title: Awake nonhuman primate brain PET imaging with minimal head restraint: evaluation of GABAA-benzodiazepine binding with 11C-flumazenil in awake and anesthetized animals.
abstract: Neuroreceptor imaging in the nonhuman primate (NHP) is valuable for translational research approaches in humans. However, most NHP studies are conducted under anesthesia, which affects the interpretability of receptor binding measures. The aims of this study were to develop awake NHP imaging with minimal head restraint and to compare in vivo binding of the γ-aminobutyric acid type A (GABAA)-benzodiazepine radiotracer (11)C-flumazenil under anesthetized and awake conditions. We hypothesized that (11)C-flumazenil binding potential (BPND) would be higher in isoflurane-anesthetized monkeys.
  
  
  METHODS
  The small animal PET scanner was fitted to a mechanical device that raised and tilted the scanner 45° while the awake NHP was tilted back 35° in a custom chair for optimal brain positioning, which required acclimation of the animals to the chair, touch-screen tasks, intravenous catheter insertion, and tilting. For PET studies, the bolus-plus-constant infusion method was used for (11)C-flumazenil administration. Two rhesus monkeys were scanned under the awake (n = 6 scans) and isoflurane-anesthetized (n = 4 scans) conditions. An infrared camera was used to track head motion during PET scans. Under the awake condition, emission and head motion-tracking data were acquired for 40-75 min after injection. Anesthetized monkeys were scanned for 90 min. Cortisol measurements were acquired during awake and anesthetized scans. Equilibrium analysis was used for both the anesthetized (n = 4) and the awake (n = 5) datasets to compute mean BPND images in NHP template space, using the pons as a reference region. The percentage change per minute in radioactivity concentration was calculated in high- and low-binding regions to assess the quality of equilibrium.
  
  
  RESULTS
  The monkeys acclimated to procedures in the NHP chair necessary to perform awake PET imaging. Image quality was comparable between awake and anesthetized conditions. The relationship between awake and anesthetized values was BPND (awake) = 0.94 BPND (anesthetized) + 0.36 (r(2) = 0.95). Cortisol levels were significantly higher under the awake condition (P < 0.05).
  
  
  CONCLUSIONS
  We successfully performed awake NHP imaging with minimal head restraint. There was close agreement in (11)C-flumazenil BPND values between awake and anesthetized conditions.
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, Connecticut.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Sandiego
authors.forename: Xiao
authors.initials: X
authors.lastname: Jin
authors.forename: Tim
authors.initials: T
authors.lastname: Mulnix
authors.forename: Krista
authors.initials: K
authors.lastname: Fowles
authors.forename: David
authors.initials: D
authors.lastname: Labaree
authors.forename: Jim
authors.initials: J
authors.lastname: Ropchan
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.forename: Kelly
authors.initials: K
authors.lastname: Cosgrove
authors.forename: Stacy A
authors.initials: SA
authors.lastname: Castner
authors.forename: Graham V
authors.initials: GV
authors.lastname: Williams
authors.forename: Lisa
authors.initials: L
authors.lastname: Wells
authors.forename: Eugenii A
authors.initials: EA
authors.lastname: Rabiner
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
mesh_terms: D000758:Anesthesia; D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D002250:Carbon Radioisotopes; D005260:Female; D005442:Flumazenil / Q000378:metabolism*; D006257:Head; D008253:Macaca mulatta; D008297:Male; D049268:Positron-Emission Tomography / Q000295:instrumentation / Q000379:methods*; D012149:Restraint, Physical; D014851:Wakefulness; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D002250:Carbon Radioisotopes; D001569:Benzodiazepines; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid
keywords: GABA shift; PET; conscious; cortisol; flumazenil; isoflurane; monkey