YNIMG Journal 2010 Journal Article
- Christian la Fougère
- Guido Böning
- Hero Bartmann
- Björn Wängler
- Sebastian Nowak
- Theresa Just
- Erika Wagner
- Petra Winter
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 (K 1-weighted), were validated as a surrogate marker for the physiological blood–brain clearance (K 1; 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 K 1-weighted uptake and BPND was 25%. TQD treatment evoked a global dose-dependent increase in K 1-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.