title: Synthesis and evaluation of [N-methyl-11C]N-desmethyl-loperamide as a new and improved PET radiotracer for imaging P-gp function.
abstract: [(11)C]Loperamide has been proposed for imaging P-glycoprotein (P-gp) function with positron emission tomography (PET), but its metabolism to [N-methyl-(11)C] N-desmethyl-loperamide ([(11)C]dLop; [(11)C]3) precludes quantification. We considered that [(11)C]3 might itself be a superior radiotracer for imaging brain P-gp function and therefore aimed to prepare [(11)C]3 and characterize its efficacy. An amide precursor (2) was synthesized and methylated with [(11)C]iodomethane to give [(11)C]3. After administration of [(11)C]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. [(11)C]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.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1103, USA.
authors.forename: Neva
authors.initials: N
authors.lastname: Lazarova
authors.forename: Sami S
authors.initials: SS
authors.lastname: Zoghbi
authors.forename: Jinsoo
authors.initials: J
authors.lastname: Hong
authors.forename: Nicholas
authors.initials: N
authors.lastname: Seneca
authors.forename: Ed
authors.initials: E
authors.lastname: Tuan
authors.forename: Robert L
authors.initials: RL
authors.lastname: Gladding
authors.forename: Jeih-San
authors.initials: JS
authors.lastname: Liow
authors.forename: Andrew
authors.initials: A
authors.lastname: Taku
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes; D007275:Injections, Intravenous; D008139:Loperamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D013237:Stereoisomerism; D013997:Time Factors
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; C419149:N-demethylloperamide; D008139:Loperamide
references.citation: J Histochem Cytochem. 1990 Sep;38(9):1277-87
references.pmid: 1974900
references.citation: J Nucl Med. 2005 Mar;46(3):484-94
references.pmid: 15750163
references.citation: Int J Rad Appl Instrum B. 1991;18(3):281-8
references.pmid: 2071440
references.citation: J Neurochem. 2001 Feb;76(4):1121-8
references.pmid: 11181832
references.citation: Nat Rev Cancer. 2002 Jan;2(1):48-58
references.pmid: 11902585
references.citation: J Pharmacol Exp Ther. 1999 Aug;290(2):854-62
references.pmid: 10411602
references.citation: Int J Cancer. 2003 Jan 1;103(1):121-5
references.pmid: 12455064
references.citation: Eur J Pharmacol. 1977 Dec 1;46(3):199-205
references.pmid: 22440
references.citation: J Nucl Med. 2006 Mar;47(3):520-7
references.pmid: 16513622
references.citation: J Nucl Med. 2008 Apr;49(4):649-56
references.pmid: 18344435
references.citation: Mol Imaging Biol. 2005 Jan-Feb;7(1):37-44
references.pmid: 15912274
references.citation: J Nucl Med. 1996 Sep;37(9):1571-5
references.pmid: 8790221
references.citation: Biomed Mass Spectrom. 1979 Jun;6(6):253-9
references.pmid: 476289
references.citation: J Med Chem. 2008 Jan 10;51(1):17-30
references.pmid: 18067245
references.citation: J Nucl Med. 2000 Mar;41(3):493-501
references.pmid: 10716325
references.citation: J Nucl Med. 2003 Aug;44(8):1330-9
references.pmid: 12902425
references.citation: J Psychopharmacol. 1993 Jan;7(2):139-58
references.pmid: 22290661
references.citation: J Nucl Med. 2006 Sep;47(9):1427-33
references.pmid: 16954549
references.citation: Dig Dis Sci. 1993 Jun;38(6):977-95
references.pmid: 8508715
references.citation: Cell. 1994 May 20;77(4):491-502
references.pmid: 7910522
references.citation: J Clin Invest. 2005 Nov;115(11):3285-90
references.pmid: 16239972
references.citation: J Nucl Med. 2007 Feb;48(2):207-13
references.pmid: 17268016
references.citation: Eur J Nucl Med. 1997 Feb;24(2):150-9
references.pmid: 9021112
references.citation: Curr Pharm Des. 2004;10(13):1493-503
references.pmid: 15134571
references.citation: Ann Neurol. 2005 Feb;57(2):176-9
references.pmid: 15668963
references.citation: Mol Imaging Biol. 2003 Nov-Dec;5(6):376-89
references.pmid: 14667492
references.citation: Synapse. 2007 Feb;61(2):96-105
references.pmid: 17117422
references.citation: J Clin Invest. 1998 Jan 15;101(2):289-94
references.pmid: 9435299
references.citation: Drug Metab Dispos. 2004 Sep;32(9):943-52
references.pmid: 15319335
references.citation: J Neurosci Methods. 1988 Mar;23(2):121-9
references.pmid: 2833666
references.citation: J Neuropathol Exp Neurol. 2004 Oct;63(10):1038-47
references.pmid: 15535131
references.citation: Mol Imaging. 2005 Jan-Mar;4(1):30-9
references.pmid: 15967124
references.citation: J Clin Invest. 1996 Jun 1;97(11):2517-24
references.pmid: 8647944
references.citation: Clin Pharmacol Ther. 2000 Sep;68(3):231-7
references.pmid: 11014404
references.citation: J Med Chem. 1973 Jul;16(7):782-6
references.pmid: 4725924
references.citation: Pharmacogenetics. 2002 Oct;12(7):535-41
references.pmid: 12360104