Synthesis and evaluation of [11C]XR9576 to assess the function of drug efflux transporters using PET

Kawamura, Kazunori; Konno, Fujiko; Yui, Joji; Yamasaki, Tomoteru; Hatori, Akiko; Yanamoto, Kazuhiko; Wakizaka, Hidekatsu; Takei, Makoto; Nengaki, Nobuki; Fukumura, Toshimitsu; Zhang, Ming‐Rong

doi:10.1007/s12149-010-0373-y

Cited by 37 publications

(54 citation statements)

References 31 publications

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“…Unexpectedly, our PET studies showed very low brain uptake of both tracers in wild-type mice, but uptake increased several times in Pgp/Bcrp1-deficient mice (Dörner et al, 2009;Bauer et al, 2010), indicating a possible substrate-like behavior. In parallel to our studies, Kawamura et al (2010Kawamura et al ( , 2011 reported similar findings. Nevertheless, until now it was still unclear if ELC and TQD are indeed MDT substrates in vivo.…”

Section: Introductionsupporting

confidence: 91%

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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Section: Introductionsupporting

confidence: 91%

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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“…3) supports the possibility that both of the radiotracers or their radiolabeled metabolites are excreted into bile. A previous study assessed the effect of increasing doses of unlabeled tariquidar on whole-body distribution of 11 C-tariquidar in mice and found a dosedependent decrease in the radioactivity recovered from the small intestine (14). This result suggests a saturable, transportermediated mechanism of biliary excretion or intestinal secretion.…”

Section: Discussionmentioning

confidence: 89%

Whole-Body Distribution and Radiation Dosimetry of ¹¹C-Elacridar and ¹¹C-Tariquidar in Humans

et al. 2016

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11 C-elacridar and 11 C-tariquidar are new PET tracers to assess the transport activity of P-glycoprotein (adenosine triphosphate-binding cassette subfamily B, member 1 [ABCB1]) and breast cancer resistance protein (adenosine triphosphate-binding cassette subfamily G, member 2 [ABCG2]). This study investigated the whole-body distribution and radiation dosimetry of both radiotracers in humans. Methods: Twelve healthy volunteers (6 women, 6 men) underwent whole-body PET/CT imaging over the 90 min after injection of either 11 C-elacridar or 11 C-tariquidar. Radiation doses were calculated with OLINDA/EXM software using adult reference phantoms. Results: Biodistribution was consistent with a major elimination route of hepatobiliary excretion, which may be mediated by ABCB1 and ABCG2. High radioactivity uptake was seen in liver, followed by spleen and kidneys, whereas brain uptake was lowest. Effective doses were 3.41 ± 0.06 μSv/MBq for 11 C-elacidar and 3.62 ± 0.11 μSv/MBq for 11 C-tariquidar. Conclusion: Our data indicate that both 11 C-elacridar and 11 C-tariquidar are safe radiotracers, for which an injected activity of 400 MBq corresponds to a total effective dose of approximately 1.5 mSv.

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“…The LLC-BCRP cells were generated in this study (Fig. 5), whereas the LLC-MDR1, LLC-vector, and LLC-EQ cells have previously been characterized (Fung et al, 2014a,b , and Bcrp1 (2/2) mice (Bauer et al, 2010;Kawamura et al, 2010). Although these results were counterintuitive at the time, the authors concluded that [ 11 C]TQR was a nontransported inhibitor of P-gp because of existing in vitro data and data from another study, which showed increased [ 11 C]TQR signal in a rat model of P-gp overexpression compared with naïve rats (Kuntner et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…11 C]TQR, only mice genetically lacking both BCRP and P-gp exhibited brain penetration of [ 11 C]TQR as compared with mice lacking either BCRP or P-gp (Bauer et al, 2010;Kawamura et al, 2010). Third, Bankstahl et al (2013) reported that, in a transwell apparatus, cells expressing mouse or human P-gp accumulated more [ 3 H]TQR in the presence of the P-gp inhibitor PSC833 (6-[(2S,4R,6E)-4-methyl-2-(methylamino)-3-oxo-6-octenoic acid]-7-L-valine-cyclosporin A).…”

Section: Introductionmentioning

confidence: 99%

Tariquidar Is an Inhibitor and Not a Substrate of Human and Mouse P-glycoprotein

Weidner

Fung

Kannan

et al. 2015

Drug Metabolism and Disposition

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Since its development, tariquidar (TQR; XR9576;4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]carbamoyl]-4,5-dimethoxyphenyl]quinoline-3-carboxamide) has been widely regarded as one of the more potent inhibitors of P-glycoprotein (P-gp), an efflux transporter of the ATP-binding cassette (ABC) transporter family. A third-generation inhibitor, TQR exhibits high affinity for P-gp, although it is also a substrate of another ABC transporter, breast cancer resistance protein (BCRP). Recently, several studies have questioned the mechanism by which TQR interfaces with P-gp, suggesting that TQR is a substrate for P-gp instead of a noncompetitive inhibitor. We investigated TQR and its interaction with human and mouse P-gp to determine if TQR is a substrate of P-gp in vitro. To address these questions, we used multiple in vitro transporter assays, including cytotoxicity, flow cytometry, accumulation, ATPase, and transwell assays. A newly generated BCRP cell line was used as a positive control that demonstrates TQR-mediated transport. Based on our results, we conclude that TQR is a potent inhibitor of both human and mouse P-gp and shows no signs of being a substrate at the concentrations tested. These in vitro data further support our position that the in vivo uptake of [ 11 C]TQR into the brain can be explained by its highaffinity binding to P-gp and by it being a substrate of BCRP, followed by amplification of the brain signal by ionic trapping in acidic lysosomes.

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Synthesis and evaluation of [11C]XR9576 to assess the function of drug efflux transporters using PET

Abstract: PET studies using [(11)C]XR9576 may be a promising approach for evaluating deficiency of the function of drug efflux transporters targeting intracranial diseases and tumors.

Cited by 37 publications

References 31 publications

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

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

Whole-Body Distribution and Radiation Dosimetry of ¹¹C-Elacridar and ¹¹C-Tariquidar in Humans

Tariquidar Is an Inhibitor and Not a Substrate of Human and Mouse P-glycoprotein

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Synthesis and evaluation of [11C]XR9576 to assess the function of drug efflux transporters using PET

Abstract: PET studies using [(11)C]XR9576 may be a promising approach for evaluating deficiency of the function of drug efflux transporters targeting intracranial diseases and tumors.

Cited by 37 publications

References 31 publications

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

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

Whole-Body Distribution and Radiation Dosimetry of 11C-Elacridar and 11C-Tariquidar in Humans

Tariquidar Is an Inhibitor and Not a Substrate of Human and Mouse P-glycoprotein

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Whole-Body Distribution and Radiation Dosimetry of ¹¹C-Elacridar and ¹¹C-Tariquidar in Humans