title: Determination of receptor occupancy in the presence of mass dose: [11C]GSK189254 PET imaging of histamine H3receptor occupancy by PF-03654746.
abstract: Measurements of drug occupancies using positron emission tomography (PET) can be biased if the radioligand concentration exceeds "tracer" levels. Negative bias would also arise in successive PET scans if clearance of the radioligand is slow, resulting in a carryover effect. We developed a method to (1) estimate the in vivo dissociation constant Kdof a radioligand from PET studies displaying a non-tracer carryover (NTCO) effect and (2) correct the NTCO bias in occupancy studies taking into account the plasma concentration of the radioligand and its in vivo Kd. This method was applied in a study of healthy human subjects with the histamine H3receptor radioligand [11C]GSK189254 to measure the PK-occupancy relationship of the H3antagonist PF-03654746. From three test/retest studies, [11C]GSK189254 Kdwas estimated to be 9.5 ± 5.9 pM. Oral administration of 0.1 to 4 mg of PF-03654746 resulted in occupancy estimates of 71%-97% and 30%-93% at 3 and 24 h post-drug, respectively. NTCO correction adjusted the occupancy estimates by 0%-15%. Analysis of the relationship between corrected occupancies and PF-03654746 plasma levels indicated that PF-03654746 can fully occupy H3binding sites ( ROmax= 100%), and its IC50was estimated to be 0.144 ± 0.010 ng/mL. The uncorrected IC50was 26% higher.
authors.affiliation: 1 Yale PET Center, Yale University, New Haven, CT, USA.
authors.forename: Jean-Dominique
authors.initials: JD
authors.lastname: Gallezot
authors.affiliation: 1 Yale PET Center, Yale University, New Haven, CT, USA.
authors.forename: Beata
authors.initials: B
authors.lastname: Planeta
authors.affiliation: 1 Yale PET Center, Yale University, New Haven, CT, USA.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Nabulsi
authors.affiliation: 2 Pfizer Worldwide Research and Development, Cambridge, MA, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Palumbo
authors.affiliation: 2 Pfizer Worldwide Research and Development, Cambridge, MA, USA.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Li
authors.affiliation: 2 Pfizer Worldwide Research and Development, Cambridge, MA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: 2 Pfizer Worldwide Research and Development, Cambridge, MA, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Rowinski
authors.affiliation: 2 Pfizer Worldwide Research and Development, Cambridge, MA, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Chidsey
authors.affiliation: 1 Yale PET Center, Yale University, New Haven, CT, USA.
authors.forename: David
authors.initials: D
authors.lastname: Labaree
authors.affiliation: 1 Yale PET Center, Yale University, New Haven, CT, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Ropchan
authors.affiliation: 1 Yale PET Center, Yale University, New Haven, CT, USA.
authors.forename: Shu-Fei
authors.initials: SF
authors.lastname: Lin
authors.affiliation: 2 Pfizer Worldwide Research and Development, Cambridge, MA, USA.
authors.forename: Aarti
authors.initials: A
authors.lastname: Sawant-Basak
authors.affiliation: 2 Pfizer Worldwide Research and Development, Cambridge, MA, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: McCarthy
authors.affiliation: 2 Pfizer Worldwide Research and Development, Cambridge, MA, USA.
authors.forename: Anne W
authors.initials: AW
authors.lastname: Schmidt
authors.affiliation: 1 Yale PET Center, Yale University, New Haven, CT, USA.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: 1 Yale PET Center, Yale University, New Haven, CT, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
mesh_terms: D000328:Adult; D001552:Benzazepines / Q000097:blood / Q000378:metabolism*; D002250:Carbon Radioisotopes; D003503:Cyclobutanes / Q000008:administration & dosage / Q000097:blood; D006801:Humans; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000097:blood; D011869:Radioligand Assay / Q000379:methods; D018100:Receptors, Histamine H3 / Q000032:analysis* / Q000378:metabolism; D055815:Young Adult
chemical_list: D001552:Benzazepines; D002250:Carbon Radioisotopes; D003503:Cyclobutanes; C569672:N-ethyl-3-fluoro-3-(3-fluoro-4-(pyrrolidinylmethyl)phenyl)cyclobutanecarboxamide; D011759:Pyrrolidines; D018100:Receptors, Histamine H3; D009536:Niacinamide; C521312:6-((3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy)-N-methyl-3-pyridinecarboxamide
keywords: Mathematical modeling; kinetic modeling; pharmacokinetics; positron emission tomography; receptor imaging