title: Synthesis and in vivo evaluation of the putative breast cancer resistance protein inhibitor [11C]methyl 4-((4-(2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl)phenyl)amino-carbonyl)-2-(quinoline-2-carbonylamino)benzoate.
abstract: BACKGROUND
  The multidrug efflux transporter breast cancer resistance protein (BCRP) is highly expressed in the blood-brain barrier (BBB), where it limits brain entry of a broad range of endogenous and exogenous substrates. Methyl is a recently discovered BCRP-selective inhibitor, which is structurally derived from the potent P-glycoprotein (P-gp) inhibitor tariquidar. The aim of this study was to develop a new PET tracer based on 1 to map BCRP expression levels in vivo.
  
  
  METHODS
  Compound 1 was labelled with (11)C in its methyl ester function by reaction of the corresponding carboxylic acid 2 with [(11)C]methyl triflate. Positron emission tomography (PET) imaging of [(11)C]-1 was performed in wild-type, Mdr1a/b((-/-)), Bcrp1((-/-)) and Mdr1a/b((-/-))Bcrp1((-/-)) mice (n=3 per mouse type) and radiotracer metabolism was assessed in plasma and brain.
  
  
  RESULTS
  Brain-to-plasma ratios of unchanged [(11)C]-1 were 4.8- and 10.3-fold higher in Mdr1a/b((-/-)) and in Mdr1a/b((-/-))Bcrp1((-/-)) mice, respectively, as compared to wild-type animals, but only modestly increased in Bcrp1((-/-)) mice. [(11)C]-1 was rapidly metabolized in vivo giving rise to a polar radiometabolite which was taken up into brain tissue.
  
  
  CONCLUSIONS
  Our data suggest that [(11)C]-1 preferably interacts with P-gp rather than BCRP at the murine BBB which questions its reported in vitro BCRP selectivity. Consequently, [(11)C]-1 appears to be unsuitable as a PET tracer to map cerebral BCRP expression.
authors.affiliation: Department of Medicinal Chemistry, University of Vienna, 1090 Vienna, Austria.
authors.forename: Severin
authors.initials: S
authors.lastname: Mairinger
authors.forename: Oliver
authors.initials: O
authors.lastname: Langer
authors.forename: Claudia
authors.initials: C
authors.lastname: Kuntner
authors.forename: Thomas
authors.initials: T
authors.lastname: Wanek
authors.forename: Jens P
authors.initials: JP
authors.lastname: Bankstahl
authors.forename: Marion
authors.initials: M
authors.lastname: Bankstahl
authors.forename: Johann
authors.initials: J
authors.lastname: Stanek
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörner
authors.forename: Florian
authors.initials: F
authors.lastname: Bauer
authors.forename: Christoph
authors.initials: C
authors.lastname: Baumgartner
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Löscher
authors.forename: Thomas
authors.initials: T
authors.lastname: Erker
authors.forename: Markus
authors.initials: M
authors.lastname: Müller
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* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis* / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D005260:Female; D055786:Gene Knockout Techniques; D051379:Mice; D049268:Positron-Emission Tomography; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011849:Radioactive Tracers
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; D001565:Benzoates; D011804:Quinolines; D011849:Radioactive Tracers; C552746:methyl 4-((4-(2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl)phenyl)aminocarbonyl)-2-(quinoline-2-carbonylamino)benzoate