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.
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.
Mairinger
Severin
S
Department of Medicinal Chemistry, University of Vienna, 1090 Vienna, Austria.
Langer
Oliver
O
Kuntner
Claudia
C
Wanek
Thomas
T
Bankstahl
Jens P
JP
Bankstahl
Marion
M
Stanek
Johann
J
Dörner
Bernd
B
Bauer
Florian
F
Baumgartner
Christoph
C
Löscher
Wolfgang
W
Erker
Thomas
T
Müller
Markus
M
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
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