title: Pre-clinical characterization of [11C]R05013853 as a novel radiotracer for imaging of the glycine transporter type 1 by positron emission tomography.
abstract: A specific positron emission tomography (PET) radiotracer for the glycine transporter type 1 (GlyT1) would constitute an imaging biomarker to investigate the distribution of GlyT1 in normal individuals and those with neuropsychiatric disorders. In addition it could demonstrate the ability of a novel drug to reach its target in the brain and enable receptor occupancy studies, thus facilitating drug development. In this article we describe the evaluation in non-human primates of two candidate PET radiotracers ([(11)C]RO5013852 and [(11)C]RO5013853) previously characterized in the rat. Both radiotracers showed acceptable uptake in the baboon brain and heterogeneous distribution consistent with that reported for GlyT1. In vivo blockade studies with two specific glycine reuptake inhibitors (GRIs), RO5013853 and bitopertin (RG1678, reduced uptake of both tracers to homogenous levels across brain regions and demonstrated specificity of the signal. [(11)C]RO5013853 showed a larger specific signal and slightly higher brain uptake and was therefore selected for further characterization. Quantitative compartmental analysis of PET data showed that the 2-tissue compartment model with 5 parameters was the most appropriate to describe the kinetics of [(11)C]RO5013853. Two additional methods were used: a) the Logan graphical analysis using plasma input and, b) a linear parametric imaging approach with the 2-tissue compartmental model. These produced VT estimates of comparable magnitude, namely, pons, thalamus and cerebellum>caudate, putamen and cortical regions. High resolution autoradiography with tritiated RO5013853 was used to confirm the binding pattern observed by PET. In vivo metabolism studies in the baboon demonstrated the formation of a single, radiolabeled metabolite more polar than the parent compound. Finally, [(11)C]RO5013853 was used to quantify the degree of cerebral GlyT1 occupancy observed in the baboon following oral administration of bitopertin, a selective GRI presently in Phase III clinical trial. Plasma concentrations of approximately 150-300 ng/mL were estimated to produce 50% GlyT1 occupancy in the thalamus, the cerebellum and the pons. [(11)C]RO5013853 is a promising radiotracer for in vivo imaging of the GlyT1. It can be easily radiolabeled, exhibits moderate metabolism, displays a good specific signal, and is suitable for receptor occupancy studies of therapeutic compounds that target the GlyT1. The successful characterization of [(11)C]RO5013853 in healthy volunteers is presented in this NeuroImage issue (Wong et al., 2013).
authors.affiliation: Neuroscience Department, Pharmaceutical Division, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland. Electronic address: edilio.borroni@roche.com.
authors.forename: Edilio
authors.initials: E
authors.lastname: Borroni
authors.affiliation: The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21287-0807, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Neuroscience Department, Pharmaceutical Division, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland.
authors.forename: Susanne
authors.initials: S
authors.lastname: Ostrowitzki
authors.affiliation: Neuroscience Department, Pharmaceutical Division, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Alberati
authors.affiliation: The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21287-0807, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Nonclinical Safety Department, Pharmaceutical Division, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland.
authors.forename: Dominik
authors.initials: D
authors.lastname: Hainzl
authors.affiliation: Process Research & Synthesis Department, Pharmaceutical Division, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hartung
authors.affiliation: The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21287-0807, USA.
authors.forename: John
authors.initials: J
authors.lastname: Hilton
authors.affiliation: The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21287-0807, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Dannals
authors.affiliation: The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21287-0807, USA; Department of Psychiatry, The Johns Hopkins University School of Medicine, 601 N. Caroline St., JHOC, Baltimore, MD 21287-0807, USA; Department of Neuroscience, The Johns Hopkins University School of Medicine, 601 N. Caroline St., JHOC, Baltimore, MD 21287-0807, USA; Department of Environmental Health Sciences, The Johns Hopkins University School of Medicine, 601 N. Caroline St., JHOC, Baltimore, MD 21287-0807, USA; Honorary Professor of Neuroscience and Pharmacology, University of Copenhagen, Denmark.
authors.forename: Dean F
authors.initials: DF
authors.lastname: Wong
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D050487:Glycine Plasma Membrane Transport Proteins / Q000378:metabolism*; D008297:Male; D010215:Papio; D010879:Piperazines / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D013450:Sulfones / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: C550631:(4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)(5-methanesulfonyl-2-(2,2,2-trifluoro-1-methylethoxy)phenyl)methanone; D002250:Carbon Radioisotopes; D050487:Glycine Plasma Membrane Transport Proteins; D010879:Piperazines; D019275:Radiopharmaceuticals; D013450:Sulfones