[11C]metoclopramide is a sensitive radiotracer to measure moderate decreases in P-glycoprotein function at the blood-brain barrier

Severin Mairinger; S. Leterrier; Thomas Filip; Mathilde Loebsch; Jens Pahnke; Irene Hernández-Lozano; J. Stanek; Nicolas Tournier; Markus Zeitlinger; Marcus Hacker; Oliver Langer; Thomas Wanek

doi:10.1177/0271678X231202336

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Title (eng)

[11C]metoclopramide is a sensitive radiotracer to measure moderate decreases in P-glycoprotein function at the blood-brain barrier

Author

Severin Mairinger

S. Leterrier

Thomas Filip

University of Veterinary Medicine Vienna

Mathilde Loebsch

Jens Pahnke

Irene Hernández-Lozano

J. Stanek

Nicolas Tournier

Markus Zeitlinger

Marcus Hacker

Oliver Langer

Thomas Wanek

Abstract (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.

Keywords (eng)

P-GlycoproteinBlood-Brain BarrierPET[11C]metoclopramideHeterozygous Abcb1a/b Knockout Mice

Type (eng)

journal article

Language

[eng]

Persistent identifier

https://phaidra.vetmeduni.ac.at/o:4452

DOI

10.1177/0271678X231202336

Is in series

Title (eng)