Abstracts

Rationale: [¹¹C]flumazenil, a GABA_A-receptor antagonist, is an important PET tracer for assessing GABAergic function in epilepsy by determining receptor density and affinity. Recently, several PET radioligands were found to be P-glycoprotein (P-gp) substrates (1-3). If this is also relevant for [¹¹C]flumazenil, increased P-gp function due to epilepsy could lead to changes in ligand uptake and thereby to erroneous interpretation with respect to GABAergic function. To this end [¹¹C]flumazenil studies were performed in naive and kainic acid treated rats (epilepsy model) as well as in wild type (WT) and P-gp knockout (KO) mice. Methods: Rats received i.p. kainate injections to induce status epilepticus, 7 days before PET scanning. Naive animals received vehicle injections. WT and P-gp KO mice were not pretreated. Each animal underwent two consecutive [¹¹C]flumazenil scans, each of 30 minutes duration. Prior to the second scan, 15 mg.kg^-1 tariquidar, a dose that completely blocks P-gp function, was administered i.v.. Brain concentrations of [¹¹C]flumazenil pre and post P-gp inhibition were compared. Results: In rats, average whole brain [¹¹C]flumazenil concentrations increased 52% (range 31-90%) after tariquidar treatment. Kainate treated rats tended to have a somewhat larger increase in [¹¹C]flumazenil concentrations. This is in line with the hypothesis that these animals have an upregulated P-gp expression. P-gp KO mice had a 33% higher uptake of [¹¹C]flumazenil than WT mice. After P-gp blockage, [¹¹C]flumazenil concentrations increased with 51% in WT mice, while changes in P-gp KO mice were negligible. These results indicate that [¹¹C]flumazenil is indeed a P-gp substrate. It should be noted, however, that more avid P-gp substrates, such as [¹¹C]verapamil, show a much larger (i.e. 10-fold) increase in brain concentrations after the same dose of tariquidar (4). Nonetheless, changes in P-gp function could potentially confound interpretation of [¹¹C]flumazenil scans. Conclusions: [¹¹C]flumazenil is a moderate P-gp substrate. In a disease state such as epilepsy apparent altered binding of [¹¹C]flumazenil may be the result of changes in both GABA_A-receptor density and P-gp function. This work was funded by the EU 7th framework programme EURIPIDES, grant nr HEALTH-F5-2007-201380. References: (1) Passchier J et al. (2000) Eur J Pharmacol. 407:273-80. (2) Liow JS et al. (2007) Synapse 61:96-105. (3) Syv nen S et al. (2009) Drug Metab Dispos. 37:635-43. (4) Bankstahl JP et al. (2008) J Nucl Med. 49:1328-35