title: Comparative evaluation of two glycine transporter 1 radiotracers [11C]GSK931145 and [18F]MK-6577 in baboons.
abstract: Glycine transporter type-1 (GlyT1) has been proposed as a target for drug development for schizophrenia. PET imaging with a GlyT1 specific radiotracer will allow for the measurement of target occupancy of GlyT1 inhibitors, and for in vivo investigation of GlyT1 alterations in schizophrenia. We conducted a comparative evaluation of two GlyT1 radiotracers, [(11) C]GSK931145, and [(18) F]MK-6577, in baboons. Two baboons were imaged with [(11) C]GSK931145 and [(18) F]MK-6577. Blocking studies with GSK931145 (0.3 or 0.2 mg/kg) were conducted to determine the level of tracer specific binding. [(11) C]GSK931145 and [(18) F]MK-6577 were synthesized in good yield and high specific activity. Moderately fast metabolism was observed for both tracers, with ∼ 30% of parent at 30 min post-injection. In the brain, both radiotracers showed good uptake and distribution profiles consistent with regional GlyT1 densities. [(18) F]MK-6577 displayed higher uptake and faster kinetics than [(11) C]GSK931145. Time activity curves were well described by the two-tissue compartment model. Regional volume of distribution (VT ) values were higher for [(18) F]MK-6577 than [(11) C]GSK931145. Pretreatment with GSK931145 reduced tracer uptake to a homogeneous level throughout the brain, indicating in vivo binding specificity and lack of a reference region for both radiotracers. Linear regression analysis of VT estimates between tracers indicated higher specific binding for [(18) F]MK-6577 than [(11) C]GSK931145, consistent with higher regional binding potential (BPND ) values of [(18) F]MK-6577 calculated using VT from the baseline scans and non-displaceable distribution volume (VND ) derived from blocking studies. [(18) F]MK-6577 appears to be a superior radiotracer with higher brain uptake, faster kinetics, and higher specific binding signals than [(11) C]GSK931145.
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University School of Medicine, PET Center, New Haven, Connecticut.
authors.forename: Ming-Qiang
authors.initials: MQ
authors.lastname: Zheng
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University School of Medicine, PET Center, New Haven, Connecticut.
authors.forename: Shu-Fei
authors.initials: SF
authors.lastname: Lin
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University School of Medicine, PET Center, New Haven, Connecticut.
authors.forename: Daniel
authors.initials: D
authors.lastname: Holden
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University School of Medicine, PET Center, New Haven, Connecticut.
authors.forename: Mika
authors.initials: M
authors.lastname: Naganawa
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University School of Medicine, PET Center, New Haven, Connecticut.
authors.forename: Jim R
authors.initials: JR
authors.lastname: Ropchan
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University School of Medicine, PET Center, New Haven, Connecticut.
authors.forename: Soheila
authors.initials: S
authors.lastname: Najafzaden
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University School of Medicine, PET Center, New Haven, Connecticut.
authors.forename: Michael
authors.initials: M
authors.lastname: Kapinos
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University School of Medicine, PET Center, New Haven, Connecticut.
authors.forename: Mike
authors.initials: M
authors.lastname: Tabriz
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University School of Medicine, PET Center, New Haven, Connecticut.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
authors.affiliation: Discovery Imaging, Merck Research Laboratories, West Point, Pennsylvania.
authors.forename: Terence G
authors.initials: TG
authors.lastname: Hamill
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University School of Medicine, PET Center, New Haven, Connecticut.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D001931:Brain Mapping; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D004353:Drug Evaluation, Preclinical; D005260:Female; D018684:Glycine Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D050487:Glycine Plasma Membrane Transport Proteins / Q000378:metabolism*; D007700:Kinetics; D016014:Linear Models; D008279:Magnetic Resonance Imaging; D015394:Molecular Structure; D010215:Papio; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D001549:Benzamides; D002250:Carbon Radioisotopes; C561922:GSK 931145; D018684:Glycine Agents; D050487:Glycine Plasma Membrane Transport Proteins; C000599710:MK-6577; D019275:Radiopharmaceuticals; D013449:Sulfonamides
keywords: GlyT1; PET imaging; [11C]GSK931145; [18F]MK-6577