title: Pharmacokinetic modeling of [11C]flumazenil kinetics in the rat brain.
abstract: BACKGROUND
  Preferred models for the pharmacokinetic analysis of [11C]flumazenil human studies have been previously established. However, direct translation of these models and settings to animal studies might be sub-optimal. Therefore, this study evaluates pharmacokinetic models for the quantification of [11C]flumazenil binding in the rat brain. Dynamic (60 min) [11C]flumazenil brain PET scans were performed in two groups of male Wistar rats (tracer dose (TD), n = 10 and pre-saturated (PS), n = 2). Time-activity curves from five regions were analyzed, including the pons (pseudo-reference region). Distribution volume (VT) was calculated using one- and two-tissue compartment models (1TCM and 2TCM) and spectral analysis (SA). Binding potential (BPND) was determined from full and simplified reference tissue models with one or two compartments for the reference tissue (FRTM, SRTM, and SRTM-2C). Model preference was determined by Akaike information criterion (AIC), while parameter agreement was assessed by linear regression, repeated measurements ANOVA and Bland-Altman plots.
  
  
  RESULTS
  1TCM and 2TCM fits of regions with high specific binding showed similar AIC, a preference for the 1TCM, and good VTagreement (0.1% difference). In contrast, the 2TCM was markedly preferred and necessary for fitting low specific-binding regions, where a worse VTagreement (17.6% difference) and significant VTdifferences between the models (p < 0.005) were seen. The PS group displayed results similar to those of low specific-binding regions. All reference models (FRTM, SRTM, and SRTM-2C) resulted in at least 13% underestimation of BPND.
  
  
  CONCLUSIONS
  Although the 1TCM was sufficient for the quantification of high specific-binding regions, the 2TCM was found to be the most adequate for the quantification of [11C]flumazenil in the rat brain based on (1) higher fit quality, (2) lower AIC values, and (3) ability to provide reliable fits for all regions. Reference models resulted in negatively biased BPNDand were affected by specific binding in the pons of the rat.
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Isadora
authors.initials: I
authors.lastname: Lopes Alves
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: David
authors.initials: D
authors.lastname: Vállez García
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Andrea
authors.initials: A
authors.lastname: Parente
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Janine
authors.initials: J
authors.lastname: Doorduin
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Rudi
authors.initials: R
authors.lastname: Dierckx
authors.affiliation: Laboratory of Medical Imaging, School of Physics, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Marques da Silva
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, KU Leuven, Leuven, Belgium.
authors.forename: Michel
authors.initials: M
authors.lastname: Koole
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Antoon
authors.initials: A
authors.lastname: Willemsen
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. r.boellaard@umcg.nl.
authors.forename: Ronald
authors.initials: R
authors.lastname: Boellaard
keywords: GABAA receptors; PET; Pharmacokinetic modeling; Rat; [11C]Flumazenil