title: The Inhibitor Ko143 Is Not Specific for ABCG2.
abstract: Imaging ATP-binding cassette (ABC) transporter activity in vivo with positron emission tomography requires both a substrate and a transporter inhibitor. However, for ABCG2, there is no inhibitor proven to be specific to that transporter alone at the blood-brain barrier. Ko143 [[(3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino[1',2':1,6]pyrido[3,4- b]indole-3-propanoic acid 1,1-dimethylethyl ester], a nontoxic analog of fungal toxin fumitremorgin C, is a potent inhibitor of ABCG2, although its specificity in mouse and human systems is unclear. This study examined the selectivity of Ko143 using human embryonic kidney cell lines transfected with ABCG2, ABCB1, or ABCC1 in several in vitro assays. The stability of Ko143 in rat plasma was measured using high performance liquid chromatography. Our results show that, in addition to being a potent inhibitor of ABCG2, at higher concentrations (≥1 μM) Ko143 also has an effect on the transport activity of both ABCB1 and ABCC1. Furthermore, Ko143 was found to be unstable in rat plasma. These findings indicate that Ko143 lacks specificity for ABCG2 and this should be taken into consideration when using Ko143 for both in vitro and in vivo experiments.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland (L.D.W., S.S.Z., S.L., V.W.P., R.B.I.); Karolinska Institutet, Department of Neuroscience, Stockholm, Sweden (L.D.W., J.M.); and Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (S.S., S.V.A., M.M.G., M.D.H.) lora.deuitch@nih.gov.
authors.forename: Lora D
authors.initials: LD
authors.lastname: Weidner
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland (L.D.W., S.S.Z., S.L., V.W.P., R.B.I.); Karolinska Institutet, Department of Neuroscience, Stockholm, Sweden (L.D.W., J.M.); and Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (S.S., S.V.A., M.M.G., M.D.H.).
authors.forename: Sami S
authors.initials: SS
authors.lastname: Zoghbi
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland (L.D.W., S.S.Z., S.L., V.W.P., R.B.I.); Karolinska Institutet, Department of Neuroscience, Stockholm, Sweden (L.D.W., J.M.); and Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (S.S., S.V.A., M.M.G., M.D.H.).
authors.forename: Shuiyu
authors.initials: S
authors.lastname: Lu
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland (L.D.W., S.S.Z., S.L., V.W.P., R.B.I.); Karolinska Institutet, Department of Neuroscience, Stockholm, Sweden (L.D.W., J.M.); and Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (S.S., S.V.A., M.M.G., M.D.H.).
authors.forename: Suneet
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland (L.D.W., S.S.Z., S.L., V.W.P., R.B.I.); Karolinska Institutet, Department of Neuroscience, Stockholm, Sweden (L.D.W., J.M.); and Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (S.S., S.V.A., M.M.G., M.D.H.).
authors.forename: Suresh V
authors.initials: SV
authors.lastname: Ambudkar
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland (L.D.W., S.S.Z., S.L., V.W.P., R.B.I.); Karolinska Institutet, Department of Neuroscience, Stockholm, Sweden (L.D.W., J.M.); and Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (S.S., S.V.A., M.M.G., M.D.H.).
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland (L.D.W., S.S.Z., S.L., V.W.P., R.B.I.); Karolinska Institutet, Department of Neuroscience, Stockholm, Sweden (L.D.W., J.M.); and Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (S.S., S.V.A., M.M.G., M.D.H.).
authors.forename: Jan
authors.initials: J
authors.lastname: Mulder
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland (L.D.W., S.S.Z., S.L., V.W.P., R.B.I.); Karolinska Institutet, Department of Neuroscience, Stockholm, Sweden (L.D.W., J.M.); and Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (S.S., S.V.A., M.M.G., M.D.H.).
authors.forename: Michael M
authors.initials: MM
authors.lastname: Gottesman
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland (L.D.W., S.S.Z., S.L., V.W.P., R.B.I.); Karolinska Institutet, Department of Neuroscience, Stockholm, Sweden (L.D.W., J.M.); and Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (S.S., S.V.A., M.M.G., M.D.H.).
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland (L.D.W., S.S.Z., S.L., V.W.P., R.B.I.); Karolinska Institutet, Department of Neuroscience, Stockholm, Sweden (L.D.W., J.M.); and Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (S.S., S.V.A., M.M.G., M.D.H.).
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hall
mesh_terms: D016475:3T3 Cells; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D054659:Diketopiperazines; D057809:HEK293 Cells; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000241:Adenosine; D054659:Diketopiperazines; D006576:Heterocyclic Compounds, 4 or More Rings; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; 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