Synthesis and Evaluation of [N-methyl-11C]N-Desmethyl-loperamide as a New and Improved PET Radiotracer for Imaging P-gp Function

• Published in: Journal of medicinal chemistry Vol. 51; no. 19; pp. 6034 - 6043
• Main Authors: Lazarova, Neva, Zoghbi, Sami S, Hong, Jinsoo, Seneca, Nicholas, Tuan, Ed, Gladding, Robert L, Liow, Jeih-San, Taku, Andrew, Innis, Robert B, Pike, Victor W
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.10.2008; Amer Chemical Soc
• Subjects: Animals; ATP Binding Cassette Transporter, Subfamily B - deficiency; ATP Binding Cassette Transporter, Subfamily B - metabolism; Biological and medical sciences; Brain - diagnostic imaging; Brain - metabolism; Carbon Radioisotopes; Chemistry, Medicinal; Contrast media. Radiopharmaceuticals; Injections, Intravenous; Life Sciences & Biomedicine; Loperamide - analogs & derivatives; Loperamide - chemical synthesis; Loperamide - chemistry; Loperamide - pharmacokinetics; Macaca mulatta; Male; Medical sciences; Mice; Mice, Knockout; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Positron-Emission Tomography - methods; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - pharmacokinetics; Science & Technology; Stereoisomerism; Time Factors; GLYCOPROTEIN FUNCTION; TRANSPORTER; RADIOMETABOLITE; IN-VIVO; LOPERAMIDE; OPIOID RECEPTORS; MULTIDRUG-RESISTANCE; BLOOD-BRAIN-BARRIER; EXPRESSION; MODULATION; Transmembrane protein; Loperamide; Intravenous administration; Radiolabelling; Rodentia; P Glycoprotein; Monkey; Central nervous system; Antidiarrheal agent; Carbon Isotopes; Vertebrata; Mammalia; Mouse; Scintigraphic agent; Animal; Piperidine derivatives; Primates; Carbon 11; Carboxamide; Chemical synthesis; Positron emission tomography; Carrier protein
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800510m

[11C]Loperamide has been proposed for imaging P-glycoprotein (P-gp) function with positron emission tomography (PET), but its metabolism to [N-methyl-11C]N-desmethyl-loperamide ([11C]dLop; [11C]3) precludes quantification. We considered that [11C]3 might itself be a superior radiotracer for imaging brain P-gp function and therefore aimed to prepare [11C]3 and characterize its efficacy. An amide precursor (2) was synthesized and methylated with [11C]iodomethane to give [11C]3. After administration of [11C]3 to wild-type mice, brain radioactivity uptake was very low. In P-gp (mdr-1a(−/−)) 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. [11C]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.