Assessment of cerebral P-glycoprotein expression and function with PET by combined [11C]inhibitor and [11C]substrate scans in rats.

Introduction: The adenosine triphosphate-binding cassette (ABC) transporter P-glycoprotein (Pgp) protects the brain from accumulation of lipophilic compounds by active efflux transport across the blood-brain barrier. Changes in Pgp function/expression may occur in neurological disorders, such as epilepsy, Alzheimer's or Parkinson's disease. In this work we investigated the suitability of the radiolabeled Pgp inhibitors [(11)C]elacridar and [(11)C]tariquidar to visualize Pgp density in rat brain with PET.

Methods: Rats underwent a first PET scan with [(11)C]elacridar (n = 5) or [(11)C]tariquidar (n = 6) followed by a second scan with the Pgp substrate (R)-[(11)C]verapamil after administration of unlabeled tariquidar at a dose which half-maximally inhibits cerebral Pgp (3 mg/kg). Compartmental modeling using an arterial input function and Logan graphical analysis were used to estimate rate constants and volumes of distribution (VT) of radiotracers in different brain regions.

Results: Brain PET signals of [(11)C]elacridar and [(11)C]tariquidar were very low (~0.5 standardized uptake value, SUV). There was a significant negative correlation between VT and K1 (i.e. influx rate constant from plasma into brain) values of [(11)C]elacridar or [(11)C]tariquidar and VT and K1 values of (R)-[(11)C]verapamil in different brain regions which was consistent with binding of [(11)C]inhibitors to Pgp and efflux of (R)-[(11)C]verapamil by Pgp.

Conclusion: The small Pgp binding signals obtained with [(11)C]elacridar and [(11)C]tariquidar limit the applicability of these tracers to measure cerebral Pgp density. PET tracers with higher (i.e. subnanomolar) binding affinities will be needed to visualize the low density of Pgp in brain.