https://phaidra.vetmeduni.ac.at/o:4452 [11C]metoclopramide is a sensitive radiotracer to measure moderate decreases in P-glycoprotein function at the blood-brain barrier Mairinger, Severin Severin Mairinger Leterrier, S. S. Leterrier Filip, Thomas Thomas Filip 0009-0006-9169-6032 University of Veterinary Medicine Vienna Loebsch, Mathilde Mathilde Loebsch Pahnke, Jens Jens Pahnke Hernández-Lozano, Irene Irene Hernández-Lozano Stanek, J. J. Stanek Tournier, Nicolas Nicolas Tournier Zeitlinger, Markus Markus Zeitlinger Hacker, Marcus Marcus Hacker Langer, Oliver Oliver Langer Wanek, Thomas Thomas Wanek Sage journal article open access eng The efflux transporter P-glycoprotein (P-gp) at the blood-brain barrier limits the cerebral uptake of various xenobiotics. To assess the sensitivity of [11C]metoclopramide to measure decreased cerebral P-gp function, we performed [11C]metoclopramide PET scans without (baseline) and with partial P-gp inhibition by tariquidar in wild-type, heterozygous Abcb1a/b(+/−) and homozygous Abcb1a/b(−/−) mice as models with controlled levels of cerebral P-gp expression. Brains were collected to quantify P-gp expression with immunohistochemistry. Brain uptake of [11C]metoclopramide was expressed as the area under the brain time-activity curve (AUCbrain) and compared with data previously obtained with (R)-[11C]verapamil and [11C]N-desmethyl-loperamide. Abcb1a/b(+/−) mice had intermediate P-gp expression compared to wild-type and Abcb1a/b(−/−) mice. In baseline scans, all three radiotracers were able to discriminate Abcb1a/b(−/−) from wild-type mice (2.5- to 4.6-fold increased AUCbrain, p ≤ 0.0001). However, only [11C]metoclopramide could discriminate Abcb1a/b(+/−) from wild-type mice (1.46-fold increased AUCbrain, p ≤ 0.001). After partial P-gp inhibition, differences in [11C]metoclopramide AUCbrain between Abcb1a/b(+/−) and wild-type mice (1.39-fold, p ≤ 0.001) remained comparable to baseline. There was a negative correlation between baseline [11C]metoclopramide AUCbrain and ex-vivo-measured P-gp immunofluorescence (r = −0.9875, p ≤ 0.0001). Our data suggest that [11C]metoclopramide is a sensitive radiotracer to measure moderate, but (patho-)physiologically relevant decreases in cerebral P-gp function without the need to co-administer a P-gp inhibitor. P-Glycoprotein Blood-Brain Barrier PET [11C]metoclopramide Heterozygous Abcb1a/b Knockout Mice http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:4452/download 10.1177/0271678X231202336 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Journal Of Cerebral Blood Flow And Metabolism issn:1559-7016 VoR Journal Of Cerebral Blood Flow And Metabolism 44 1 729.76 kB 2024