title: N-desmethyl-loperamide is selective for P-glycoprotein among three ATP-binding cassette transporters at the blood-brain barrier.
abstract: [(11)C]N-desmethyl-Loperamide ([(11)C]dLop) is used in positron emission tomography (PET) to measure the in vivo activity of efflux transporters that block the passage of drugs across the blood-brain barrier. The three most prevalent ATP-binding cassette efflux transporters at the blood-brain barrier are P-glycoprotein (P-gp), multidrug resistance protein 1 (Mrp1), and breast cancer resistance protein (BCRP). We sought to measure the selectivity of dLop among these three transporters. The selectivity of dLop at low concentrations (< or =1 nM) was measured both as the accumulation of [(3)H]dLop in human cells that overexpress each transporter and as the uptake of [(11)C]dLop in brains of mice that lack genes encoding P-gp, Mrp1, or BCRP. The selectivity of dLop at high concentrations (> or =20 microM) was measured as the inhibition of uptake of a fluorescent substrate and the change in cytotoxicity of drugs effluxed at each transporter. Accumulation of [(3)H]dLop was lowest in cells overexpressing P-gp, and the uptake of [(11)C]dLop was highest in brains of mice lacking P-gp. At high concentrations, dLop selectively inhibited P-gp function and also decreased the resistance of only the P-gp-expressing cells to cytotoxic agents. dLop is selective for P-gp among these three transporters, but its activity is dependent on concentration. At low concentrations (< or =1 nM), dLop acts only as a substrate; at high concentrations (> or =20 microM), it acts as both a substrate and an inhibitor (i.e., a competitive substrate). Because low concentrations of radiotracer are used for PET imaging, [(11)C]dLop acts selectively and only as a substrate for P-gp.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Pavitra
authors.initials: P
authors.lastname: Kannan
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Brimacombe
authors.forename: Sami S
authors.initials: SS
authors.lastname: Zoghbi
authors.forename: Jeih-San
authors.initials: JS
authors.lastname: Liow
authors.forename: Cheryl
authors.initials: C
authors.lastname: Morse
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Taku
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
authors.forename: Michael M
authors.initials: MM
authors.lastname: Gottesman
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hall
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000493:pharmacokinetics; D001692:Biological Transport / Q000502:physiology*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002560:Cerebrovascular Circulation; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D008139:Loperamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D019380:Anti-HIV Agents; D006023:Glycoproteins; D008139:Loperamide; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019275:Radiopharmaceuticals; C419149:N-demethylloperamide