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 barrier to protect the brain from exogenous toxins. P-gp almost completely blocks brain entry of the PET radiotracer 11C-N-desmethyl-loperamide (11C-dLop). We examined the ability of 11C-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 11C-dLop at baseline and after increasing doses of tariquidar (2, 4, and 6 mg/kg intravenously). A subset of subjects received PET with 15O-H2O to measure cerebral blood flow. Brain uptake of 11C-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 (AUC10–30). With arterial blood data, brain uptake was quantified with compartmental modeling to estimate the rates of entry into (K1) and efflux from (k2) 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 (K1), because efflux (k2) 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 K1 correlated linearly with absolute cerebral blood flow, consistent with high single-pass extraction of 11C-dLop. AUC10–30 correlated linearly with K1. Conclusion: P-gp function at the blood–brain barrier in humans can be quantified using PET and 11C-dLop. A simple measure of brain uptake (AUC10–30) may be used as a surrogate of the fully quantified rate constant for brain entry (K1) 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).