Glycine Transporter Type 1 Occupancy by Bitopertin: a Positron Emission Tomography Study in Healthy Volunteers

Abstract

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 B30 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 (B0.8 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 B190, B200, and B130 ng/ml, respectively. E max was B92% independently of the model used. Bitopertin plasma concentration was a reliable predictor of occupancy because the concentrationoccupancy 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.

Comparative Pro-cognitive and Neurochemical Profiles of Glycine Modulatory Site Agonists and Glycine Reuptake Inhibitors in the Rat: Potential Relevance to Cognitive Dysfunction and Its Management

“…The only other change was a modest increase in dopamine by sarcosine (Table 1). These observations are important since, to our knowledge, this is the first comprehensive neurochemical characterisation of sarcosine, despite its extensive use as a specific "GlyT1 inhibitor" and an adjunctive agent in schizophrenia patients [12,73,74]. Lack of change in 5-HT is important given concerns about a potential interaction with serotonergic transmission at a clinical dose of 2 g [75] and a transient elevation of rat PFC 5-HT with an extremely high dose (2 g/kg p.o.)…”

Imaging glutamate in schizophrenia: review of findings and implications for drug discovery

“…Although no MRS, PET or SPECT studies of the glycine transporter have been performed in SCZ, several PET tracers that target the glycine transporter type 1 (GlyT-1), such as [ 11 C]GSK931145 (see refs. 105 and 106) and [ 11 C]RO5013853, 107,108 have been developed. These have proven useful for quantifying occupancy of GlyT-1 by other, unlabeled compounds, but it is not yet clear whether they are suitably sensitive enough for examining GlyT-1 availability in psychiatric populations including SCZ.…”

Glycine Reuptake Inhibitors in the Treatment of Negative Symptoms of Schizophrenia

“…In preclinical studies, bitopertin has proven to be effective in rat models to reverse PCP-induced positive and negative symptoms of the SZ phenotype and it has good bioavailability in the brain with oral dosing in positive emission tomography (PET) studies in baboons 28 . Human PET studies with bitopertin have demonstrated an inverted U pharmacokinetic therapeutic window, and have provided evidence for ideal dosing of bitopertin to be 10mg orally and daily, with less pronounced but effective results at 30mg daily 29 .…”