Radiosynthesis and in vivo evaluation of 1-[18F]fluoroelacridar as a positron emission tomography tracer for P-glycoprotein and breast cancer resistance protein

Efflux transporters located at the blood–brain barrier, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), regulate the passage of many drugs in and out of the brain. Changes in the function and density of these proteins, in particular P-gp, may play a role in several neurological disorders. Several radioligands have been developed for measuring P-gp function at the blood–brain barrier of human subjects with positron emission tomography (PET). However, attempts to measure P-gp density with radiolabeled inhibitors that bind to these proteins in vivo have not thus far provided useful, quantifiable PET signals. Herein, we argue that not only the low density of transporters in the brain as a whole but also their very high density in brain capillaries act to lower the concentration of ligand in the plasma and thereby contribute to absent or low signals in PET studies of P-gp density. Our calculations, based on published data and theoretical approximations, estimate that whole brain densities of many efflux transporters at the blood–brain barrier range from 0.04 to 5.19 nM. We conclude that the moderate affinities (>5 nM) of currently labeled inhibitors may not allow measurement of efflux transporter density at the blood–brain barrier, and inhibitors with substantially higher affinity will be needed for density imaging of P-gp and other blood–brain barrier transporters.

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“…Brain uptake of other radiolabeled inhibitors followed a similar pattern in the four strains of mice. 16,17,21,22 …”

Section: Results From Pet Studies Measuring P-gp Densitymentioning

confidence: 99%

Factors That Limit Positron Emission Tomography Imaging of P-Glycoprotein Density at the Blood–Brain Barrier

et al. 2013

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“…In addition, an O ‐[ 18 F]fluoroethyl analog of elacridar was prepared by reaction of O ‐desmethyl elacridar with 2‐[ 18 F]fluoroethyl bromide (Scheme ) and shown to possess similar in vivo pharmacokinetics as [ 11 C]elacridar . A direct fluorination attempt at the para ‐position of the carboxylamide group in the acridone moiety of elacridar was also made (Scheme ), by reacting K[ 18 F]F‐K 222 at high temperature (175 °C) with the corresponding nitro‐precursor affording 1‐[ 18 F]fluoroelacridar in relatively low RCY (2%) and with low specific activity (approximately 8 GBq/µmol) . In rats and mice, 1‐[ 18 F]fluoroelacridar showed comparable pharmacokinetics as [ 11 C]elacridar; however, a significant degree of in vivo defluorination was observed .…”

Section: Radiolabeled Pgp Inhibitorsmentioning

confidence: 99%

Radioligands targeting P‐glycoprotein and other drug efflux proteins at the blood–brain barrier

Wanek

Mairinger

Langer

2013

Labelled Comp Radiopharmac

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Brain penetration of radiopharmaceuticals or therapeutic drugs may be restricted by adenosine triphosphate-binding cassette (ABC) transporters, such as P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), or the multidrug resistance-associated proteins. These transporters are expressed in the luminal membrane of brain capillary endothelial cells forming the blood-brain barrier (BBB), where they actively efflux a wide range of chemically unrelated compounds from the brain back into the blood. Most efforts to visualize ABC transporters at the BBB with positron emission tomography have concentrated on Pgp. Pgp imaging probes can be classified as radiolabeled substrates or inhibitors. The radiolabeled substrates (R)-[(11) C]verapamil and [(11) C]-N-desmethyl-loperamide have been successfully used to assess Pgp function at the BBB of animals and humans. Radiolabeled Pgp inhibitors, such as [(11) C]tariquidar, [(11) C]elacridar, or [(11) C]laniquidar, were developed to measure Pgp expression levels at the BBB, which has so far remained unsuccessful as these probes were unexpectedly recognized at tracer concentrations by Pgp and BCRP as substrates resulting in low brain uptake. Studies on positron emission tomography tracers for other ABC transporters than Pgp (BCRP and multidrug resistance-associated proteins) are still in their infancy. It is hoped that the experience gained with the imaging of Pgp will be successfully translated to the development of radiotracers to visualize other ABC transporters.

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“…Therefore, to visualize regionally overexpressed Pgp in disease states, it is necessary to coadminister Pgp inhibitors like tariquidar (TQD) at nonmaximal inhibiting doses . As an alternative strategy in several recent studies, we described the synthesis and in vivo pharmacokinetic properties of the radiolabeled MDT inhibitors [ 11 C]TQD and [ 11 C]ELC (elacridar) (Dörner et al, 2009;Bauer et al, 2010;Dörner et al, 2011;Wanek et al, 2012a, b).…”

Section: Introductionmentioning

confidence: 99%

Tariquidar and Elacridar Are Dose-Dependently Transported by P-Glycoprotein and Bcrp at the Blood-Brain Barrier: A Small-Animal Positron Emission Tomography and In Vitro Study

et al. 2013

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Elacridar (ELC) and tariquidar (TQD) are generally thought to be nontransported inhibitors of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP), but recent data indicate that they may also be substrates of these multidrug transporters (MDTs). The present study was designed to investigate potential transport of ELC and TQD by MDTs at the blood-brain barrier at tracer doses as used in positron emission tomography (PET) studies. We performed PET scans with carbon-11-labeled ELC and TQD before and after MDT inhibition in wild-type and transporterknockout mice as well as in in vitro transport assays in MDToverexpressing cells.

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Radiosynthesis and in vivo evaluation of 1-[18F]fluoroelacridar as a positron emission tomography tracer for P-glycoprotein and breast cancer resistance protein

Cited by 27 publications

References 22 publications

Factors That Limit Positron Emission Tomography Imaging of P-Glycoprotein Density at the Blood–Brain Barrier

Factors That Limit Positron Emission Tomography Imaging of P-Glycoprotein Density at the Blood–Brain Barrier

Radioligands targeting P‐glycoprotein and other drug efflux proteins at the blood–brain barrier

Tariquidar and Elacridar Are Dose-Dependently Transported by P-Glycoprotein and Bcrp at the Blood-Brain Barrier: A Small-Animal Positron Emission Tomography and In Vitro Study

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