title: Investigation of cross-species translatability of pharmacological MRI in awake nonhuman primate - a buprenorphine challenge study.
abstract: BACKGROUND
  Pharmacological MRI (phMRI) is a neuroimaging technique where drug-induced hemodynamic responses can represent a pharmacodynamic biomarker to delineate underlying biological consequences of drug actions. In most preclinical studies, animals are anesthetized during image acquisition to minimize movement. However, it has been demonstrated anesthesia could attenuate basal neuronal activity, which can confound interpretation of drug-induced brain activation patterns. Significant efforts have been made to establish awake imaging in rodents and nonhuman primates (NHP). Whilst various platforms have been developed for imaging awake NHP, comparison and validation of phMRI data as translational biomarkers across species remain to be explored.
  
  
  METHODS
  We have established an awake NHP imaging model that encompasses comprehensive acclimation procedures with a dedicated animal restrainer. Using a cerebral blood volume (CBV)-based phMRI approach, we have determined differential responses of brain activation elicited by the systemic administration of buprenorphine (0.03 mg/kg i.v.), a partial µ-opioid receptor agonist, in the same animal under awake and anesthetized conditions. Additionally, region-of-interest analyses were performed to determine regional drug-induced CBV time-course data and corresponding area-under-curve (AUC) values from brain areas with high density of µ-opioid receptors.
  
  
  RESULTS
  In awake NHPs, group-level analyses revealed buprenorphine significantly activated brain regions including, thalamus, striatum, frontal and cingulate cortices (paired t-test, versus saline vehicle, p<0.05, n = 4). This observation is strikingly consistent with µ-opioid receptor distribution depicted by [6-O-[(11)C]methyl]buprenorphine ([(11)C]BPN) positron emission tomography imaging study in baboons. Furthermore, our findings are consistent with previous buprenorphine phMRI studies in humans and conscious rats which collectively demonstrate the cross-species translatability of awake imaging. Conversely, no significant change in activated brain regions was found in the same animals imaged under the anesthetized condition.
  
  
  CONCLUSIONS
  Our data highlight the utility and importance of awake NHP imaging as a translational imaging biomarker for drug research.
authors.affiliation: Imaging, Merck & Co. Inc., West Point, Pennsylvania, United States of America; Translational Medicine Research Centre, MSD, Singapore, Singapore.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Seah
authors.affiliation: Imaging, Merck & Co. Inc., West Point, Pennsylvania, United States of America; Translational Medicine Research Centre, MSD, Singapore, Singapore.
authors.forename: Abu Bakar Ali
authors.initials: AB
authors.lastname: Asad
authors.affiliation: Biostatistics and Research Decision Sciences, Merck & Co. Inc., Rahway, New Jersey, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Baumgartner
authors.affiliation: Biostatistics and Research Decision Sciences, Merck & Co. Inc., Rahway, New Jersey, United States of America.
authors.forename: Dai
authors.initials: D
authors.lastname: Feng
authors.affiliation: Imaging, Merck & Co. Inc., West Point, Pennsylvania, United States of America.
authors.forename: Donald S
authors.initials: DS
authors.lastname: Williams
authors.affiliation: Imaging, Maccine Pte Ltd, Singapore, Singapore.
authors.forename: Elaine
authors.initials: E
authors.lastname: Manigbas
authors.affiliation: Imaging, Maccine Pte Ltd, Singapore, Singapore.
authors.forename: John D
authors.initials: JD
authors.lastname: Beaver
authors.affiliation: Translational Medicine Research Centre, MSD, Singapore, Singapore.
authors.forename: Torsten
authors.initials: T
authors.lastname: Reese
authors.affiliation: Translational Medicine Research Centre, MSD, Singapore, Singapore.
authors.forename: Brian
authors.initials: B
authors.lastname: Henry
authors.affiliation: Imaging, Merck & Co. Inc., West Point, Pennsylvania, United States of America.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Evelhoch
authors.affiliation: Imaging, Merck & Co. Inc., West Point, Pennsylvania, United States of America; Translational Medicine Research Centre, MSD, Singapore, Singapore.
authors.forename: Chih-Liang
authors.initials: CL
authors.lastname: Chin
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000768:Anesthesia, General; D000818:Animals; D002047:Buprenorphine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects* / Q000502:physiology; D006179:Gyrus Cinguli / Q000187:drug effects* / Q000502:physiology; D008252:Macaca fascicularis / Q000502:physiology; D008279:Magnetic Resonance Imaging / Q000379:methods; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism; D013788:Thalamus / Q000187:drug effects* / Q000502:physiology; D057170:Translational Research, Biomedical; D014851:Wakefulness / Q000502:physiology
chemical_list: D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D002047:Buprenorphine