Synthesis and in vivo evaluation of 11Ctariquidar a positron emission tomography radiotracer based on a third-generation P-glycoprotein inhibitor

摘要

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. O-desmethyl->1 was synthesized and reacted with [¹¹C]methyl triflate to afford [¹¹C]->1. Small-animal PET imaging of [¹¹C]->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 wild-type, Mdr1a/b^(−/−), Bcrp1^(−/−) and Mdr1a/b^(−/−)Bcrp1^(−/−) mice (n=3). In vitro autoradiography was performed with [¹¹C]->1 using brain sections of all 4 mouse types, with and without co-incubation 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-to-blood 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 [¹¹C]->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 [¹¹C]->1 interacts specifically with P-gp and BCRP in the BBB. However, further investigations are needed to assess if [¹¹C]->1 behaves in vivo as a transported or a non-transported inhibitor.