Uptake and binding of the serotonin 5-HT1A antagonist [18F]-MPPF in brain of rats: Effects of the novel P-glycoprotein inhibitor tariquidar

We used microPET to map the dose-response to the novel P-glycoprotein (P-gp) inhibitor tariquidar (TQD) of the initial influx of the P-gp substrate [18F]-MPPF in rat brain, and to test for effects of P-gp inhibition on the subsequent binding of [18F]-MPPF to serotonin 5-HT1A receptors. Summation maps of [18F]-MPPF uptake during the first 100 seconds after intravenous injection were calculated in groups of rats with vehicle (glucose 5%) pretreatment, or following pretreatment with TQD at doses of 5, 15, or 30 mg/kg. The early summation image (K1-weighted), were validated as a surrogate marker for the physiological blood-brain clearance (K1; ml g− 1 min− 1) by linear graphic analysis of the unidirectional blood-brain clearance relative to an image-based arterial input measured in the left ventricle of the heart. In the same animals, parametric maps of the [18F]-MPPF binding potential (BPND) were calculated from the entire 60-minute emission recordings using conventional reference tissue methods. All [18F]-MPPF recordings were followed by an [18F]-FDG emission recording, the summation of which was used for spatial normalization to a rat brain atlas. Test-retest variability of K1-weighted uptake and BPND was 25%. TQD treatment evoked a global dose-dependent increase in K1-weighted summation, which increased 2.5-fold with TQD (30 mg/kg), suggesting an IC50 of 5 mg/kg TQD. All TQD doses increased the apparent [18F]-MPPF BPND calculated by the Logan method by 30%-40%, a bias likely arising due to increased free [18F]-MPPF concentrations in brain. TQD (15 mg/kg) evoked a 45% global increase in [18F]-FDG uptake, suggesting perturbation of brain energy metabolism due to P-gp blockade.