Relationship between glycine transporter 1 inhibition as measured with positron emission tomography and changes in cognitive performances in nonhuman primates

Abstract

Several lines of evidence suggest that schizophrenia is associated with deficits in glutamatergic transmission at the N-methyl-d-aspartate (NMDA) receptors. Glycine is a NMDA receptor co-agonist, and extracellular levels of glycine are regulated in the forebrain by the glycine type-1 transporters (GlyT-1). GlyT-1 inhibitors elevate extracellular glycine and thus potentiate NMDA transmission. This mechanism represents a promising new avenue for the treatment of schizophrenia. Here, the recently introduced positron emission tomography radiotracer [11C]GSK931145 was used to quantify the relationship between occupancy of GlyT-1 by a GlyT-1 inhibitor, Org 25935, and its impact on spatial working memory performances in rhesus monkeys. The effect of Org 25935 on working memory was assessed both in control conditions and during a state of relative NMDA hypofunction induced by ketamine administration, at a dose selected for each animal to reduce task performance by about 50%. Under control conditions, Org 25935 had no effect on working memory at GlyT-1 occupancies lower than 75% and significantly impaired working memory at occupancies higher than 75%. Under ketamine conditions, Org 25935 reversed the deficit in working memory induced by ketamine and did so optimally in the 40-70% GlyT-1 occupancy range. The results confirm the efficacy of this mechanism to correct working memory deficits associated with NMDA hypofunction. These data also suggest the existence of an inverted-U dose-response curve in the potential therapeutic effect of this class of compounds.

Figure 1

(a) MR slices from rhesus monkey in transverse, sagittal, and coronal orientations. (b) Registered PET images in the control study following bolus injection of [11C]GSK931145. (c) Matching images following administration of 0.5 mg/kg Org 25935. PET images are on a common SUV scale (corrected for injection dose and body weight). Blockade of specific binding is visible by increased uniformity in the blocking scans. The activity concentration at the level of the midbrain (arrows) is not detected after Org 25935 administration.

Figure 2

Example of time-activity curves and fits to the 2T model from two regions from the study shown above (ie, in image figure). Circles are brainstem and triangles are occipital cortex values. Filled symbols are from the baseline scan and open symbols are from the scan performed following blockade with Org 25935.

Figure 3

Effects of the GlyT1 inhibitor under control conditions. (a) Effect on cognitive performance of the four doses tested in comparison with vehicle. The highest dose of 1.0 mg/kg impaired working memory as compared with the vehicle/placebo (* indicates significant difference from vehicle/placebo P=0.001 by Scheffe post-hoc comparison). (b) The mean number of errors at short and long delays (N=0–1 and N=3–4) for spatial delayed response performance for the single ascending dose study of Org 25935.

Figure 4

Relationship between working memory performance and plasma exposure to Org 25935 under controlled condition. A linear negative correlation was found between performance and plasma Org 25935 concentration.

Figure 5

Effects of the GlyT1 inhibitor under ketamine conditions: (a) Ketamine profoundly impaired spatial working memory and pretreatment with Org 25935 (0.5 and 1.0 mg/kg) provided significant protection against this deficit (* indicates significant difference between vehicle and ketamine: 0.5 mg/kg: P=0.008 and 1.0 mg/kg: P 0.050 by Scheffe post-hoc comparison, respectively). (b) Mean number of errors at short and long delays (N=1–10 s dependent upon task difficulty) for spatial delayed response performance for the ketamine challenge study with Org 25935.

Figure 6

Relationship between working memory performance and plasma exposure to Org 25935 under controlled condition. A quadratic model provided a better fit than a linear model for the relationship between cognitive performance and plasma Org 25935 concentration under ketamine conditions.