| Title: |
[ 11 C]metoclopramide is a sensitive radiotracer to measure moderate decreases in P-glycoprotein function at the blood-brain barrier. |
| Authors: |
Mairinger, Severin; Leterrier, Sarah; Filip, Thomas; Löbsch, Mathilde; Pahnke, Jens; Hernández-Lozano, Irene; Stanek, Johann; Tournier, Nicolas; Zeitlinger, Markus; Hacker, Marcus; Langer, Oliver; Wanek, Thomas |
| Source: |
Journal of Cerebral Blood Flow & Metabolism; Jan2024, Vol. 44 Issue 1, p142-152, 11p |
| Abstract: |
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. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |