title: Interaction of 11C-tariquidar and 11C-elacridar with P-glycoprotein and breast cancer resistance protein at the human blood-brain barrier.
abstract: The adenosine triphosphate-binding cassette transporters P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) are 2 major gatekeepers at the blood-brain barrier (BBB) that restrict brain distribution of several clinically used drugs. In this study, we investigated the suitability of the radiolabeled Pgp/BCRP inhibitors (11)C-tariquidar and (11)C-elacridar to assess Pgp density in the human brain with PET.
  
  
  METHODS
  Healthy subjects underwent a first PET scan of 120-min duration with either (11)C-tariquidar (n = 6) or (11)C-elacridar (n = 5) followed by a second PET scan of 60-min duration with (R)-(11)C-verapamil. During scan 1 (at 60 min after radiotracer injection), unlabeled tariquidar (3 mg/kg) was intravenously administered. Data were analyzed using 1-tissue 2-rate-constant (1T2K) and 2-tissue 4-rate-constant (2T4K) compartment models and either metabolite-corrected or uncorrected arterial input functions.
  
  
  RESULTS
  After injection of (11)C-tariquidar or (11)C-elacridar, the brain PET signal corrected for radioactivity in the vasculature was low (~0.1 standardized uptake value), with slow washout. In response to tariquidar injection, a moderate but statistically significant rise in brain PET signal was observed for (11)C-tariquidar (+27% ± 15%, P = 0.014, paired t test) and (11)C-elacridar (+21% ± 15%, P = 0.014) without changes in plasma activity concentrations. Low levels of radiolabeled metabolites (<25%) were detected in plasma up to 60 min after injection of (11)C-tariquidar or (11)C-elacridar. The 2T4K model provided better data fits than the 1T2K model. Model outcome parameters were similar when metabolite-corrected or uncorrected input functions were used. There was no significant correlation between distribution volumes of (11)C-tariquidar or (11)C-elacridar and distribution volumes of (R)-(11)C-verapamil in different brain regions.
  
  
  CONCLUSIONS
  The in vivo behavior of (11)C-tariquidar and (11)C-elacridar was consistent with that of dual Pgp/BCRP substrates. Both tracers were unable to visualize cerebral Pgp density, most likely because of insufficiently high binding affinities in relation to the low density of Pgp in human brain (∼1.3 nM). Despite their inability to visualize Pgp density, (11)C-tariquidar and (11)C-elacridar may find use as a new class of radiotracers to study the interplay of Pgp and BCRP at the human BBB in limiting brain uptake of dual substrates.
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Bauer
authors.forename: Rudolf
authors.initials: R
authors.lastname: Karch
authors.forename: Markus
authors.initials: M
authors.lastname: Zeitlinger
authors.forename: Johann
authors.initials: J
authors.lastname: Stanek
authors.forename: Cécile
authors.initials: C
authors.lastname: Philippe
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wadsak
authors.forename: Markus
authors.initials: M
authors.lastname: Mitterhauser
authors.forename: Walter
authors.initials: W
authors.lastname: Jäger
authors.forename: Helmuth
authors.initials: H
authors.lastname: Haslacher
authors.forename: Markus
authors.initials: M
authors.lastname: Müller
authors.forename: Oliver
authors.initials: O
authors.lastname: 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 / Q000378:metabolism*; D000166:Acridines / Q000378:metabolism*; D000328:Adult; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011804:Quinolines / Q000378:metabolism*; D044005:Tetrahydroisoquinolines / Q000378:metabolism*
chemical_list: 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; D000166:Acridines; D002250:Carbon Radioisotopes; D009363:Neoplasm Proteins; D011804:Quinolines; D044005:Tetrahydroisoquinolines; C402343:tariquidar; C083501:Elacridar
keywords: 11C-elacridar; 11C-tariquidar; P-glycoprotein; blood-brain barrier; breast cancer resistance protein