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

Abstract

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 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 tariquidartreated 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).

The “Specific” P-Glycoprotein Inhibitor Tariquidar Is Also a Substrate and an Inhibitor for Breast Cancer Resistance Protein (BCRP/ABCG2)

“…For example, the substrate [ 11 C]N-desmethyl-loperamide (dLop) has very limited entry into the human brain but has high uptake in the brain after P-gp inhibition (7). However, substrate radiotracers cannot be used directly to measure the expression or density of P-gp at the blood-brain barrier, because they do not bind to the transporter in a classical receptor-ligand fashion (6).…”

Transport of Selected PET Radiotracers by Human P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2): An In Vitro Screening

“…However, some differences in the spectra of ABC substrates of the human and rodent isoforms of Pgp indicate that models of human ABCs should be used (9,10). A few studies have been done on humans, but they require expensive, time-consuming experimental protocols using cyclosporine A or newer-generation P-gp inhibitors (11,12). These technical issues readily explain why the interactions between clinically useful PET radiotracers and human P-gp are poorly documented.…”

Molecular Imaging of Membrane Transporters’ Activity in Cancer: a Picture is Worth a Thousand Tubes

“…11 C]-verapamil (29,36,69,70) and its (R)-enantiomer (39,(71)(72)(73) and the radiolabeled loperamide metabolite, [ 11 C]-dLop (48,74). In addition to these compounds, cytotoxic drugs, such as daunorubicin (43) and paclitaxel (75), have been radiolabelled and evaluated in various tumor models in rodents (Table III).…”