Glycine transporter type 1 occupancy by bitopertin: a positron emission tomography study in healthy volunteers.
Neuropsychopharmacology
; 38(3): 504-12, 2013 Feb.
Article
en En
| MEDLINE
| ID: mdl-23132267
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 â¼30 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 (â¼0.8 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 â¼190, â¼200, and â¼130 ng/ml, respectively. E(max) was â¼92% 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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Piperazinas
/
Sulfonas
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Encéfalo
/
Estado de Salud
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Tomografía de Emisión de Positrones
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Proteínas de Transporte de Glicina en la Membrana Plasmática
Tipo de estudio:
Prognostic_studies
Aspecto:
Determinantes_sociais_saude
/
Patient_preference
Límite:
Adult
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Neuropsychopharmacology
Asunto de la revista:
NEUROLOGIA
/
PSICOFARMACOLOGIA
Año:
2013
Tipo del documento:
Article
País de afiliación:
Suiza