title: Determination of the in vivo selectivity of a new κ-opioid receptor antagonist PET tracer 11C-LY2795050 in the rhesus monkey.
abstract: (11)C-LY2795050 is a novel κ-selective antagonist PET tracer. The in vitro binding affinities (Ki) of LY2795050 at the κ-opioid (KOR) and μ-opioid (MOR) receptors are 0.72 and 25.8 nM, respectively. Thus, the in vitro KOR/MOR binding selectivity is about 36:1. Our goal in this study was to determine the in vivo selectivity of this new KOR antagonist tracer in the monkey.
  
  
  METHODS
  To estimate the ED50 value (dose of a compound [or drug] that gives 50% occupancy of the target receptor) of LY2795050 at the MOR and KOR sites, 2 series of blocking experiments were performed in 3 rhesus monkeys using (11)C-LY2795050 and (11)C-carfentanil with coinjections of various doses of unlabeled LY2795050. Kinetic modeling was applied to calculate regional binding potential (BP(ND)), and 1- and 2-site binding curves were fitted to these data to measure (11)C-LY2795050 binding selectivity.
  
  
  RESULTS
  The LY2795050 ED50 at MOR was 119 μg/kg based on a 1-site model for (11)C-carfentanil. The 1-site binding model was also deemed sufficient to describe the specific binding of (11)C-LY2795050 at KOR. The ED50 at KOR estimated from the 1-site model was 15.6 μg/kg. Thus, the ED50 ratio for MOR:KOR was 7.6.
  
  
  CONCLUSIONS
  The in vivo selectivity of (11)C-LY2795050 for KOR over MOR is 7.6. (11)C-LY2795050 has 4.7-fold-lower selectivity at KOR over MOR in vivo as compared with in vitro. Nevertheless, on the basis of our finding in vivo, 88% of the PET-observed specific binding of (11)C-LY2795050 under baseline conditions will be due to binding of the tracer at the KOR site in a region with similar prevalence of KOR and MOR. (11)C-LY2795050 is sufficiently selective for KOR over MOR in vivo to be considered an appropriate probe for studying the KOR with PET.
authors.affiliation: Yale PET Center, Yale University, New Haven, Connecticut 06510, USA.
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Ming-Qiang
authors.initials: MQ
authors.lastname: Zheng
authors.forename: Nabeel
authors.initials: N
authors.lastname: Nabulsi
authors.forename: David
authors.initials: D
authors.lastname: Labaree
authors.forename: Jim
authors.initials: J
authors.lastname: Ropchan
authors.forename: Soheila
authors.initials: S
authors.lastname: Najafzadeh
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.forename: Evan D
authors.initials: ED
authors.lastname: Morris
mesh_terms: D000818:Animals; D001549:Benzamides / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D003198:Computer Simulation; D007090:Image Interpretation, Computer-Assisted / Q000379:methods*; D008253:Macaca mulatta; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D049268:Positron-Emission Tomography / Q000379:methods*; D011759:Pyrrolidines / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution
chemical_list: C570402:3-chloro-4-(4-((2-(3-pyridyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide; D001549:Benzamides; D011759:Pyrrolidines; D019275:Radiopharmaceuticals; D017473:Receptors, Opioid, kappa
keywords: PET; in vivo; selectivity; κ-opioid receptor
references.citation: Alcohol Clin Exp Res. 2005 May;29(5):730-8
references.pmid: 15897716
references.citation: Alcohol Clin Exp Res. 2011 Dec;35(12):2162-73
references.pmid: 21689118
references.citation: J Cereb Blood Flow Metab. 2010 Jan;30(1):46-50
references.pmid: 19738632
references.citation: J Med Chem. 2003 Jul 3;46(14):3127-37
references.pmid: 12825951
references.citation: Neuropsychopharmacology. 2008 Feb;33(3):653-65
references.pmid: 17487229
references.citation: Mol Imaging Biol. 2007 May-Jun;9(3):117-25
references.pmid: 17473957
references.citation: J Nucl Med. 2013 Mar;54(3):455-63
references.pmid: 23353688
references.citation: Neuroimage. 1996 Dec;4(3 Pt 1):153-8
references.pmid: 9345505
references.citation: Psychopharmacology (Berl). 1985;86(3):274-80
references.pmid: 2994144
references.citation: Life Sci. 2000 Apr 7;66(20):1915-27
references.pmid: 10821116
references.citation: Brain Res. 1987 Jun 23;414(1):8-14
references.pmid: 3040166
references.citation: J Nucl Med. 2005 Mar;46(3):484-94
references.pmid: 15750163
references.citation: Trends Neurosci. 1988 Jul;11(7):308-14
references.pmid: 2465635
references.citation: Neuroscience. 1999;94(2):651-62
references.pmid: 10579225
references.citation: Nucl Med Biol. 2008 Jul;35(5):561-9
references.pmid: 18589300
references.citation: J Cereb Blood Flow Metab. 2002 Oct;22(10):1271-81
references.pmid: 12368666
references.citation: Hum Mol Genet. 2008 Jun 15;17(12):1783-9
references.pmid: 18319328
references.citation: Neuroimage. 2002 Aug;16(4):1015-27
references.pmid: 12202089
references.citation: Nucl Med Biol. 2010 Feb;37(2):205-14
references.pmid: 20152720
references.citation: Neurobiol Aging. 2007 Nov;28(11):1700-8
references.pmid: 16914231
references.citation: Nucl Med Biol. 2003 Feb;30(2):177-86
references.pmid: 12623117
references.citation: Pharmacol Ther. 2007 Nov;116(2):306-21
references.pmid: 17868902
references.citation: Alcohol Clin Exp Res. 1999 Aug;23(8):1296-305
references.pmid: 10470971
references.citation: Neuroreport. 1998 May 11;9(7):1459-64
references.pmid: 9631448
references.citation: J Pharmacol Exp Ther. 1998 May;285(2):518-26
references.pmid: 9580592
references.citation: Nucl Med Biol. 1999 Oct;26(7):737-41
references.pmid: 10628552
references.citation: Psychopharmacology (Berl). 2004 Sep;175(3):274-86
references.pmid: 15024551
references.citation: Neuroimage. 2013 Jan 1;64:571-81
references.pmid: 22926293
references.citation: Biol Psychiatry. 2010 Aug 15;68(4):392-9
references.pmid: 20599188