Synthesis and in vivo evaluation of [11C]tariquidar, a positron emission tomography radiotracer based on a third-generation P-glycoprotein inhibitor

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 [C-11] methyl triflate to afford [C-11]-1. Small-animal PET imaging of [C-11]-1 was performed in naive 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 four mouse types, with and without co-incubation with unlabeled 1 or elacridar (1 mu M). 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 [C-11]-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 [C-11]-1 interacts specifically with P-gp and BCRP in the BBB. However, further investigations are needed to assess if [C-11]-1 behaves in vivo as a transported or a non-transported inhibitor. (C) 2010 Elsevier Ltd. All rights reserved.