Evaluation of [11C]elacridar and [11C]tariquidar in transporter knockout mice using small-animal PET

Kuntner, Claudia; Bankstahl, Marion; Stanek, Johann; Wanek, Thomas; Dörner, Bernd; Bauer, Florian; Mairinger, Severin; Erker, Thomas; Müller, Markus; Löscher, Wolfgang; Langer, Oliver

doi:10.1016/j.neuroimage.2010.04.209

Cited by 5 publications

(8 citation statements)

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“…Previous data point to pronounced species differences in the P-gp system between rats and humans. 31, 38 We were able to show that comparable plasma concentrations of 1 had an effect about 10 times smaller on ( R )-[ 11 C]verapamil brain distribution in humans as compared to rats, suggesting that P-gp expression is higher in the human BBB. 14-15 This is also consistent with the observation that baseline brain distribution volume of ( R )-[ 11 C]verapamil was 2 times lower in humans than in rats.…”

Section: Discussionmentioning

confidence: 76%

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

Bauer

Kuntner

Bankstahl

et al. 2010

Bioorganic & Medicinal Chemistry

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109

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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.

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Section: Discussionmentioning

confidence: 76%

“…Our assumption that [ 11 C]- 1 binds to P-gp and is not transported by P-gp is further supported by pilot data acquired in a rat model of P-gp overexpression, 30 which revealed increased brain uptake of [ 11 C]- 1 as compared to naïve rats, whereas brain uptake of the P-gp substrate ( R )-[ 11 C]verapamil was decreased. 31…”

Section: Discussionmentioning

confidence: 99%

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

Bauer

Kuntner

Bankstahl

et al. 2010

Bioorganic & Medicinal Chemistry

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109

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“…Apart from Pgp, tariquidar also inhibits breast cancer resistance protein (BCRP, ABCG2), another important ABC transporter expressed at the BBB 30 . Because ( R )‐[ 11 C]verapamil is not transported by BCRP at the BBB, 31 we were able to selectively study cerebral Pgp inhibition using a combination of ( R )‐[ 11 C]verapamil and tariquidar.…”

Section: Discussionmentioning

confidence: 99%

“…verapamil is not transported by BCRP at the BBB, 31 we were able to selectively study cerebral Pgp inhibition using a combination of (R)-[ 11 C]verapamil and tariquidar.…”

Section: Table 1 Outcome Parameters (Whole Brain) Of 2-tissue-4-rate mentioning

confidence: 99%

“…17 In both the rat study and the human study, brain uptake of (R)-[ 11 C]verapamil approached plateau values after administration of increasing tariquidar doses, essentially at plasma tariquidar concentrations >1,000 ng/ml (Figure 4). Although it seems likely that complete inhibition of Pgp was reached at the BBB in rats (as indicated by the finding that concentration levels in rat brains after administration of tariquidar doses >6 mg/kg are comparable to those in the brains of Mdr1a/b (−/−) mice), 31 it is not known whether the observed plateau in concentration levels in human brains indeed represented full Pgp inhibition at the BBB.…”

Section: Table 1 Outcome Parameters (Whole Brain) Of 2-tissue-4-rate mentioning

confidence: 99%

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Pgp-Mediated Interaction Between (R)-[11C]Verapamil and Tariquidar at the Human Blood–Brain Barrier: A Comparison With Rat Data

Bauer

Zeitlinger

Karch

et al. 2011

Clin Pharmacol Ther

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119

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Using positron emission tomography (PET) imaging we assessed, in vivo, the interaction between a microdose of (R)-[(11)C]verapamil (a P-glycoprotein (Pgp) substrate) and escalating doses of the Pgp inhibitor tariquidar (3, 4, 6, and 8 mg/kg) at the blood-brain barrier (BBB) in healthy human subjects. We compared the dose-response relationship of tariquidar in humans with data obtained in rats using a similar methodology. Tariquidar was equipotent in humans and rats in its effect of increasing (R)-[(11)C]verapamil brain uptake (expressed as whole-brain volume of distribution (V(T))), with very similar half-maximum-effect concentrations. Both in humans and in rats, brain V(T) approached plateau levels at plasma tariquidar concentrations >1,000 ng/ml. However, Pgp inhibition in humans led to only a 2.7-fold increase in brain V(T) relative to baseline scans (before administration of tariquidar) as compared with 11.0-fold in rats. The results of this translational study add to the accumulating evidence that there are marked species-dependent differences in Pgp expression and functionality at the BBB.

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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

Dörner¹,

Kuntner²,

Wanek³

et al. 2011

Bioorganic & Medicinal Chemistry

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Aim of this study was to label the potent dual P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) inhibitor elacridar (1) with 18 F to provide a positron emission tomography (PET) radiotracer to visualize Pgp and BCRP. A series of new 1-and 2-halogen-and nitro-substituted derivatives of 1 (4a-e) was synthesized as precursor molecules and reference compounds for radiolabelling and shown to display comparable in vitro potency to 1 in increasing rhodamine 123 accumulation in a cell line overexpressing human Pgp (MDCKII-MDR1). 1-[ 18 F]fluoroelacridar ([ 18 F]4b) was synthesized in a decay-corrected radiochemical yield of 1.7±0.9% by a 1-step nocarrier added nucleophilic aromatic 18 F-substitution of 1-nitro precursor 4c. Small-animal PET imaging of [ 18 F]4b was performed in naïve rats, before and after administration of unlabelled 1 (5 mg/kg, n=3), as well as in wild-type and Mdr1a/b (−/−) Bcrp1 (−/−) mice (n=3). In PET experiments in rats, administration of unlabelled 1 increased brain activity uptake by a factor of 9.5 (p=0.0002, 2-tailed Student's t-test), whereas blood activity levels remained unchanged. In Mdr1a/ b (−/−) Bcrp1 (−/−) mice, the mean brain-to-blood ratio of activity at 60 min after tracer injection was 7.6 times higher as compared to wild-type animals (p=0.0002). HPLC analysis of rat brain tissue extracts collected at 40 min after injection of [ 18 F]4b revealed that 93±7% of total radioactivity in brain was in the form of unchanged [ 18 F]4b. In conclusion, the in vivo behavior of [ 18 F]4b was found to be similar to previously described

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Evaluation of [11C]elacridar and [11C]tariquidar in transporter knockout mice using small-animal PET

Cited by 5 publications

References 0 publications

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

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

Pgp-Mediated Interaction Between (R)-[11C]Verapamil and Tariquidar at the Human Blood–Brain Barrier: A Comparison With Rat Data

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

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