Imaging Type I Glycine Transporters in the CNS using Positron Emission Tomography

1. Type 1 glycine transporters in the human brain remain an attractive and relevant target for PET imaging. Schizophrenia is a severe mental disorder with a significant impact on life expectancy and a relatively high incidence (0.03– 0.07 % of global population). Partial inhibition of GlyT1 activity is proposed to improve cognitive impairment in schizophrenics. 2. In order to accurately understand the clinical relationship between the dose of a GlyT1 inhibitor and its effectiveness in cognitive models, an appropriate radioligand for use in PET or SPECT studies has to be available. There is thus an ongoing need for access to imaging tools which can be used in drug development and research focused on greater understanding of mechanisms underlying human disease. 3. Out of many currently reported radiopharmaceuticals for GlyT1, [ 11C] Ro5013853 appears to be the best suitable for determination of transporter occupancy by nonradioactive drugs. 4. Data from a range of tracers indicate that GlyT1 is expressed throughout the brain with no available reference region, resulting in high tracer binding in cerebellum, pons, thalamus and white matter of the frontal cortex, with lower tracer binding in putamen, caudate and cortical grey matter. 5. Many tracer candidates have not yet been fully characterised. For [ 18 F] MK6577, [ 11 C]-N-methyl-SSR5-4734 and [ 11 C]SA1, human data are missing. The specificity of [ 11 C]Ro5013853 for GlyT1 vs GlyT2 has not yet been examined. Further radiopharmaceutical development is necessary to improve on the existing choice