Abstract
1149
Objectives: Loperamide, a µ-opioid receptor, does not cross the BBB because it is a substrate for the P-glycoprotein (P-gp) efflux pump. [11C]Loperamide has been proposed as a PET radiotracer to measure changes in brain P-gp function in vivo. Our aim was to evaluate it in vivo and ex vivo. Methods: Monkey brain PET scans were obtained with [11C]loperamide (~ 7.2 mCi) on an HRRT camera over 120 min. A baseline scan was followed by one with pre-administration of the P-gp inhibitor, tariquidar (8 mg/kg, i.v.). Scans (439 µCi) were also obtained in 3 P-gp knockout (KO) and 3 wild type (WT) mice for 90 min. Arterial plasma parent input function and plasma free fraction (f1) were determined in monkey. Ex vivo mice (2 KO, 2 WT) forebrain, cerebellum and plasma were analyzed with reverse phase radio-HPLC at 30 min after intravenous injection of radiotracer (423 μCi). Results: The pharmacological inhibition of P-gp in monkey gave a 3.7 fold increase of brain activity (from 40 to 146% standard uptake value). f1 with tariquidar treatment was 12% less than control. Plasma parent area under curve was 21% larger than control. Six radiometabolites were detected in monkey plasma. Parent plasma composition decreased to 50% over 17 min in baseline, and over 20 min in tariquidar. The genetic absence of P-gp gave 2-3-fold higher PET measures of brain activity uptake and about 15-fold higher in total ex vivo brain activity. Four radiometabolites were detected in mice plasma and brain tissues. The most lipophilic radiometabolite was identified by radio-HPLC coelution as N-des-methylloperamide (dLop). Brain composition in WT was 26% parent and 4.3% dLop while in KO was 63% and 21% respectively. Only parent and dLop concentrations increased 30- and 59-fold over control respectively. Parent was selective to forebrain while dLop distributed evenly in cerebellum and forebrain. dLop was inhibited by P-gp more than loperamide. Conclusions: Both loperamide and its radiometabolite dLop are avid P-gp substrates. [11C]dLop may be superior to [11C]loperamide since it will have one less radiometabolite in brain and because it appears to lack significant affinity for the opiate receptors.
Research Support (if any): Intramural Program of NIMH
- Society of Nuclear Medicine, Inc.