title: Evaluation of the sensitivity of the novel α4β2* nicotinic acetylcholine receptor PET radioligand 18F-(-)-NCFHEB to increases in synaptic acetylcholine levels in rhesus monkeys.
abstract: OBJECTIVE
  18F-(-)-NCFHEB (also known as 18F-(-)-Flubatine) is a new radioligand to image α4β2* nicotinic acetylcholine receptors in vivo with positron emission tomography (PET), with faster kinetics than previous radioligands such as 18F-2-F-A85380. The goal of this study was to assess the sensitivity of 18F-(-)-NCFHEB-PET to increases in synaptic acetylcholine concentration induced by acetylcholinesterase inhibitors.
  
  
  METHODS
  Two rhesus monkeys were scanned four times each on a Focus 220 scanner: first at baseline, then during two bolus plus infusions of physostigmine (0.06-0.28 mg/kg), and finally following a bolus injection of donepezil (0.25 mg/kg). The arterial input function and the plasma free fraction fP were measured. 18F-(-)-NCFHEB volume of distribution VT was estimated using the multilinear analysis MA1 and then normalized by plasma free fraction fP .
  
  
  RESULTS
  18F-(-)-NCFHEB fP was 0.89±0.04. At baseline, 18F-(-)-NCFHEB VT /fP ranged from 7.9±1.3 mL plasma/cm3 tissue in the cerebellum to 34.3±8.4 mL plasma/cm3 tissue in the thalamus. Physostigmine induced a dose-dependent reduction of 18F-(-)-NCFHEB VT /fP of 34±9% in the putamen, 32±8% in the thalamus, 25±8% in the cortex, and 23±10% in the hippocampus. With donepezil, 18F-(-)-NCFHEB VT /fP was reduced by 24±2%, 14+3% and 14±5%, 10±6% in the same regions.
  
  
  CONCLUSIONS
  18F-(-)-NCFHEB can be used to detect changes in synaptic acetylcholine concentration and is a promising tracer to study acetylcholine dynamics with shorter scan durations than previous radioligands.
authors.affiliation: Department of Diagnostic Radiology, Yale University, New Haven, Connecticut.
authors.forename: Jean-Dominique
authors.initials: JD
authors.lastname: Gallezot
authors.forename: Irina
authors.initials: I
authors.lastname: Esterlis
authors.forename: Frederic
authors.initials: F
authors.lastname: Bois
authors.forename: Ming-Qiang
authors.initials: MQ
authors.lastname: Zheng
authors.forename: Shu-Fei
authors.initials: SF
authors.lastname: Lin
authors.forename: Tracy
authors.initials: T
authors.lastname: Kloczynski
authors.forename: John H
authors.initials: JH
authors.lastname: Krystal
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.forename: Osama
authors.initials: O
authors.lastname: Sabri
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
authors.forename: Kelly P
authors.initials: KP
authors.lastname: Cosgrove
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics*; D008253:Macaca mulatta; D008297:Male; D049268:Positron-Emission Tomography; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012680:Sensitivity and Specificity; D013569:Synapses / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic; C115362:fluoronorchloroepibatidine; C403531:nicotinic receptor alpha4beta2; D000109:Acetylcholine
keywords: 18F-(-)-Flubatine; 18F-(-)-NCFHEB; acetylcholine; brain; donepezil; nicotinic acetylcholine receptors; physostigmine; rhesus monkeys