P-Glycoprotein Function at the Blood–Brain Barrier in Humans Can Be Quantified with the Substrate Radiotracer 11C-N-Desmethyl-Loperamide

Permeability-glycoprotein (P-gp), an efflux transporter in several organs, acts at the blood-brain barrierto protect the brain from exogenous toxins. P-gp almost completely blocks brain entry of the PET radiotracer 11 C-N-desmethyl-loperamide ( 11 C-dLop). We examined the ability of 11 C-dLop to quantify P-gp function in humans after increasing doses of tariquidar, an inhibitor of P-gp. Methods: Seventeen healthy volunteers had a total of 23 PET scans with 11 C-dLop at baseline and after increasing doses of tariquidar (2, 4, and 6 mg/kg intravenously). A subset of subjects received PET with 15 O-H 2 O to measure cerebral blood flow. Brain uptake of 11 C-dLop was quantified in 2 ways. Without blood data, uptake was measured as area under the time-activity curve in the brain from 10 to 30 min (AUC 10―30 ). With arterial blood data, brain uptake was quantified with compartmental modeling to estimate the rates of entry into (K 1 ) and efflux from (k 2 ) the brain. Results: Brain uptake of radioactivity was negligible at baseline and increased only slightly (∼30%) after 2 mg of tariquidar per kilogram. In contrast, 4 and 6 mg of tariquidar per kilogram increased brain uptake 2- and 4-fold, respectively. Greater brain uptake reflected greater brain entry (K 1 ), because efflux (k 2 ) and cerebral blood flow did not differ between tariquidar-treated and untreated subjects. In the subjects who received the highest dose of tariquidar (and had the highest brain uptake), regional values of K 1 correlated linearly with absolute cerebral blood flow, consistent with high single-pass extraction of 11 C-dLop. AUC 10―30 correlated linearly with K 1 . Conclusion: P-gp function at the blood-brain barrier in humans can be quantified using PET and 11 C-dLop. A simple measure of brain uptake (AUC 10―30 ) may be used as a surrogate of the fully quantified rate constant for brain entry (K 1 ) and thereby avoid arterial sampling. However, to dissect the function of P-gp itself, both brain uptake and the influx rate constant must be corrected for radiotracer delivery (blood flow).