Reduced
NMDA receptor functioning is hypothesized to underlie the cognitive and negative symptoms associated with
schizophrenia. However, because direct activation of the
NMDA receptor is accompanied by neurotoxicity, mechanisms that activate the
glycine co-agonist site on the
NMDA receptor could carry greater therapeutic potential. In the current study, the effects of two
glycine transporter 1 (GlyT1) inhibitors,
RG1678 and
ORG25935, were characterized in the object-retrieval detour (ORD) task in
scopolamine-impaired rhesus monkeys and, using positron emission tomography (PET), the GlyT1 occupancy to efficacy relationship of each compound was established.
Scopolamine exerted a significant decrease in accuracy in the ORD task. Lower doses of
RG1678 (0.3 and 1.0 mg/kg, p.o.) significantly attenuated the impact of
scopolamine, whereas the highest dose tested (1.8 mg/kg) did not. The predicted GlyT1 occupancies of
RG1678 at the effective doses were ~10 and 30 %.
ORG25935 (0.1, 0.3, and 1 mg/kg, p.o.) also significantly attenuated the impact of
scopolamine on the ORD task, whereas 3 mg/kg did not. The predicted GlyT1 occupancies of
ORG25935 at the effective doses ranged from 16 to 80 %. These data suggest that GlyT1 inhibitors have the potential to improve performance on prefrontal cortex-dependent tests such as the ORD task, but that efficacy is lost when higher occupancies are achieved. Importantly, recent Ph2B data published by Roche suggests that low but not high doses of
RG1678 improved negative symptoms in patients with
schizophrenia, highlighting the potential translational nature of the current preclinical findings.