Sylvain Auvity1, Fabien Caillé1, Solène Marie1, Catriona Wimberley1, Martin Bauer2, Oliver Langer2,3,4, Irène Buvat1, Sébastien Goutal1,5, Nicolas Tournier6. 1. UMR 1023 IMIV, Service Hospitalier Frédéric Joliot, CEA, INSERM, Université Paris Sud, CNRS, Université Paris-Saclay, Orsay, France. 2. Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. 3. Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria. 4. Biomedical Systems, Center for Health and Bioresources, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria; and. 5. MIRCen, CEA and CNRS-UMR9199, Université Paris Sud, Fontenay-aux-Roses, France. 6. UMR 1023 IMIV, Service Hospitalier Frédéric Joliot, CEA, INSERM, Université Paris Sud, CNRS, Université Paris-Saclay, Orsay, France nicolas.tournier@cea.fr.
Abstract
PET imaging using radiolabeled avid substrates of the ATP-binding cassette (ABC) transporter P-glycoprotein (ABCB1) has convincingly revealed the role of this major efflux transporter in limiting the influx of its substrates from blood into the brain across the blood-brain barrier (BBB). Many drugs, such as metoclopramide, are weak ABCB1 substrates and distribute into the brain even when ABCB1 is fully functional. In this study, we used kinetic modeling and validated simplified methods to highlight and quantify the impact of ABCB1 on the BBB influx and efflux of 11C-metoclopramide, as a model of a weak ABCB1 substrate, in nonhuman primates. Methods: The regional brain kinetics of a tracer dose of 11C-metoclopramide (298 ± 44 MBq) were assessed in baboons using PET without (n = 4) or with (n = 4) intravenous coinfusion of the ABCB1 inhibitor tariquidar (4 mg/kg/h). Metabolite-corrected arterial input functions were generated to estimate the regional volume of distribution (V T), as well as the influx (K 1) and efflux (k 2) rate constants, using a 1-tissue-compartment model. Modeling outcome parameters were correlated with image-derived parameters, that is, areas under the regional time-activity curves (AUCs) from 0 to 30 min and from 30 to 60 min (SUV⋅min) and the elimination slope (k E; min-1) from 30 to 60 min. Results: Tariquidar significantly increased the brain distribution of 11C-metoclopramide (V T = 4.3 ± 0.5 mL/cm3 and 8.7 ± 0.5 mL/cm3 for baseline and ABCB1 inhibition conditions, respectively, P < 0.001), with a 1.28-fold increase in K 1 (P < 0.05) and a 1.64-fold decrease in k 2 (P < 0.001). The effect of tariquidar was homogeneous across different brain regions. The parameters most sensitive to ABCB1 inhibition were V T (2.02-fold increase) and AUC from 30 to 60 min (2.02-fold increase). V T correlated significantly (P < 0.0001) with AUC from 30 to 60 min (r 2 = 0.95), with AUC from 0 to 30 min (r 2 = 0.87), and with k E (r 2 = 0.62). Conclusion: 11C-metoclopramide PET imaging revealed the relative importance of both the influx hindrance and the efflux enhancement components of ABCB1 in a relevant model of the human BBB. The overall impact of ABCB1 on drug delivery to the brain can be noninvasively estimated from image-derived outcome parameters without the need for an arterial input function.
PET imaging using radiolabeled avid substrates of the ATP-binding cassette (ABC) transporter P-glycoprotein (ABCB1) has convincingly revealed the role of this major efflux transporter in limiting the influx of its substrates from blood into the brain across the blood-brain barrier (BBB). Many drugs, such as metoclopramide, are weak ABCB1 substrates and distribute into the brain even when ABCB1 is fully functional. In this study, we used kinetic modeling and validated simplified methods to highlight and quantify the impact of ABCB1 on the BBB influx and efflux of 11C-metoclopramide, as a model of a weak ABCB1 substrate, in nonhuman primates. Methods: The regional brain kinetics of a tracer dose of 11C-metoclopramide (298 ± 44 MBq) were assessed in baboons using PET without (n = 4) or with (n = 4) intravenous coinfusion of the ABCB1 inhibitor tariquidar (4 mg/kg/h). Metabolite-corrected arterial input functions were generated to estimate the regional volume of distribution (V T), as well as the influx (K 1) and efflux (k 2) rate constants, using a 1-tissue-compartment model. Modeling outcome parameters were correlated with image-derived parameters, that is, areas under the regional time-activity curves (AUCs) from 0 to 30 min and from 30 to 60 min (SUV⋅min) and the elimination slope (k E; min-1) from 30 to 60 min. Results:Tariquidar significantly increased the brain distribution of 11C-metoclopramide (V T = 4.3 ± 0.5 mL/cm3 and 8.7 ± 0.5 mL/cm3 for baseline and ABCB1 inhibition conditions, respectively, P < 0.001), with a 1.28-fold increase in K 1 (P < 0.05) and a 1.64-fold decrease in k 2 (P < 0.001). The effect of tariquidar was homogeneous across different brain regions. The parameters most sensitive to ABCB1 inhibition were V T (2.02-fold increase) and AUC from 30 to 60 min (2.02-fold increase). V T correlated significantly (P < 0.0001) with AUC from 30 to 60 min (r 2 = 0.95), with AUC from 0 to 30 min (r 2 = 0.87), and with k E (r 2 = 0.62). Conclusion:11C-metoclopramide PET imaging revealed the relative importance of both the influx hindrance and the efflux enhancement components of ABCB1 in a relevant model of the human BBB. The overall impact of ABCB1 on drug delivery to the brain can be noninvasively estimated from image-derived outcome parameters without the need for an arterial input function.
Authors: Nicolas Tournier; Sebastien Goutal; Severin Mairinger; Irene Hernández-Lozano; Thomas Filip; Michael Sauberer; Fabien Caillé; Louise Breuil; Johann Stanek; Anna F Freeman; Gaia Novarino; Charles Truillet; Thomas Wanek; Oliver Langer Journal: J Cereb Blood Flow Metab Date: 2020-10-20 Impact factor: 6.200
Authors: Viktoria Zoufal; Severin Mairinger; Mirjam Brackhan; Markus Krohn; Thomas Filip; Michael Sauberer; Johann Stanek; Thomas Wanek; Nicolas Tournier; Martin Bauer; Jens Pahnke; Oliver Langer Journal: J Nucl Med Date: 2019-12-05 Impact factor: 11.082
Authors: Nicolas Tournier; Martin Bauer; Verena Pichler; Lukas Nics; Eva-Maria Klebermass; Karsten Bamminger; Peter Matzneller; Maria Weber; Rudolf Karch; Fabien Caillé; Sylvain Auvity; Solène Marie; Walter Jäger; Wolfgang Wadsak; Marcus Hacker; Markus Zeitlinger; Oliver Langer Journal: J Nucl Med Date: 2019-01-10 Impact factor: 11.082
Authors: Lara García-Varela; Wejdan M Arif; David Vállez García; Takeharu Kakiuchi; Hiroyuki Ohba; Norihiro Harada; Tetsuro Tago; Philip H Elsinga; Hideo Tsukada; Nicola Antonio Colabufo; Rudi A J O Dierckx; Aren van Waarde; Jun Toyohara; Ronald Boellaard; Gert Luurtsema Journal: Mol Pharm Date: 2020-08-17 Impact factor: 4.939
Authors: Lara García-Varela; David Vállez García; Manuel Rodríguez-Pérez; Aren van Waarde; Jürgen W A Sijbesma; Anna Schildt; Chantal Kwizera; Pablo Aguiar; Tomás Sobrino; Rudi A J O Dierckx; Philip H Elsinga; Gert Luurtsema Journal: ACS Chem Neurosci Date: 2020-02-03 Impact factor: 4.418