title: Synthesis and evaluation of 18F-FE-PEO in rodents: an 18F-labeled full agonist for opioid receptor imaging.
abstract: We have investigated the opioid receptor (OR) agonist (20R)-4,5-α-epoxy-6-(2-(18)F-fluoroethoxy)-3-hydroxy-α,17-dimethyl-α-(2-phenyleth-1-yl)-6,14-ethenomorphinan-7-methanol ((18)F-FE-PEO) as a candidate OR PET ligand. This tracer is attractive because it combines (18)F labeling, is suited to the slow kinetics of high-affinity ligands, and has agonist binding, which has been shown to be more sensitive to changes in OR occupation than is antagonist binding.
  
  
  METHODS
  Agonist potency and off-target binding were investigated in vitro, and autoradiographic studies on rat brain sections were used to assess binding patterns. Quantification of the tracer in vivo was investigated using small-animal PET in rats with blood sampling.
  
  
  RESULTS
  (18)F-FE-PEO was obtained by direct nucleophilic radiofluorination and subsequent deprotection with a yield of 28% ± 15%, a specific activity of 52-224 MBq/nmol, and a radiochemical purity of more than 97% (90 min from end of bombardment). In vitro studies showed it to be a full agonist ligand, which selectively binds to OR with high affinity, although it is not selective to a single OR subtype (inhibition constant, 0.4-1.6 nM across OR subtypes). Autoradiography binding patterns were consistent with the known distribution of OR, although nondisplaceable signal typically constituted one third of the signal in OR-dense regions. Although metabolites were present in blood (∼40% of plasma radioactivity was nonparent 3 h after injection), no significant metabolite fraction was found in brain tissue, aiding PET quantification. A plasma input 2-tissue-compartment model provided good fits to the PET data, and regional distribution volumes from the latter correlated well with those from Logan plot analysis (r(2) = 0.98). The cerebellum had the lowest distribution volume, but the time-activity curve data could not be adequately fitted with a 1-tissue-compartment model. Reference tissue models using the cerebellum as the reference region did not provide good fits to the data, so blood-based kinetic analysis is recommended.
  
  
  CONCLUSIONS
  As the first (18)F-labeled OR agonist ligand, (18)F-FE-PEO is a useful addition to the existing OR ligand portfolio.
authors.affiliation: Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, United Kingdom. pr340@wbic.cam.ac.uk
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Riss
authors.forename: Young T
authors.initials: YT
authors.lastname: Hong
authors.forename: János
authors.initials: J
authors.lastname: Marton
authors.forename: Daniele
authors.initials: D
authors.lastname: Caprioli
authors.forename: David J
authors.initials: DJ
authors.lastname: Williamson
authors.forename: Valentina
authors.initials: V
authors.lastname: Ferrari
authors.forename: Neil
authors.initials: N
authors.lastname: Saigal
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Gjermund
authors.initials: G
authors.lastname: Henriksen
authors.forename: Tim D
authors.initials: TD
authors.lastname: Fryer
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Dalley
authors.forename: Franklin I
authors.initials: FI
authors.lastname: Aigbirhio
mesh_terms: D000818:Animals; D001331:Automation; D001345:Autoradiography / Q000379:methods; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D005462:Fluorine Radioisotopes / Q000494:pharmacology*; D007700:Kinetics; D008024:Ligands; D008956:Models, Chemical; D009019:Morphinans / Q000737:chemistry / Q000494:pharmacology*; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding; D051381:Rats; D011957:Receptors, Opioid / Q000819:agonists*; D012044:Regression Analysis; D014018:Tissue Distribution
chemical_list: C579337:4,5-alpha-epoxy-6-(2-fluoroethoxy)-3-hydroxy-alpha,17-dimethyl-alpha-(2-phenyleth-1-yl)-6,14-ethenomorphinan-7-methanol; D005462:Fluorine Radioisotopes; D008024:Ligands; D009019:Morphinans; D011957:Receptors, Opioid