title: Contribution of neuroinflammation to changes in [11C]flumazenil binding in the rat brain: Evaluation of the inflamed pons as reference tissue.
abstract: BACKGROUND
  [11C]Flumazenil is a well-known PET tracer for GABAAreceptors and is mainly used as an imaging biomarker for neuronal loss. Recently, GABAAreceptors on immune cells have been investigated as target for modulation of inflammation. Since neuronal loss is often accompanied by neuroinflammation, PET imaging with [11C]flumazenil is potentially affected by infiltrating immune cells. This may also compromise the validity of using the pons as reference tissue in quantitative pharmacokinetic analysis. This study aims to evaluate whether inflammatory processes in the brain can influence [11C]flumazenil uptake and affect the outcome of pharmacokinetic modeling when the pons is used as reference tissue.
  
  
  METHODS
  The herpes simplex encephalitis (HSE) rat model is known to cause neuroinflammation in the brainstem. Dynamic [11C]flumazenil PET scans of 60-min, accompanied by arterial blood sampling and metabolite analysis, were acquired at day 6-7days post-infection of male Wistar rats (HSE, n=5 and control, n=6). Additionally, the GABAAreceptor was saturated by injection of unlabeled flumazenil prior to the tracer injection in 4 rats per group. PET data were analyzed by pharmacokinetic modeling.
  
  
  RESULTS
  No statistically significant differences were found in the volume of distribution (VT) or non-displaceable binding potential (BPND) between control and HSE rats in any of the brain regions. Pre-saturation with unlabeled flumazenil resulted in a statistically significant reduction in [11C]flumazenil VTin all brain regions. The BPNDobtained from SRTM exhibited a good correlation to DVR - 1 values from the two-tissue compartment model, coupled with some level of underestimation.
  
  
  CONCLUSIONS
  Reliable quantification of [11C]flumazenil binding in rats can be obtained by pharmacokinetic analysis using the pons as a pseudo-reference tissue even in the presence of strong acute neuroinflammation.
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Andrea
authors.initials: A
authors.lastname: Parente
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: David
authors.initials: D
authors.lastname: Vállez García
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Center of Nuclear Medicine, University of Sao Paulo, University of Sao Paulo Medical School, Sao Paulo, Brazil.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Shoji
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Isadora
authors.initials: I
authors.lastname: Lopes Alves
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Bram
authors.initials: B
authors.lastname: Maas
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Rolf
authors.initials: R
authors.lastname: Zijlma
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Rudi Ajo
authors.initials: RA
authors.lastname: Dierckx
authors.affiliation: Center of Nuclear Medicine, University of Sao Paulo, University of Sao Paulo Medical School, Sao Paulo, Brazil.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Buchpiguel
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Erik Fj
authors.initials: EF
authors.lastname: de Vries
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: j.doorduin@umcg.nl.
authors.forename: Janine
authors.initials: J
authors.lastname: Doorduin
mesh_terms: D000818:Animals; D001692:Biological Transport; D002250:Carbon Radioisotopes; D005442:Flumazenil / Q000378:metabolism* / Q000493:pharmacokinetics; D007249:Inflammation / Q000000981:diagnostic imaging / Q000378:metabolism; D008297:Male; D011149:Pons / Q000000981:diagnostic imaging / Q000378:metabolism*; D049268:Positron-Emission Tomography; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; D005442:Flumazenil
keywords: GABA; Herpes simplex encephalitis; Neuroinflammation; PET; Pharmacokinetic modeling; [(11)C]flumazenil