title: Evaluation of [(11)C]CB184 for imaging and quantification of TSPO overexpression in a rat model of herpes encephalitis.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  [(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.
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB, Groningen, The Netherlands, d.vallez-garcia@umcg.nl.
authors.forename: David
authors.initials: D
authors.lastname: Vállez Garcia
authors.forename: Erik F J
authors.initials: EF
authors.lastname: de Vries
authors.forename: Jun
authors.initials: J
authors.lastname: Toyohara
authors.forename: Kiichi
authors.initials: K
authors.lastname: Ishiwata
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hatano
authors.forename: Rudi A J O
authors.initials: RA
authors.lastname: Dierckx
authors.forename: Janine
authors.initials: J
authors.lastname: Doorduin
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020803:Encephalitis, Herpes Simplex / Q000000981:diagnostic imaging* / Q000235:genetics; D007093:Imidazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D008297:Male; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: C000604727:CB184 compound; D002352:Carrier Proteins; D007093:Imidazoles; D011725:Pyridines; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A; C069997:Tspo protein, rat