We characterize a novel radioligand for the glycine transporter type 1 (GlyT1), [11 C]RO5013853, in humans. Ten healthy male volunteers, 23–60 years of age, were enrolled in this PET study; seven subjects participated in the evaluation of test-retest reliability and three subjects in whole body dosimetry. Subjects were administered intravenous bolus injections of approximately 1100 MBq (30 mCi) [11 C]RO5013853 with a high specific activity of about 481 GBq (13 Ci)/μmol. Standard compartmental model analysis with arterial plasma input function, and an alternative noninvasive analysis method which was evaluated and validated by occupancy studies in both baboons and humans, were performed. Mean parameter estimates of the volumes of distribution (VT) obtained by a 2-tissue 5-parameter model were higher in the cerebellum, pons, and thalamus (1.99 to 2.59 mL/mL), and lower in the putamen, caudate, and cortical areas (0.86 to 1.13 mL/mL), with estimates showing less than 10% difference between test and retest scans. Tracer retention was effectively blocked by the specific glycine reuptake inhibitor (GRI), bitopertin (RG1678). [11 C]RO5013853 was safe and well tolerated. Human dosimetry studies showed that the effective dose was approximately 0.0033 mSv/MBq, with the liver receiving the highest absorbed dose.
In conclusion, quantitative dynamic PET of the human brain after intravenous injection of [11C]RO5013853 attains reliable measurements of GlyT1 binding in accordance with the expected transporter distribution in the human brain. [11C]RO5013853 is a radioligand suitable for further clinical PET studies. Full characterization of a novel radiotracer for GlyT1 in humans is provided. The tracer has subsequently been used to assess receptor occupancy in healthy volunteers and to estimate occupancy at doses associated with best efficacy in a clinical trial with schizophrenic patients with predominantly negative symptoms.