The aim of this study was to develop a positron emission tomography (PET) tracer based on the dual P-glycoprotein (P-gp) breast cancer resistance protein (BCRP) inhibitor tariquidar (1) to study the interaction of 1 with P-gp and BCRP in the blood-brain barrier (BBB) in vivo. Odesmethyl-1 was synthesized and reacted with [ 11 C]methyl triflate to afford [ 11 C]-1. Small-animal PET imaging of [ 11 C]-1 was performed in naïve rats, before and after administration of unlabeled 1 (15 mg/kg, n=3) or the dual P-gp/BCRP inhibitor elacridar (5 mg/kg, n=2), as well as in wildtype, Mdr1a/b (−/−) , Bcrp1 (−/−) and Mdr1a/b (−/−) Bcrp1 (−/−) mice (n=3). In vitro autoradiography was performed with [ 11 C]-1 using brain sections of all 4 mouse types, with and without coincubation with unlabeled 1 or elacridar (1 μM). In PET experiments in rats, administration of unlabeled 1 or elacridar increased brain activity uptake by a factor of 3-4, whereas blood activity levels remained unchanged. In Mdr1a/b (−/−) , Bcrp1 (−/−) and Mdr1a/b (−/−) Bcrp1 (−/−) mice, brain-toblood ratios of activity at 25 min after tracer injection were 3.4, 1.8 and 14.5 times higher, respectively, as compared to wild-type animals. Autoradiography showed approximately 50% less [ 11 C]-1 binding in transporter knockout mice compared to wild-type mice and significant displacement by unlabeled elacridar in wild-type and Mdr1a/b (−/−) mouse brains. Our data suggest that [ 11 C]-1 interacts specifically with P-gp and BCRP in the BBB. However, further investigations are needed to assess if [ 11 C]-1 behaves in vivo as a transported or a non-transported inhibitor.
With the aim to develop a positron emission tomography (PET) tracer to assess the distribution of P-glycoprotein (P-gp) at the blood-brain barrier (BBB) in vivo, the potent third-generation P-gp inhibitor elacridar (1) was labeled with 11 C by reaction of O-desmethyl 1 with [ 11 C]-methyl triflate. In vitro autoradiography and small-animal PET imaging of [ 11 C]-1 was performed in rats (n=3), before and after administration of unlabeled 1, as well as in wild-type, Mdr1a/b (−/−) and Bcrp1 (−/−) mice (n=3). In PET experiments in rats, administration of unlabeled 1 increased brain activity uptake 5.4-fold, whereas blood activity levels remained unchanged. In Mdr1a/b (−/−) mice, brain activity uptake was 2.5-fold higher compared to wild-type animals, whereas in Bcrp1 (−/−) mice brain activity uptake was only 1.3-fold higher. In vitro autoradiography showed that 63% of [ 11 C]-1 binding was displaceable by an excess of unlabeled 1. As the signal obtained with [ 11 C]-1 appeared to be specific for P-gp at the BBB, its utility for the visualization of cerebral P-gp merits further investigation.
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