Specific and non-specific binding of a tracer for the translocator-specific protein in schizophrenia: an [11C]-PBR28 blocking study

Objective The mitochondrial 18-kDa translocator protein (TSPO) is expressed by activated microglia and positron emission tomography enables the measurement of TSPO levels in the brain. Findings in schizophrenia have shown to vary depending on the outcome measure used and this discrepancy in TSPO results could be explained by lower non-displaceable binding (V-ND) in schizophrenia, which could obscure increases in specific binding. In this study, we have used the TSPO ligand XBD173 to block the TSPO radioligand [C-11]-PBR28 and used an occupancy plot to quantify V-ND in patients with schizophrenia. Methods A total of 7 patients with a diagnosis of schizophrenia were recruited for this study. Each patient received two separate PET scans with [C-11]PBR28, one at baseline and one after the administration of the TSPO ligand XBD173. All patients were high-affinity binders (HABs) for the TSPO gene. We used an occupancy plot to quantify the non-displaceable component (V-ND) using 2TCM kinetic estimates with and without vascular correction. Finally we computed the V-ND at a single subject level using the SIME method. Results All patients showed a global and generalized reduction in [C-11]PBR28 uptake after the administration of XBD173. Constraining the V-ND to be equal for all patients, the population V-ND was estimated to be 1.99 mL/cm(3) (95% CI 1.90 to 2.08). When we used vascular correction, the fractional TSPO occupancy remained similar. Conclusions In schizophrenia patients, a substantial component of the [C-11]PBR28 signal represents specific binding to TSPO. Furthermore, the V-ND in patients with schizophrenia is similar to that previously reported in healthy controls. These results suggest that changes in non-specific binding between schizophrenia patients and healthy controls do not account for discrepant PET findings in this disorder.

Automated summary

In patients with schizophrenia, a substantial proportion of the [C-11]PBR28 signal represents specific binding to TSPO. After the administration of the TSPO ligand XBD173, there was a global reduction in [C-11]PBR28 uptake in all patients. The V-ND in schizophrenia patients was found to be similar to that in healthy controls, indicating that differences in non-specific binding do not explain discrepant PET findings in this disorder.