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01-04-2016 | Research Article

P-Glycoprotein, not BCRP, Limits the Brain Uptake of [¹⁸F]Mefway in Rodent Brain

Authors: Jae Yong Choi, Jin Sook Song, Minkyung Lee, Woon-Ki Cho, Jin Chung, Chul Hyoung Lyoo, Chul Hoon Kim, Jiae Park, Kyo Chul Lee, Kyeong Min Kim, Jee Hae Kang, Myung Ae Bae, Young Hoon Ryu

Published in: Molecular Imaging and Biology | Issue 2/2016

Abstract

Purpose

The aim of this study was to determine whether the brain uptake of [¹⁸F]Mefway is influenced by the action of P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) in rodents.

Procedures

[¹⁸F]Mefway was applied to rats pharmacologically inhibited with tariquidar (TQD) and to genetically disrupted mice.

Results

Pretreatment of TQD results in 160 % higher hippocampal uptake compared with control rats. In genetically disrupted mice, a maximal brain uptake value of 3.2 SUV in the triple knockout mice (tKO, Mdr1a/b^(−/−)Bcrp1^(−/−)) was comparable to that of the double knockout mice (dKO, Mdr1a/b^(−/−)) and 2-fold those of the wild-type and Bcrp1^(−/−) knockout mice. The differences of binding values were statistically insignificant between control and experimental groups. The brain-to-plasma ratios for tKO mice were also two to five times higher than those for other groups.

Conclusions

[¹⁸F]Mefway is modulated by P-gp, and not by Bcrp in rodents.

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Celada P, Bortolozzi A, Artigas F (2013) Serotonin 5-HT_1A receptors as targets for agents to treat psychiatric disorders: rationale and current status of research. CNS Drugs 27:703–716CrossRefPubMed

Girardin F (2006) Membrane transporter proteins: a challenge for CNS drug development. Dialogues Clin Neurosci 8:311–321PubMedPubMedCentral

Tsuji A (1998) P-glycoprotein-mediated efflux transport of anticancer drugs at the blood–brain barrier. Ther Drug Monit 20:588–590CrossRefPubMed

Elsinga PH, Hendrikse NH, Bart J et al (2004) PET Studies on P-glycoprotein function in the blood–brain barrier: how it affects uptake and binding of drugs within the CNS. Curr Pharm Des 10:1493–1503CrossRefPubMed

Sisodiya SM, Martinian L, Scheffer GL et al (2006) Vascular colocalization of P-glycoprotein, multidrug-resistance associated protein 1, breast cancer resistance protein and major vault protein in human epileptogenic pathologies. Neuropathol Appl Neurobiol 32:51–63CrossRefPubMed

Begley DJ (2004) ABC transporters and the blood–brain barrier. Curr Pharm Des 10:1295–1312CrossRefPubMed

Loscher W, Potschka H (2005) Blood–brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx 2:86–98CrossRefPubMedPubMedCentral

van Assema DM, Lubberink M, Bauer M et al (2012) Blood–brain barrier P-glycoprotein function in Alzheimer’s disease. Brain 135:181–189CrossRefPubMed

Sisodiya SM, Lin WR, Harding BN et al (2002) Drug resistance in epilepsy: expression of drug resistance proteins in common causes of refractory epilepsy. Brain 125:22–31CrossRefPubMed

10.

Jones T (1996) The role of positron emission tomography within the spectrum of medical imaging. Eur J Nucl Med 23:207–211CrossRefPubMed

11.

Carson RE, Lang L, Watabe H et al (2000) PET evaluation of [¹⁸F]FCWAY, an analog of the 5-HT1A receptor antagonist, WAY-100635. Nucl Med Biol 27:493–497CrossRefPubMed

12.

Gunn RN, Sargent PA, Bench CJ et al (1998) Tracer kinetic modeling of the 5-HT_1A receptor ligand [carbonyl-¹¹C]WAY-100635 for PET. Neuroimage 8:426–440CrossRefPubMed

13.

Lacan G, Plenevaux A, Rubins DJ et al (2008) Cyclosporine, a P-glycoprotein modulator, increases [¹⁸F]MPPF uptake in rat brain and peripheral tissues: microPET and ex vivo studies. Eur J Nucl Med Mol Imaging 35:2256–2266CrossRefPubMed

14.

Choi JY, Lyoo CH, Kim JS et al (2015) ¹⁸F-Mefway PET imaging of serotonin 1A receptors in humans: a comparison with ¹⁸F-FCWAY. PLoS ONE 10:e0121342CrossRefPubMedPubMedCentral

15.

Wooten DW, Hillmer AT, Murali D et al (2014) Initial in vivo PET imaging of 5-HT_1A receptors with 3-[¹⁸F]mefway. Am J Nucl Med Mol Imaging 4:483–489PubMedPubMedCentral

16.

Lee M, Ryu YH, Cho WG et al (2014) Dopaminergic neuron destruction reduces hippocampal serotonin 1A receptor uptake of trans-[¹⁸F]Mefway. Appl Radiat Isot 94:30–34CrossRefPubMed

17.

Hillmer AT, Wooten DW, Bajwa AK et al (2014) First-in-human evaluation of ¹⁸F-mefway, a PET radioligand specific to serotonin-1A receptors. J Nucl Med 55:1973–1979CrossRefPubMedPubMedCentral

18.

Choi JY, Kim BS, Kim CH, et al. (2014) Translational possibility of [¹⁸F]Mefway to image serotonin 1A receptors in humans: Comparison with [¹⁸F]FCWAY in rodents. Synapse 68:595–603

19.

Saigal N, Bajwa AK, Faheem SS et al (2013) Evaluation of serotonin 5-HT_1A receptors in rodent models using [¹⁸F]Mefway PET. Synapse 67:596–608CrossRefPubMedPubMedCentral

20.

Constantinescu CC, Sevrioukov E, Garcia A et al (2013) Evaluation of [¹⁸F]Mefway biodistribution and dosimetry based on whole-body PET imaging of mice. Mol Imaging Biol 15:222–229CrossRefPubMed

21.

Choi JY, Kim CH, Jeon TJ et al (2012) Effective microPET imaging of brain 5-HT_1A receptors in rats with [¹⁸F]MeFWAY by suppression of radioligand defluorination. Synapse 66:1015–1023CrossRefPubMed

22.

Wooten DW, Moraino JD, Hillmer AT et al (2011) In vivo kinetics of [F-18]MEFWAY: a comparison with [C-11]WAY100635 and [F-18]MPPF in the nonhuman primate. Synapse 65:592–600CrossRefPubMedPubMedCentral

23.

Saigal N, Pichika R, Easwaramoorthy B et al (2006) Synthesis and biologic evaluation of a novel serotonin 5-HT_1A receptor radioligand, ¹⁸F-labeled mefway, in rodents and imaging by PET in a nonhuman primate. J Nucl Med 47:1697–1706PubMed

24.

Pike VW (2009) PET radiotracers: crossing the blood–brain barrier and surviving metabolism. Trends Pharmacol Sci 30:431–440CrossRefPubMedPubMedCentral

25.

la Fougere C, Boning G, Bartmann H et al (2010) Uptake and binding of the serotonin 5-HT_1A antagonist [¹⁸F]MPPF in brain of rats: effects of the novel P-glycoprotein inhibitor tariquidar. Neuroimage 49:1406–1415CrossRefPubMed

26.

Liow JS, Lu S, McCarron JA et al (2007) Effect of a P-glycoprotein inhibitor, Cyclosporin A, on the disposition in rodent brain and blood of the 5-HT_1A receptor radioligand, [¹¹C](R)-(−)-RWAY. Synapse 61:96–105CrossRefPubMed

27.

Elsinga PH, Hendrikse NH, Bart J et al (2005) Positron emission tomography studies on binding of central nervous system drugs and P-glycoprotein function in the rodent brain. Mol Imaging Biol 7:37–44CrossRefPubMed

28.

Tournier N, Cisternino S, Peyronneau MA et al (2012) Discrepancies in the P-glycoprotein-mediated transport of ¹⁸F-MPPF: a pharmacokinetic study in mice and non-human primates. Pharm Res 29:2468–2476CrossRefPubMed

29.

Choi JY, Kim CH, Ryu YH et al (2013) Optimization of the radiosynthesis of [¹⁸F]MEFWAY for imaging brain serotonin 1A receptors by using the GE TracerLab FX_FN-Pro module. J Labelled Comp Radiopharm 56:589–594CrossRefPubMed

30.

Bauer M, Zeitlinger M, Karch R et al (2012) Pgp-mediated interaction between (R)-[¹¹C]verapamil and tariquidar at the human blood–brain barrier: a comparison with rat data. Clin Pharmacol Ther 91:227–233CrossRefPubMedPubMedCentral

31.

Ichise M, Liow JS, Lu JQ et al (2003) Linearized reference tissue parametric imaging methods: application to [¹¹C]DASB positron emission tomography studies of the serotonin transporter in human brain. J Cereb Blood Flow Metab 23:1096–1112CrossRefPubMed

32.

Logan J, Fowler JS, Volkow ND et al (1996) Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab 16:834–840CrossRefPubMed

33.

Mistry P, Stewart AJ, Dangerfield W et al (2001) In vitro and in vivo reversal of P-glycoprotein-mediated multidrug resistance by a novel potent modulator, XR9576. Cancer Res 61:749–758PubMed

34.

Amin ML (2013) P-glycoprotein Inhibition for Optimal Drug Delivery. Drug Targets Insights 7:27–34CrossRef

35.

Bankstahl JP, Bankstahl M, Romermann K et al (2013) 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. Drug Metab Dispos 41:754–762CrossRefPubMed

36.

Mahar Doan KM, Humphreys JE, Webster LO et al (2002) Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J Pharmacol Exp Ther 303:1029–1037CrossRefPubMed

37.

Schinkel AH (1999) P-Glycoprotein, a gatekeeper in the blood–brain barrier. Adv Drug Deliv Rev 36:179–194CrossRefPubMed

38.

Piel M, Schmitt U, Bausbacher N et al (2014) Evaluation of P-glycoprotein (abcb1a/b) modulation of [¹⁸F]fallypride in MicroPET imaging studies. Neuropharmacology 84:152–158CrossRefPubMed

39.

Syvanen S, Lindhe O, Palner M et al (2009) Species differences in blood–brain barrier transport of three positron emission tomography radioligands with emphasis on P-glycoprotein transport. Drug Metab Dispos 37:635–643CrossRefPubMed

40.

Uchida Y, Ohtsuki S, Katsukura Y et al (2011) Quantitative targeted absolute proteomics of human blood–brain barrier transporters and receptors. J Neurochem 117:333–345CrossRefPubMed

41.

Wooten DW, Hillmer AT, Moirano JM et al (2013) 5-HT1A sex based differences in Bmax, in vivo KD, and BPND in the nonhuman primate. Neuroimage 77:125–132CrossRefPubMed

42.

Taamalli A, Abaza L, Arraez Roman D et al (2013) Characterisation of phenolic compounds by HPLC-TOF/IT/MS in buds and open flowers of ‘Chemlali’ olive cultivar. Phytochem Anal 24:504–512CrossRefPubMed

43.

Passchier J, van Waarde A, Vaalburg W, Willemsen AT (2001) On the quantification of [¹⁸F]MPPF binding to 5-HT1A receptors in the human brain. J Nucl Med 42:1025–1031PubMed

44.

Ryu YH, Liow JS, Zoghbi S et al (2007) Disulfiram inhibits defluorination of ¹⁸F-FCWAY, reduces bone radioactivity, and enhances visualization of radioligand binding to serotonin 5-HT_1A receptors in human brain. J Nucl Med 48:1154–1161CrossRefPubMed

Title: P-Glycoprotein, not BCRP, Limits the Brain Uptake of [18F]Mefway in Rodent Brain
Authors: Jae Yong Choi
Jin Sook Song
Minkyung Lee
Woon-Ki Cho
Jin Chung
Chul Hyoung Lyoo
Chul Hoon Kim
Jiae Park
Kyo Chul Lee
Kyeong Min Kim
Jee Hae Kang
Myung Ae Bae
Young Hoon Ryu
Publication date: 01-04-2016
Publisher: Springer US
Published in: Molecular Imaging and Biology / Issue 2/2016
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI: https://doi.org/10.1007/s11307-015-0883-z

Keynote webinar | Spotlight on medication adherence

Springer Medicine

P-Glycoprotein, not BCRP, Limits the Brain Uptake of [¹⁸F]Mefway in Rodent Brain

Abstract

Purpose

Procedures

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Procedures

Results

Conclusions

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