Interaction of 11C-tariquidar and 11C-elacridar with P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) at the human blood-brain barrier (BBB)

Objectives The adenosine triphosphate-binding cassette transporters Pgp and BCRP are 2 major gatekeepers at the BBB which restrict brain distribution of several drugs. In this study we investigated the suitability of the radiolabeled Pgp/BCRP inhibitors 11C-tariquidar and 11C-elacridar to assess Pgp density in human brain with PET.

Methods Healthy subjects underwent a first PET scan of 120 min duration with either 11C-tariquidar (n = 6) or 11C-elacridar (n = 5) followed by a second PET scan of 60 min duration with (R)-11C-verapamil. During scan 1 (at 60 min after radiotracer injection) unlabeled tariquidar (3 mg/kg) was intravenously administered. The kinetic model describing best tracer BBB transport was investigated.

Results Following injection of 11C-tariquidar or 11C-elacridar, brain PET signal corrected for radioactivity in vasculature was yery low (~0.1 SUV) with slow washout. In response to tariquidar injection, a moderate rise in brain PET signal was observed for 11C-tariquidar (+27±15%, P=0.01 paired t-test) and 11C-elacridar (+21±15%, P=0.01) without changes in plasma activity concentrations and low levels of radiolabeled metabolites (<25%) for both tracers at 60 min after injection. The 2T4K model provided best data fits. There was no significant correlation between distribution volumes (VT) of 11C-tariquidar or 11C-elacridar and VTs of (R)-11C-verapamil in different brain regions.

Conclusions The in vivo behavior of 11C-tariquidar and 11C-elacridar was consistent with that of dual Pgp/BCRP substrates. Tracers were unable to visualize cerebral Pgp density, most likely related to insufficiently high binding affinities in relation to the very low density of Pgp in human brain. Both new tracers may find use as a new class of radiotracers to study the interplay of Pgp and BCRP at the human BBB in limiting brain uptake of dual substrates.

Research Support European Community’s FP7/2007-2013 (201380) and Austrian Science Fund project ‘‘Transmembrane Transporters in Health and Disease’’ (SFB F35)