Synthesis and evaluation of [N-methyl-11C]N-desmethyl-loperamide as a new and improved PET radiotracer for imaging P-gp function.
[(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.
Lazarova
Neva
N
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1103, USA.
Zoghbi
Sami S
SS
Hong
Jinsoo
J
Seneca
Nicholas
N
Tuan
Ed
E
Gladding
Robert L
RL
Liow
Jeih-San
JS
Taku
Andrew
A
Innis
Robert B
RB
Pike
Victor W
VW
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
D018435:ATP Binding Cassette Transporter, Subfamily B; D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; C419149:N-demethylloperamide; D008139:Loperamide
J Histochem Cytochem. 1990 Sep;38(9):1277-87
1974900
J Nucl Med. 2005 Mar;46(3):484-94
15750163
Int J Rad Appl Instrum B. 1991;18(3):281-8
2071440
J Neurochem. 2001 Feb;76(4):1121-8
11181832
Nat Rev Cancer. 2002 Jan;2(1):48-58
11902585
J Pharmacol Exp Ther. 1999 Aug;290(2):854-62
10411602
Int J Cancer. 2003 Jan 1;103(1):121-5
12455064
Eur J Pharmacol. 1977 Dec 1;46(3):199-205
22440
J Nucl Med. 2006 Mar;47(3):520-7
16513622
J Nucl Med. 2008 Apr;49(4):649-56
18344435
Mol Imaging Biol. 2005 Jan-Feb;7(1):37-44
15912274
J Nucl Med. 1996 Sep;37(9):1571-5
8790221
Biomed Mass Spectrom. 1979 Jun;6(6):253-9
476289
J Med Chem. 2008 Jan 10;51(1):17-30
18067245
J Nucl Med. 2000 Mar;41(3):493-501
10716325
J Nucl Med. 2003 Aug;44(8):1330-9
12902425
J Psychopharmacol. 1993 Jan;7(2):139-58
22290661
J Nucl Med. 2006 Sep;47(9):1427-33
16954549
Dig Dis Sci. 1993 Jun;38(6):977-95
8508715
Cell. 1994 May 20;77(4):491-502
7910522
J Clin Invest. 2005 Nov;115(11):3285-90
16239972
J Nucl Med. 2007 Feb;48(2):207-13
17268016
Eur J Nucl Med. 1997 Feb;24(2):150-9
9021112
Curr Pharm Des. 2004;10(13):1493-503
15134571
Ann Neurol. 2005 Feb;57(2):176-9
15668963
Mol Imaging Biol. 2003 Nov-Dec;5(6):376-89
14667492
Synapse. 2007 Feb;61(2):96-105
17117422
J Clin Invest. 1998 Jan 15;101(2):289-94
9435299
Drug Metab Dispos. 2004 Sep;32(9):943-52
15319335
J Neurosci Methods. 1988 Mar;23(2):121-9
2833666
J Neuropathol Exp Neurol. 2004 Oct;63(10):1038-47
15535131
Mol Imaging. 2005 Jan-Mar;4(1):30-9
15967124
J Clin Invest. 1996 Jun 1;97(11):2517-24
8647944
Clin Pharmacol Ther. 2000 Sep;68(3):231-7
11014404
J Med Chem. 1973 Jul;16(7):782-6
4725924
Pharmacogenetics. 2002 Oct;12(7):535-41
12360104