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 (AUC_10–30). 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. AUC_10–30 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 (AUC_10–30) 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).