Abstract
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Objectives Drug resistance is a problem in the treatment of various diseases, such as epilepsy. One of mechanisms responsible for this resistance may be up-regulation of P-glycoprotein (P-gp) drug efflux pump. In this rat brain study, we sought to evaluate the potential of newly developed P-gp PET tracer, 11C-N-desmethyl-loperamide 11C-dLop), for measuring P-gp function.
Methods 11C-dLop was synthesized as described previously (J. Med. Chem. 2008, 51, 6034-6043). We studied two groups of rats, controls (n=4) and inhibitors (n=5), with cyclosporine A (CsA), 50mg/kg, or tariquidar (TQ), 20mg/kg. MicroPET brain scans were performed for 120min with arterial blood sampling. One-tissue compartment model was used to estimate the distribution volume (VT) of radiotracer as the outcome measure of P-gp function.
Results Parent 11C-dLop in plasma rapidly decreased to <0.1 SUV at 60min. In controls, brain uptake of 11C-dLop was very low <0.1 SUV. In contrast, the SUVs were significantly higher in CsA (0.51) and TQ (0.22). A 70min scan was sufficient to obtain stable VT (control=2.1, CsA=7.3, TQ=4.7), showing significant effects of P-gp inhibition.
Conclusions 11C-dLop is a substrate for P-gp and shows very low brain uptake without P-gp inhibition, but with inhibition, there is a significant rise in the tracer brain uptake. 11C-dLop is a promising radiotracer to study the P-gp function.
- © 2009 by Society of Nuclear Medicine