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

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. 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.

The “Specific” P-Glycoprotein Inhibitor Tariquidar Is Also a Substrate and an Inhibitor for Breast Cancer Resistance Protein (BCRP/ABCG2)

“…Neurosci. (2011), 2, 82-89 pubs.acs.org/acschemicalneuroscience Letter abcb1a/b/abcg2 mice (8,9). Tariquidar has been reported to inhibit the function of BCRP at micromolar concentrations (11,12), but the imaging studies indicate that tariquidar may interact with BCRP at much lower concentrations, suggesting to us that it may be a substrate of BCRP.…”

The Blood Brain Barrier — Regulation of Fatty Acid and Drug Transport

“…The third generation inhibitors including tariquidar and elacridar are much more specific and more potent than earlier compounds. Unlike the first and second generation of P-gp inhibitors, the third generation of drugs acts as non-competitive inhibitors of P-gp, and the compounds themselves are not transported by Pgp [155]. Table 2 summarizes representative P-gp inhibitors [104].…”

Role of (Drug) Transporters in Imaging in Health and Disease

“…As alternative to (R)-[ 11 C]verapamil for measurement of P-gp function at the BBB, we developed [ 11 C]tariquidar as a potential radiotracer to measure P-gp density at the BBB (Bauer et al, 2010). In vitro autoradiography showed higher binding of …”