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

The efflux transporter P-glycoprotein (P-gp) at the blood-brain barrier limits the cerebral uptake of various xenobiotics. To assess the sensitivity of [C-11]metoclopramide to measure decreased cerebral P-gp function, we performed [C-11] 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 [C-11]metoclopramide was expressed as the area under the brain time-activity curve (AUCbrain) and compared with data previously obtained with (R)-[C-11]verapamil and [C-11]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 AUC(brain), p <= 0.0001). However, only [C-11]metoclopramide could discriminate Abcb1a/b((+/-)) from wild-type mice (1.46-fold increased AUC(brain), p <= 0.001). After partial P-gp inhibition, differences in [C-11]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 [C-11]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.