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Eur J Pharmacol. 2012 Dec 5;696(1-3):18-27. doi: 10.1016/j.ejphar.2012.09.013. Epub 2012 Sep 26.

Interaction of HM30181 with P-glycoprotein at the murine blood-brain barrier assessed with positron emission tomography.

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Department of Medicinal Chemistry, University of Vienna, Vienna, Austria.


HM30181, a potent and selective inhibitor of the adenosine triphosphate-binding cassette transporter P-glycoprotein (Pgp), was shown to enhance oral bioavailability and improve antitumour efficacy of paclitaxel in mouse tumour models. In search for a positron emission tomography (PET) radiotracer to visualise Pgp expression levels at the blood-brain barrier (BBB), we examined the ability of HM30181 to inhibit Pgp at the murine BBB. HM30181 was shown to be approximately equipotent with the reference Pgp inhibitor tariquidar in inhibiting rhodamine 123 efflux from CCRF-CEM T cells (IC(50), tariquidar: 8.2 ± 2.0 nM, HM30181: 13.1 ± 2.3 nM). PET scans with the Pgp substrate (R)-[(11)C]verapamil in FVB wild-type mice pretreated i.v. with HM30181 (10 or 21 mg/kg) failed to show significant increases in (R)-[(11)C]verapamil brain uptake compared with vehicle treated animals. PET scans with [(11)C]HM30181 showed low and not significantly different brain uptake of [(11)C]HM30181 in wild-type, Mdr1a/b((-/-)) and Bcrp1((-/-)) mice and significantly, i.e. 4.7-fold (P<0.01), higher brain uptake, relative to wild-type animals, in Mdr1a/b((-/-))Bcrp1((-/-)) mice. This was consistent with HM30181 being at microdoses a dual substrate of Pgp and breast cancer resistance protein (Bcrp). In vitro autoradiography on low (EMT6) and high (EMT6Ar1.0) Pgp expressing murine breast tumour sections showed 1.9 times higher binding of [(11)C]HM30181 in EMT6Ar1.0 tumours (P<0.001) which was displaceable with unlabelled tariquidar, elacridar or HM30181 (1 μM). Our data suggest that HM30181 is not able to inhibit Pgp at the murine BBB at clinically feasible doses and that [(11)C]HM30181 is not suitable as a PET tracer to visualise cerebral Pgp expression levels.

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