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European Journal of Nuclear Medicine and Molecular Imaging

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Open Access 01-12-2021 | Verapamil | Original Article

Head-to-head comparison of (R)-[¹¹C]verapamil and [¹⁸F]MC225 in non-human primates, tracers for measuring P-glycoprotein function

Authors: Lara García-Varela, David Vállez García, Pablo Aguiar, Takeharu Kakiuchi, Hiroyuki Ohba, Norihiro Harada, Shingo Nishiyama, Tetsuro Tago, Philip H. Elsinga, Hideo Tsukada, Nicola A. Colabufo, Rudi A. J. O. Dierckx, Aren van Waarde, Jun Toyohara, Ronald Boellaard, Gert Luurtsema

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 13/2021

Abstract

Purpose

P-glycoprotein (P-gp) function is altered in several brain disorders; thus, it is of interest to monitor the P-gp function in vivo using PET. (R)-[¹¹C]verapamil is considered the gold standard tracer to measure the P-gp function; however, it presents some drawbacks that limit its use. New P-gp tracers have been developed with improved properties, such as [¹⁸F]MC225. This study compares the characteristics of (R)-[¹¹C]verapamil and [¹⁸F]MC225 in the same subjects.

Methods

Three non-human primates underwent 4 PET scans: 2 with (R)-[¹¹C]verapamil and 2 with [¹⁸F]MC225, at baseline and after P-gp inhibition. The 30-min PET data were analyzed using 1-Tissue Compartment Model (1-TCM) and metabolite-corrected plasma as input function. Tracer kinetic parameters at baseline and after inhibition were compared. Regional differences and simplified methods to quantify the P-gp function were also assessed.

Results

At baseline, [¹⁸F]MC225 V_T values were higher, and k₂ values were lower than those of (R)-[¹¹C]verapamil, whereas K₁ values were not significantly different. After inhibition, V_T values of the 2 tracers were similar; however, (R)-[¹¹C]verapamil K₁ and k₂ values were higher than those of [¹⁸F]MC225. Significant regional differences between tracers were found at baseline, which disappeared after inhibition. The positive slope of the SUV-TAC was positively correlated to the K₁ and V_T of both tracers.

Conclusion

[¹⁸F]MC225 and (R)-[¹¹C]verapamil show comparable sensitivity to measure the P-gp function in non-human primates. Moreover, this study highlights the 30-min V_T as the best parameter to measure decreases in the P-gp function with both tracers. [¹⁸F]MC225 may become the first radiofluorinated tracer able to measure decreases and increases in the P-gp function due to its higher baseline V_T.

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Löscher W, Potschka H. Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog Neurobiol [Internet]. 2005;76:22–76 Available from: http://linkinghub.elsevier.com/retrieve/pii/S0301008205000444.CrossRef

Van Asperen J, Mayer U, Van Tellingen O, Beijnen JH. The functional role of P-glycoprotein in the blood–brain barrier. J Pharm Sci [Internet]. 1997;86:881–4 Available from: https://www.ncbi.nlm.nih.gov/pubmed/?term=The+Functional+Role+of+P-Glycoprotein+in+the+Blood−Brain+Barrier+J+van+asperen.CrossRef

Abbott NJ, Patabendige AAK, Dolman DEM, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis [Internet]. Elsevier Inc.; 2010;37:13–25. Available from: https://doi.org/10.1016/j.nbd.2009.07.030.

Mahringer A, Fricker G. ABC transporters at the blood–brain barrier. Expert Opin Drug Metab Toxicol [Internet]. Taylor & Francis; 2016;12:499–508. Available from: https://www.tandfonline.com/doi/full/10.1517/17425255.2016.1168804

Saidijam M, Karimi Dermani F, Sohrabi S, Patching SG. Efflux proteins at the blood–brain barrier: review and bioinformatics analysis. Xenobiotica [Internet]. Informa UK Limited, trading as Taylor & Francis Group; 2018;48:506–32. Available from: https://www.tandfonline.com/doi/full/10.1080/00498254.2017.1328148

Feldmann M, Koepp M. ABC transporters and drug resistance in patients with epilepsy. Curr Pharm Des [Internet]. 2016;22:5793–807 Available from: http://www.eurekaselect.com/openurl/content.php?genre=article&issn=1381-6128&volume=22&issue=38&spage=5793.CrossRef

DeGorter MK, Xia CQ, Yang JJ, Kim RB. Drug transporters in drug efficacy and toxicity. Annu Rev Pharmacol Toxicol [Internet]. 2012;52:249–73 Available from: http://www.annualreviews.org/doi/10.1146/annurev-pharmtox-010611-134529.CrossRef

Benadiba M, Maor Y. Importance of ABC transporters in drug development. Curr pharm des [Internet]. 2016;22:5817–29 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27514710.CrossRef

Miller DS. Regulation of P-glycoprotein and other ABC drug transporters at the blood-brain barrier. Trends Pharmacol Sci [internet] Elsevier Ltd. 2010;31:246–54. Available from. https://doi.org/10.1016/j.tips.2010.03.003.CrossRef

10.

Miller DS. Regulation of ABC Transporters Blood-Brain Barrier. The Good, the Bad, and the Ugly. [Internet]. 1st ed. Adv. Cancer Res. Elsevier Inc.; 2015. Available from: https://doi.org/10.1016/bs.acr.2014.10.002

11.

Colabufo NA, Berardi F, Cantore M, Contino M, Inglese C, Niso M, et al. Perspectives of P-glycoprotein modulating agents in oncology and neurodegenerative diseases: pharmaceutical, biological and diagnostic potentials. J Med Chem. 2010;53:1883–97.CrossRef

12.

Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP–dependent transporters. Nat Rev Cancer [Internet]. 2002;2:48–58 Available from: http://www.nature.com/doifinder/10.1038/nrc706.CrossRef

13.

Wang G-X, Wang D-W, Liu Y, Ma Y-H. Intractable epilepsy and the P-glycoprotein hypothesis. Int J Neurosci [Internet]. 2016;126:385–92 Available from: http://www.scopus.com/inward/record.url?eid=2-s2.0-84957699525&partnerID=tZOtx3y1.CrossRef

14.

Varatharajan L, Thomas SA. The transport of anti-HIV drugs across blood-CNS interfaces: summary of current knowledge and recommendations for further research. Antivir Res. 2009;82:99–109.CrossRef

15.

Vogelgesang S, Warzok RW, Cascorbi I, Kunert-Keil C, Schroeder E, Kroemer HK, et al. The role of P-glycoprotein in cerebral amyloid angiopathy; implications for the early pathogenesis of Alzheimer’s disease. Curr Alzheimer Res. 2004;1:121–5.CrossRef

16.

Droździk M, Białecka M, Myśliwiec K, Honczarenko K, Stankiewicz J, Sych Z. Polymorphism in the P-glycoprotein drug transporter MDR1 gene: a possible link between environmental and genetic factors in Parkinson’s disease. Pharm Int. 2003;13:259–63 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12724617.

17.

Efferth T. The human ATP-binding cassette transporter genes from the bench to the bedside. Curr Mol Med [Internet]. 2001;1:45–65 Available from: http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=med4&NEWS=N&AN=11899242.CrossRef

18.

Gottesman MM, Ambudkar SV. Overview: ABC transporters and human disease. J Bioenerg Biomembr. 2001;33:453–8.CrossRef

19.

Pereira C, Ferreiro E, Cardoso SM, de Oliveira CR. Cell degeneration induced by amyloid-beta peptides: implications for Alzheimer’s disease. J Mol Neurosci [internet]. 2004;23:97–104 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15126695.CrossRef

20.

Lam FC, Liu R, Lu P, Shapiro AB, Renoir J-M, Sharom FJ, et al. β-Amyloid efflux mediated by p-glycoprotein. J Neurochem [Internet]. 2001;76:1121–8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/11181832.CrossRef

21.

Vogelgesang S, Cascorbi I, Schroeder E, Pahnke J, Kroemer HK, Siegmund W, et al. Deposition of Alzheimer’s beta-amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans. Pharm Int. 2002;12:535–41 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12360104.

22.

Langer O. Use of PET imaging to evaluate transporter-mediated drug-drug interactions. J Clin Pharmacol. 2016:S143–56.

23.

Kannan P, John C, Zoghbi SS, Halldin C, Gottesman MM, Innis RB, et al. Imaging the function of P-glycoprotein with radiotracers: pharmacokinetics and in vivo applications. Clin Pharmacol Ther [Internet]. 2009;86:368–377. Available from: https://doi.org/10.1038/clpt.2009.138.

24.

Raaphorst RM, Windhorst AD, Elsinga PH, Colabufo NA, Lammertsma AA, Luurtsema G. Radiopharmaceuticals for assessing ABC transporters at the blood-brain barrier. Clin Pharmacol Ther [Internet]. 2015;97:362–71 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25669763.CrossRef

25.

Luurtsema G, Elsinga P, Dierckx R, Boellaard R, Waarde A. PET tracers for imaging of ABC transporters at the blood-brain barrier: principles and strategies. Curr Pharm Des [Internet]. 2016;22:5779–85 Available from: http://www.eurekaselect.com/openurl/content.php?genre=article&issn=1381-6128&volume=22&issue=38&spage=5779.CrossRef

26.

Mansor S, Boellaard R, Froklage FE, Bakker EDM, Yaqub M, Voskuyl RA, et al. Quantification of dynamic 11C-phenytoin PET studies. J Nucl Med [Internet]. 2015;56:1372–7 Available from: http://jnm.snmjournals.org/cgi/doi/10.2967/jnumed.115.158055.CrossRef

27.

Syvänen S, Eriksson J. Advances in PET imaging of P-glycoprotein function at the blood-brain barrier. ACS Chem Neurosci. 2013;4:225–37.CrossRef

28.

Raaphorst RM, Savolainen H, Cantore M, van de Steeg E, van Waarde A, Colabufo NA, et al. Comparison of in vitro assays in selecting radiotracers for in vivo P-glycoprotein PET imaging. Pharmaceuticals (Basel) [Internet]. 2017;10:1–25 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29036881.

29.

Kannan P, Brimacombe KR, Zoghbi SS, Liow J-S, Morse C, Taku AK, et al. N-desmethyl-loperamide is selective for P-glycoprotein among three ATP-binding cassette transporters at the blood-brain barrier. Drug Metab Dispos [Internet]. 2010;38:917–22 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20212014.CrossRef

30.

O’Brien FE, Dinan TG, Griffin BT, Cryan JF. Interactions between antidepressants and P-glycoprotein at the blood-brain barrier: clinical significance of in vitro and in vivo findings. Br J Pharmacol [Internet]. 2012;165:289–312 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21718296.CrossRef

31.

Pottier G, Marie S, Goutal S, Auvity S, Peyronneau M-A, Stute S, et al. Imaging the impact of the P-glycoprotein (ABCB1) function on the brain kinetics of metoclopramide. J Nucl Med [Internet]. 2016;57:309–14 Available from: http://jnm.snmjournals.org/cgi/doi/10.2967/jnumed.115.164350.CrossRef

32.

Toyohara J, Okamoto M, Aramaki H, Zaitsu Y, Shimizu I, Ishiwata K. ( R )-[ 11 C]Emopamil as a novel tracer for imaging enhanced P-glycoprotein function. Nucl med biol [Internet] Elsevier Inc. 2016;43:52–62. Available from. https://doi.org/10.1016/j.nucmedbio.2015.09.001.CrossRef

33.

Savolainen H, Windhorst AD, Elsinga PH, Cantore M, Colabufo NA, Willemsen AT, et al. Evaluation of [ 18 F]MC225 as a PET radiotracer for measuring P-glycoprotein function at the blood–brain barrier in rats: kinetics, metabolism, and selectivity. J Cereb Blood Flow Metab [Internet]. 2017;37:1286–98 Available from: http://jcb.sagepub.com/lookup/doi/10.1177/0271678X16654493.CrossRef

34.

Savolainen H, Cantore M, Colabufo NA, Elsinga PH, Windhorst AD, Luurtsema G. Synthesis and preclinical evaluation of three novel Fluorine-18 labeled radiopharmaceuticals for P-glycoprotein PET imaging at the blood-brain barrier. Mol Pharm. 2015;12:2265–75.CrossRef

35.

García-Varela L, Arif WM, Vállez García D, Kakiuchi T, Ohba H, Harada N, et al. Pharmacokinetic Modeling of [ 18 F]MC225 for Quantification of the P-Glycoprotein Function at the Blood–Brain Barrier in Non-Human Primates with PET. Mol Pharm [Internet]. 2020;acs.molpharmaceut.0c00514. Available from: https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.0c00514

36.

García-Varela L, García DV, Kakiuchi T, Ohba H, Nishiyama S, Tago T, et al. Pharmacokinetic modeling of ( R )-[ 11 C]verapamil to measure the P-glycoprotein function in nonhuman Primates. Mol Pharm [Internet]. 2021;18:416–28 Available from: https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.0c01014.CrossRef

37.

Toyohara J, Sakata M, Tago T, Colabufo NA, Luurtsema G. Automated synthesis, preclinical toxicity, and radiation dosimetry of [18F]MC225 for clinical use: a tracer for measuring P-glycoprotein function at the blood-brain barrier. EJNMMI Res [Internet]. EJNMMI Res. 2020;10:84 Available from: https://ejnmmires.springeropen.com/articles/10.1186/s13550-020-00674-6.CrossRef

38.

Calabrese E, Badea A, Coe CL, Lubach GR, Shi Y, Styner MA, et al. A diffusion tensor MRI atlas of the postmortem rhesus macaque brain. Neuroimage [Internet] Elsevier Inc. 2015;117:408–16. Available from. https://doi.org/10.1016/j.neuroimage.2015.05.072.CrossRef

39.

Auvity S, Caillé F, Marie S, Wimberley C, Bauer M, Langer O, et al. P-glycoprotein (ABCB1) inhibits the influx and increases the efflux of 11 C-metoclopramide across the blood-brain barrier: a PET study on non-human primates. J Nucl Med [Internet]. 2018;jnumed.118.210104. Available from: http://jnm.snmjournals.org/lookup/doi/10.2967/jnumed.118.210104

40.

Tournier N, Bauer M, Pichler V, Nics L, Klebermass E-M, Bamminger K, et al. Impact of P-Glycoprotein Function on the Brain Kinetics of the Weak Substrate 11 C-Metoclopramide Assessed with PET Imaging in Humans. J Nucl Med [Internet]. 2019;60:985–91 Available from: http://jnm.snmjournals.org/lookup/doi/10.2967/jnumed.118.219972.CrossRef

41.

Andersen PK. 1. Generalized estimating equations. James W. Hardin and Joseph M. Hilbe, chapman and hall/CRC, Boca Raton, 2003. No. of pages: xiii+ 222 pp. Price:$79.95. ISBN 1-58488-307-3. Stat med [Internet]. 2004;23:2479–80. Available from: https://doi.org/10.1002/sim.1846.

42.

K-Y LIANG, ZEGER SL. Longitudinal data analysis using generalized linear models. Biometrika [Internet]. 1986;73:13–22 Available from: https://academic.oup.com/biomet/article-lookup/doi/10.1093/biomet/73.1.13.CrossRef

43.

Renkin EM. Transport of potassium-42 from blood to tissue in isolated mammalian skeletal muscles. Am J Physiol Content [Internet]. 1959;197:1205–10 Available from: http://www.physiology.org/doi/10.1152/ajplegacy.1959.197.6.1205.CrossRef

44.

Crone C. The permeability of capillaries in various organs as determined by use of the ‘Indicator diffusion’ method. Acta Physiol Scand [Internet]. 1963;58:292–305. Available from. https://doi.org/10.1111/j.1748-1716.1963.tb02652.x.CrossRef

45.

Garcia Varela L, Vállez García D, Rodriguez-Pérez M, Moraga Amaro R, Colabufo NA, Aguiar P, et al. Evaluation of a Novel P-glycoprotein Inducer Using [18F]MC225 and PET. European. Journal of Nuclear Medicine and Molecular Imaging. 2020;47(Suppl.1):S113–1.

46.

de Klerk OL, Willemsen ATM, Bosker FJ, Bartels AL, Hendrikse NH, den Boer JA, et al. Regional increase in P-glycoprotein function in the blood-brain barrier of patients with chronic schizophrenia:. A PET study with [11C]verapamil as a probe for P-glycoprotein function. Psychiatry Res - Neuroimaging [Internet] Elsevier Ireland Ltd. 2010;183:151–2. Available from. https://doi.org/10.1016/j.pscychresns.2010.05.002.CrossRef

47.

de Klerk OL, Willemsen ATM, Roosink M, Bartels AL, Harry Hendrikse N, Bosker FJ, et al. Locally increased P-glycoprotein function in major depression: a PET study with [11C]verapamil as a probe for P-glycoprotein function in the blood–brain barrier. Int J Neuropsychopharmacol [Internet]. 2009;12:895 Available from: https://academic.oup.com/ijnp/article-lookup/doi/10.1017/S1461145709009894.CrossRef

48.

Langer O, Bauer M, Hammers A, Karch R, Pataraia E, Koepp MJ, et al. Pharmacoresistance in epilepsy: a pilot PET study with the P-glycoprotein substrate R-[11C]verapamil. Epilepsia. 2007;48:1774–84.CrossRef

49.

Kuntner C, Bankstahl JP, Bankstahl M, Stanek J, Wanek T, Stundner G, et al. Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood-brain barrier using (R)-[11C]verapamil PET. Eur J Nucl Med Mol Imaging. 2010;37:942–53.CrossRef

50.

Conti M, Eriksson L. Physics of pure and non-pure positron emitters for PET: a review and a discussion. EJNMMI Phys [Internet]. EJNMMI physics. 2016;3:8. Available from. https://doi.org/10.1186/s40658-016-0144-5.CrossRefPubMedPubMedCentral

51.

Miller PW, Long NJ, Vilar R, Gee AD. Synthesis of 11 C, 18 F, 15 O, and 13 N radiolabels for positron emission tomography. Angew Chemie Int Ed [internet]. 2008;47:8998–9033. Available from. https://doi.org/10.1002/anie.200800222.CrossRef

Title: Head-to-head comparison of (R)-[11C]verapamil and [18F]MC225 in non-human primates, tracers for measuring P-glycoprotein function
Authors: Lara García-Varela
David Vállez García
Pablo Aguiar
Takeharu Kakiuchi
Hiroyuki Ohba
Norihiro Harada
Shingo Nishiyama
Tetsuro Tago
Philip H. Elsinga
Hideo Tsukada
Nicola A. Colabufo
Rudi A. J. O. Dierckx
Aren van Waarde
Jun Toyohara
Ronald Boellaard
Gert Luurtsema
Publication date: 01-12-2021
Publisher: Springer Berlin Heidelberg
Keyword: Verapamil
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 13/2021
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-021-05411-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Head-to-head comparison of (R)-[¹¹C]verapamil and [¹⁸F]MC225 in non-human primates, tracers for measuring P-glycoprotein function

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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