title: Translational characterization of [11C]GSK931145, a PET ligand for the glycine transporter type 1.
abstract: The current interest in developing Glycine transporter Type 1 (GlyT-1) inhibitors, for diseases such as schizophrenia, has led to the demand for a GlyT-1 PET molecular imaging tool to aid drug development and dose selection. We report on [(11) C]GSK931145 as a novel GlyT-1 imaging probe in primate and man. Primate PET studies were performed to determine the level of specific binding following homologous competition with GSK931145 and the plasma-occupancy relationship of the GlyT-1 inhibitor GSK1018921. Human PET studies were performed to determine the test-retest reproducibility of [(11) C]GSK931145 and the plasma-occupancy relationship of GSK1018921. [(11) C]GSK931145 entered primate and human brain and yielded a heterogeneous pattern of uptake which was similar in both species with highest uptake in midbrain, thalamus, and cerebellum. Homologous competition in primates indicated no viable reference region and gave binding potential estimates between 1.5 and 3 for midbrain, thalamus and cerebellum, While the distribution and binding potential values were similar across species, both the plasma free fraction (f(P) : 0.8 vs. 8%) and delivery (K(1) : 0.025 vs. 0.126 ml cm(-3) min(-1) ) were significantly lower in humans. Test-retest reproducibility in humans calculated using a two tissue compartmental model was poor (VAR(V(T) ): 29-38%), but was improved using a pseudo reference tissue model (VAR(BP(ND) ): 16-23%). GSK1018921 EC(50) estimates were 22.5 and 45.7 ng/ml in primates and humans, respectively.
authors.affiliation: GlaxoSmithKline, Clinical Imaging Center, Hammersmith Hospital, London, United Kingdom. roger.n.gunn@gsk.com
authors.forename: Roger N
authors.initials: RN
authors.lastname: Gunn
authors.forename: Venkatesha
authors.initials: V
authors.lastname: Murthy
authors.forename: Ana M
authors.initials: AM
authors.lastname: Catafau
authors.forename: Graham
authors.initials: G
authors.lastname: Searle
authors.forename: Santiago
authors.initials: S
authors.lastname: Bullich
authors.forename: Mark
authors.initials: M
authors.lastname: Slifstein
authors.forename: Daniele
authors.initials: D
authors.lastname: Ouellet
authors.forename: Stefano
authors.initials: S
authors.lastname: Zamuner
authors.forename: Raul
authors.initials: R
authors.lastname: Herance
authors.forename: Cristian
authors.initials: C
authors.lastname: Salinas
authors.forename: Ricardo
authors.initials: R
authors.lastname: Pardo-Lozano
authors.forename: Eugenii A
authors.initials: EA
authors.lastname: Rabiner
authors.forename: Magi
authors.initials: M
authors.lastname: Farre
authors.forename: Marc
authors.initials: M
authors.lastname: Laruelle
mesh_terms: D000328:Adult; D000818:Animals; D001549:Benzamides / Q000097:blood* / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000097:blood; D005260:Female; D005998:Glycine / Q000378:metabolism*; D050487:Glycine Plasma Membrane Transport Proteins / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008297:Male; D048530:Papio anubis; D049268:Positron-Emission Tomography / Q000379:methods*; D015203:Reproducibility of Results; D055815:Young Adult
chemical_list: D001549:Benzamides; D002250:Carbon Radioisotopes; C561922:GSK 931145; D050487:Glycine Plasma Membrane Transport Proteins; D008024:Ligands; C493268:SLC6A9 protein, human; D005998:Glycine