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 ∼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 language | English (US) |
|---|---|
| Pages (from-to) | 504-512 |
| Number of pages | 9 |
| Journal | Neuropsychopharmacology |
| Volume | 38 |
| Issue number | 3 |
| DOIs | |
| State | Published - Feb 2013 |
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Keywords
- bitopertin
- glycine reuptake inhibitor
- glycine transporter 1
- N-methyl-D-aspartate
- Receptors
- RG1678
- schizophrenia
ASJC Scopus subject areas
- Pharmacology
- Psychiatry and Mental health
Cite this
Glycine transporter type 1 occupancy by bitopertin : A positron emission tomography study in healthy volunteers. / Martin-Facklam, Meret; Pizzagalli, Flavia; Zhou, Yun; Ostrowitzki, Susanne; Raymont, Vanessa; Brasic, James R; Parkar, Nikhat; Umbricht, Daniel; Dannals, Robert F; Goldwater, Ron; Wong, Dean Foster.
In: Neuropsychopharmacology, Vol. 38, No. 3, 02.2013, p. 504-512.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Glycine transporter type 1 occupancy by bitopertin
T2 - A positron emission tomography study in healthy volunteers
AU - Martin-Facklam, Meret
AU - Pizzagalli, Flavia
AU - Zhou, Yun
AU - Ostrowitzki, Susanne
AU - Raymont, Vanessa
AU - Brasic, James R
AU - Parkar, Nikhat
AU - Umbricht, Daniel
AU - Dannals, Robert F
AU - Goldwater, Ron
AU - Wong, Dean Foster
PY - 2013/2
Y1 - 2013/2
N2 - 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.
AB - 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.
KW - bitopertin
KW - glycine reuptake inhibitor
KW - glycine transporter 1
KW - N-methyl-D-aspartate
KW - Receptors
KW - RG1678
KW - schizophrenia
UR - http://www.scopus.com/inward/record.url?scp=84872495665&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84872495665&partnerID=8YFLogxK
U2 - 10.1038/npp.2012.212
DO - 10.1038/npp.2012.212
M3 - Article
VL - 38
SP - 504
EP - 512
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
SN - 0893-133X
IS - 3
ER -