Evaluation of [(11)C]CB184 for imaging and quantification of TSPO overexpression in a rat model of herpes encephalitis

Eur J Nucl Med Mol Imaging. 2015 Jun;42(7):1106-18. doi: 10.1007/s00259-015-3021-x. Epub 2015 Mar 13.

Abstract

Purpose: Evaluation of translocator protein (TSPO) overexpression is considered an attractive research tool for monitoring neuroinflammation in several neurological and psychiatric disorders. [(11)C]PK11195 PET imaging has been widely used for this purpose. However, it has a low sensitivity and a poor signal-to-noise ratio. For these reasons, [(11)C]CB184 was evaluated as a potentially more sensitive PET tracer.

Methods: A model of herpes simplex encephalitis (HSE) was induced in male Wistar rats. On day 6 or 7 after virus inoculation, [(11)C]CB184 PET scans were acquired followed by ex vivo evaluation of biodistribution. In addition, [(11)C]CB184 and [(11)C]PK11195 PET scans with arterial blood sampling were acquired to generate input for pharmacokinetic modelling. Differences between the saline-treated control group and the virus-treated HSE group were explored using volumes of interest and voxel-based analysis.

Results: The biodistribution study showed significantly higher [(11)C]CB184 uptake in the amygdala, olfactory bulb, medulla, pons and striatum (p < 0.05) in HSE rats than in control rats, and the voxel-based analysis showed higher bilateral uptake in the pons and medulla (p < 0.05, corrected at the cluster level). A high correlation was found between tracer uptake in the biodistribution study and on the PET scans (p < 0.001, r (2) = 0.71). Pretreatment with 5 mg/kg of unlabelled PK11195 effectively reduced (p < 0.001) [(11)C]CB184 uptake in the whole brain. Both, [(11)C]CB184 and [(11)C]PK11195, showed similar amounts of metabolites in plasma, and the binding potential (BPND) was not significantly different between the HSE rats and the control rats. In HSE rats BPND for [(11)C]CB184 was significantly higher (p < 0.05) in the amygdala, hypothalamus, medulla, pons and septum than in control rats, whereas higher uptake of [(11)C]PK11195 was only detected in the medulla.

Conclusion: [(11)C]CB184 showed nonspecific binding to healthy tissue comparable to that observed for [(11)C]PK11195, but it displayed significantly higher specific binding in those brain regions affected by the HSE. Our results suggest that [(11)C]CB184 PET is a good alternative for imaging of neuroinflammatory processes.

Publication types

  • Evaluation Study

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Encephalitis, Herpes Simplex / diagnostic imaging*
  • Encephalitis, Herpes Simplex / genetics
  • Imidazoles / chemical synthesis
  • Imidazoles / pharmacokinetics*
  • Male
  • Positron-Emission Tomography*
  • Pyridines / chemical synthesis
  • Pyridines / pharmacokinetics*
  • Radiopharmaceuticals / chemical synthesis
  • Radiopharmaceuticals / pharmacokinetics*
  • Rats
  • Rats, Wistar
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism*
  • Tissue Distribution

Substances

  • CB184 compound
  • Carrier Proteins
  • Imidazoles
  • Pyridines
  • Radiopharmaceuticals
  • Receptors, GABA-A
  • Tspo protein, rat