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

Abstract

The adenosine triphosphate-binding cassette transporters P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) are 2 major gatekeepers at the blood-brain barrier (BBB) that restrict brain distribution of several clinically used drugs. In this study, we investigated the suitability of the radiolabeled Pgp/BCRP inhibitors (11)C-tariquidar and (11)C-elacridar to assess Pgp density in the human brain with PET.

Methods: Healthy subjects underwent a first PET scan of 120-min duration with either (11)C-tariquidar (n = 6) or (11)C-elacridar (n = 5) followed by a second PET scan of 60-min duration with (R)-(11)C-verapamil. During scan 1 (at 60 min after radiotracer injection), unlabeled tariquidar (3 mg/kg) was intravenously administered. Data were analyzed using 1-tissue 2-rate-constant (1T2K) and 2-tissue 4-rate-constant (2T4K) compartment models and either metabolite-corrected or uncorrected arterial input functions.

Results: After injection of (11)C-tariquidar or (11)C-elacridar, the brain PET signal corrected for radioactivity in the vasculature was low (~0.1 standardized uptake value), with slow washout. In response to tariquidar injection, a moderate but statistically significant rise in brain PET signal was observed for (11)C-tariquidar (+27% ± 15%, P = 0.014, paired t test) and (11)C-elacridar (+21% ± 15%, P = 0.014) without changes in plasma activity concentrations. Low levels of radiolabeled metabolites (<25%) were detected in plasma up to 60 min after injection of (11)C-tariquidar or (11)C-elacridar. The 2T4K model provided better data fits than the 1T2K model. Model outcome parameters were similar when metabolite-corrected or uncorrected input functions were used. There was no significant correlation between distribution volumes of (11)C-tariquidar or (11)C-elacridar and distribution volumes of (R)-(11)C-verapamil in different brain regions.

Conclusion: The in vivo behavior of (11)C-tariquidar and (11)C-elacridar was consistent with that of dual Pgp/BCRP substrates. Both tracers were unable to visualize cerebral Pgp density, most likely because of insufficiently high binding affinities in relation to the low density of Pgp in human brain (∼1.3 nM). Despite their inability to visualize Pgp density, (11)C-tariquidar and (11)C-elacridar 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.

Keywords: 11C-elacridar; 11C-tariquidar; P-glycoprotein; blood-brain barrier; breast cancer resistance protein.

FIGURE 1

Diagram of study set-up. PET scan 1 with either ¹¹C-tariquidar or ¹¹C-elacridar over 120 min was followed by PET scan 2 with (R)-¹¹C-verapamil over 60 min with an interval of 60 min between the 2 scans. At 60 min after start of scan 1, unlabeled tariquidar was infused i.v. at a dose of 3 mg/kg over 30 min.

FIGURE 2

Representative PET summation images (0-60 min) of ¹¹C-tariquidar (A) and ¹¹C-elacridar (B) in coronal (left), transaxial (middle) and sagittal views (right). Activity concentration is expressed as SUV and the radiation scale is set from 0 to 3. Anatomical structures are labeled using white arrows (1, choroid plexus; 2, venous sinus).

FIGURE 3

Time-activity curves (mean SUV ± SD) of ¹¹C-tariquidar (open squares, n = 5) and ¹¹C-elacridar (open circles, n = 4, subject 10 not included) in arterial plasma, uncorrected for radiolabeled metabolites (A), and in whole brain gray matter, corrected for radioactivity in vasculature (B). The start of i.v. tariquidar infusion (3 mg/kg, over 30 min) is indicated by an arrow.

FIGURE 4

Fractions (mean ± SD) of unchanged ¹¹C-tariquidar (open squares, n = 5) and ¹¹C-elacridar (open circles, n= 5) in arterial plasma over time as determined by solid-phase extraction assay. The shown values are not corrected for recoveries of ¹¹C-tariquidar and ¹¹C-elacridar, which ranged from 91-94%.

FIGURE 5

Representative fits (bold solid lines) from 2T4K model using plasma input functions uncorrected for radiolabeled metabolites (open circles) for whole brain gray matter (open squares) for ¹¹C-tariquidar (A) and ¹¹C-elacridar (B).

FIGURE 6

Mean (+SD) 2T4K model-derived V_T values (using plasma input function uncorrected for radiolabeled metabolites) for ¹¹C-tariquidar (black bars, n = 5) and ¹¹C-elacridar (white bars, n = 4, subject 10 not included) in different brain regions. HI = hippocampus; CE = cerebellum; CN = caudate nucleus; PU = putamen; TH = thalamus; GP = gyrus precentralis.

FIGURE 7

Correlation of V_Ts of ¹¹C-tariquidar (A, n = 5) and ¹¹C-elacridar (B, n = 4, subject 10 not included) (using 2T4K model and plasma input function uncorrected for radiolabeled metabolites) with V_Ts of (R)-¹¹ C-verapamil in hippocampus, cerebellum, caudate nucleus, putamen, thalamus and gyrus precentralis. Solid lines represent linear regression fits (r = Pearson correlation coefficient).