Glycine transporter type 1 occupancy by bitopertin: A positron emission tomography study in healthy volunteers

Meret Martin-Facklam*, Flavia Pizzagalli, Yun Zhou, Susanne Ostrowitzki, Vanessa Raymont, James R. Brašić, Nikhat Parkar, Daniel Umbricht, Robert F. Dannals, Ron Goldwater, Dean F. Wong

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Deficient N-methyl-D-aspartate (NMDA) receptor transmission is thought to underlie schizophrenia. An approach for normalizing glutamate neurotransmission by enhancing NMDA receptor transmission is to increase glycine availability by inhibiting the glycine transporter type 1 (GlyT1). This study investigated the relationship between the plasma concentration of the glycine reuptake inhibitor bitopertin (RG1678) and brain GlyT1 occupancy. Healthy male volunteers received up to 175 mg bitopertin once daily, for 10-12 days. Three positron emission tomography scans, preceded by a single intravenous infusion of ∼30 mCi [ 11 C]RO5013853, were performed: at baseline, on the last day of bitopertin treatment, and 2 days after drug discontinuation. Eighteen subjects were enrolled. At baseline, regional volume of distribution (V T) values were highest in the pons, thalamus, and cerebellum (1.7-2.7 ml/cm 3) and lowest in cortical areas (∼0.8 ml/cm 3). V T values were reduced to a homogeneous level following administration of 175 mg bitopertin. Occupancy values derived by a two-tissue five-parameter (2T5P) model, a simplified reference tissue model (SRTM), and a pseudoreference tissue model (PRTM) were overall comparable. At steady state, the relationship between bitopertin plasma concentration and GlyT1 occupancy derived by the 2T5P model, SRTM, and PRTM exhibited an EC 50 of ∼190, ∼200, and ∼130 ng/ml, respectively. E max was ∼92% independently of the model used. Bitopertin plasma concentration was a reliable predictor of occupancy because the concentration-occupancy relationship was superimposable at steady state and 2 days after drug discontinuation. These data allow understanding of the concentration-occupancy-efficacy relationship of bitopertin and support dose selection of future molecules.

Original languageEnglish
Pages (from-to)504-512
Number of pages9
Issue number3
Publication statusPublished - Feb 2013


  • bitopertin
  • glycine reuptake inhibitor
  • glycine transporter 1
  • N-methyl-D-aspartate
  • Receptors
  • RG1678
  • schizophrenia


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