title: Kinetic modeling of (11)C-LY2795050, a novel antagonist radiotracer for PET imaging of the kappa opioid receptor in humans.
abstract: (11)C-LY2795050 is a novel kappa opioid receptor (KOR) antagonist tracer for positron emission tomography (PET) imaging. The purpose of this first-in-human study was to determine the optimal kinetic model for analysis of (11)C-LY2795050 imaging data. Sixteen subjects underwent baseline scans and blocking scans after oral naltrexone. Compartmental modeling and multilinear analysis-1 (MA1) were applied using the arterial input functions. Two-tissue compartment model and MA1 were found to be the best models to provide reliable measures of binding parameters. The rank order of (11)C-LY2795050 distribution volume (VT) matched the known regional KOR densities in the human brain. Blocking scans with naltrexone indicated no ideal reference region for (11)C-LY2795050. Three methods for calculation of the nondisplaceable distribution volume (VND) were assessed: (1) individual VND estimated from naltrexone occupancy plots, (2) mean VND across subjects, and (3) a fixed fraction of cerebellum VT. Approach (3) produced the lowest intersubject variability in the calculation of binding potentials (BPND, BPF, and BPP). Therefore, binding potentials of (11)C-LY2795050 can be determined if the specific binding fraction in the cerebellum is presumed to be unchanged by diseases and experimental conditions. In conclusion, results from the present study show the suitability of (11)C-LY2795050 to image and quantify KOR in humans.
authors.affiliation: Department of Diagnostic Radiology, PET Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Mika
authors.initials: M
authors.lastname: Naganawa
authors.affiliation: Department of Diagnostic Radiology, PET Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Ming-Qiang
authors.initials: MQ
authors.lastname: Zheng
authors.affiliation: Department of Diagnostic Radiology, PET Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Nabulsi
authors.affiliation: Department of Diagnostic Radiology, PET Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tomasi
authors.affiliation: Department of Diagnostic Radiology, PET Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Shannan
authors.initials: S
authors.lastname: Henry
authors.affiliation: Department of Diagnostic Radiology, PET Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Shu-Fei
authors.initials: SF
authors.lastname: Lin
authors.affiliation: Department of Diagnostic Radiology, PET Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Ropchan
authors.affiliation: Department of Diagnostic Radiology, PET Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: David
authors.initials: D
authors.lastname: Labaree
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: Johannes
authors.initials: J
authors.lastname: Tauscher
authors.affiliation: Department of Psychiatry and Radiology, New York University School of Medicine, New York, New York, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Neumeister
authors.affiliation: Department of Diagnostic Radiology, PET Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
authors.affiliation: Department of Diagnostic Radiology, PET Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001549:Benzamides / Q000008:administration & dosage / Q000493:pharmacokinetics; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000378:metabolism; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D049268:Positron-Emission Tomography; D011759:Pyrrolidines / Q000008:administration & dosage / Q000493:pharmacokinetics; D011849:Radioactive Tracers; D011859:Radiography; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C570402:3-chloro-4-(4-((2-(3-pyridyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide; D001549:Benzamides; D011759:Pyrrolidines; D011849:Radioactive Tracers; D017473:Receptors, Opioid, kappa; D009271:Naltrexone; C034641:naltrexazone