Imaging P-glycoprotein function in rats using [ super(11)C]-N-desmethyl-loper amide

Objective: One mechanism that may be responsible for drug resistance in epilepsy is the upregulation of P-glycoprotein (P-gp), a drug efflux pump, at the epileptogenic focus. In this study, we sought to evaluate the potential of a recently developed P-gp PET radiotracer, [ super(11)C]N-desmethyl-lopera mide ([ super(11)C]dLop), for measuring P-gp function in the rat brain. Methods: The precursor to [ super(11)C]dLop was synthesized in two steps from commercially available starting materials and subsequently radiolabeled in one step using [ super(11)C]methyl iodide. [ super(11)C]dLop was then administered to two groups of rats, controls (n = 4) and those treated with a P-gp inhibitor (n = 8). Cyclosporin A (CsA, 50 mg/kg, n = 3) and tariquidar (TQ, 20 mg/kg, n = 5) were both used as P-gp inhibitors. MicroPET brain scans were performed for 120 min with arterial blood sampling. A one-tissue compartment model was used to estimate the distribution volume of radiotracer as the outcome measure of P-gp function. Results: Plasma levels of parent [ super(11)C]dLop decreased rapidly to