title: Measurement of Bmax and Kd with the glycine transporter 1 radiotracer ¹⁸F-MK6577 using a novel multi-infusion paradigm.
abstract: Glycine is a co-agonist of glutamate at the NMDA receptor. Glycine transporter 1 (GlyT1) inhibitors are reported to be potential therapeutic agents for schizophrenia. (18)F-MK6577 is a new positron emission tomography (PET) radiotracer useful for imaging brain GlyT1 and its occupancy in humans. We devised a novel multi-infusion paradigm of radiolabeled and unlabeled compound and an iterative linear/nonlinear alternating fitting method to allow for the determination of in vivo affinity (Kd) and target concentration (Bmax) images, constraining Kd to be uniform across the brain. This paradigm was tested with (18)F-MK6577 in baboons. Voxel-based analysis produced high quality Bmax images and reliable Kd estimates, and also suggested that the nondisplaceable distribution volume (VND) is not uniform throughout the brain. In vivo GlyT1 Kd was estimated to be 1.87 nmol/L for (18)F-MK6577, and the rank order of GlyT1 distribution measured in the baboon brain was: high in the brainstem (133 nmol/L), medium in the cerebellum (83 nmol/L), and low in the cortex (30 nmol/L). These in vivo Kd and Bmax values agreed well with those determined in vitro, thus validating our novel multi-infusion approach.
authors.affiliation: PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.affiliation: PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Ming-Qiang
authors.initials: MQ
authors.lastname: Zheng
authors.affiliation: PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Holden
authors.affiliation: PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Shu-fei
authors.initials: SF
authors.lastname: Lin
authors.affiliation: PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kapinos
authors.affiliation: PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Ropchan
authors.affiliation: PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Jean-Dominique
authors.initials: JD
authors.lastname: Gallezot
authors.affiliation: PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
mesh_terms: D000465:Algorithms; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001711:Biotransformation; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins / Q000378:metabolism*; D007091:Image Processing, Computer-Assisted; D007262:Infusions, Intravenous; D008279:Magnetic Resonance Imaging; D010215:Papio / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D001549:Benzamides; D050487:Glycine Plasma Membrane Transport Proteins; C000599710:MK-6577; D019275:Radiopharmaceuticals; D013449:Sulfonamides