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

Bioorganic & Medicinal Chemistry
Florian BauerOliver Langer

Abstract

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 [(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 (5mg/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 [(11)C]-1 using brain sections of all four mouse types, with and without co-incubation with unlabeled 1 or elacridar (1 microM). 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 appro...Continue Reading

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Jan 26, 2013·Bioorganic & Medicinal Chemistry·Nicola A ColabufoRoberto Perrone
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