Pharmacokinetic analysis of [¹¹C]PBR28 in the rat model of herpes encephalitis: comparison with (R)-[¹¹C]PK11195 for pre-clinical imaging

Aim: [¹¹C]PBR28 is a second generation translocator protein (TSPO) ligand with supposedly better imaging characteristics than the most commonly used tracer [¹¹C]PK11195. Surprisingly, only limited studies have evaluated the pharmacokinetic and binding profile of [¹¹C]PBR28 in neuroinflammatory models in rodents. For this reason, [¹¹C]PBR28 was evaluated and compared to [¹¹C]PK11195 for the detection and quantification of neuroinflammation for pre-clinical research.
Materials and methods: Herpes simplex encephalitis (HSE) was induced in male Wistar rats by intranasal inoculation of the herpes simplex type-1 virus, resulting in neuroinflammation. At 6-7 days post inoculation, 60-min dynamic [¹¹C]PBR28 or [¹¹C]PK11195 PET scans were performed. During the scans arterial blood samples were taken to generate blood and metabolite-corrected plasma input curves for pharmacokinetic modeling. Differences between control and HSE rats were assessed by voxel-based analysis, using standardized uptake values, and volume-of-interest analysis, using the reversible two-tissue compartment model to determine the binding potential (BP_ND).
Results: Voxel-based analysis showed that [¹¹C]PBR28 was able to detect over-expression of TSPO in brain areas that are known to be affected in the HSE rat model. [¹¹C]PBR28 had a faster metabolism than [¹¹C]PK11195, with 50% of metabolites in plasma present at 5 min and 21 min, respectively. [¹¹C]PBR28 demonstrated a higher sensitivity than [¹¹C]PK11195 in the detection of neuroinflammation. The BP_ND of [¹¹C]PBR28 was significantly higher (p<0.05) in the medulla (150%), pons (121%), midbrain (94%), thalamus (76%), hippocampus (65%), hypothalamus (44%) and cerebellum (37%) of HSE rats when compared to control rats, while a higher BP_ND of [¹¹C]PK11195 was only found in the medulla (59%). Comparison of BP_ND between control groups showed no statistical difference, suggesting that non-specific binding of both tracers is similar.
Conclusion: [¹¹C]PBR28 performed better than [¹¹C]PK11195 in the detection of TSPO over-expression in the HSE rat model, as the BP_ND was found to be increased in more brain regions. The results of this study suggest that [¹¹C]PBR28 is a better tool for pre-clinical research of neuroinflammation.