 15 mg/kg Ko143, the maximum increase in [(11)C]tariquidar brain uptake relative to baseline scans was 6.3-fold in Mdr1a/b((-/-)) mice with a half-maximum effect dose of 4.98 mg/kg and 3.6-fold in tariquidar (8 mg/kg) pretreated wild-type mice, suggesting that the presented protocol is sensitive to visualize a range of different functional Bcrp activities at the murine BBB. We expect that this protocol can be translated to the clinic, because tariquidar can be safely administered to humans at doses that completely inhibit cerebral P-gp.
authors: Health and Environment Department, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria.
authors: Thomas
authors: T
authors: Wanek
authors: Claudia
authors: C
authors: Kuntner
authors: Jens P
authors: JP
authors: Bankstahl
authors: Severin
authors: S
authors: Mairinger
authors: Marion
authors: M
authors: Bankstahl
authors: Johann
authors: J
authors: Stanek
authors: Michael
authors: M
authors: Sauberer
authors: Thomas
authors: T
authors: Filip
authors: Thomas
authors: T
authors: Erker
authors: Markus
authors: M
authors: Müller
authors: Wolfgang
authors: W
authors: Löscher
authors: Oliver
authors: O
authors: Langer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging* / Q000378:metabolism*; D003627:Data Interpretation, Statistical; D054659:Diketopiperazines; D004305:Dose-Response Relationship, Drug; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D011804:Quinolines; D019275:Radiopharmaceuticals
chemical_list: C541506:3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester; C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D054659:Diketopiperazines; D006576:Heterocyclic Compounds, 4 or More Rings; D009363:Neoplasm Proteins; D011804:Quinolines; D019275:Radiopharmaceuticals; C402343:tariquidar; D000241:Adenosine