Synthesis and evaluation of [N-methyl-C-11]N-desmethyl-loperamide as a new and improved PET radiotracer for imaging P-gp function

摘要

[C-11]Loperamide has been proposed for imaging P-glycoprotein (P-gp) function with positron emission tomography (PET), but its metabolism to [N-methyl-C-11]N-desmethyl-loperamide ([C-11]dLop; [C-11]3) precludes quantification. We considered that [C-11]3 might itself be a superior radiotracer for imaging brain P-gp function and therefore aimed to prepare [C-11]3 and characterize its efficacy. An amide precursor (2) was synthesized and methylated with [C-11]iodomethane to give [C-11]3. After administration of [C-11]3 to wild-type mice, brain radioactivity uptake was very low. In P-gp (mdr-la(-/-)) knockout mice, brain uptake of radioactivity at 30 min increased about 3.5-fold by PET measures, and over 7-fold by ex vivo measures. In knockout mice, brain radioactivity was predominantly (90%) unchanged radiotracer. In monkey PET experiments, brain radioactivity uptake was also very low but after P-gp blockade increased more than 7-fold. [C-11]3 is an effective new radiotracer for imaging brain P-gp function and, in favor of future successful quantification, appears free of extensive brain-penetrant radiometabolites.