title: Radiosynthesis and in vivo evaluation of fluorinated huprine derivates as PET radiotracers of acetylcholinesterase.
abstract: BACKGROUND
  Developing positron emission tomography (PET) radiotracers for non-invasive study of the cholinergic system is crucial to the understanding of neurodegenerative diseases. Although several acetylcholinesterase (AChE) PET tracers radiolabeled with carbon-11 exist, no fluorinated radiotracer is currently used in clinical imaging studies. The purpose of the present study is to describe the first fluorinated PET radiotracer for this brain enzyme.
  
  
  METHODS
  Three structural analogs of huprine, a specific AChE inhibitor presenting high affinity towards AChE in vitro, were synthesized and labeled with fluorine-18 via a mesylate/fluoro-nucleophilic aliphatic substitution: ([(18)F]-FHUa, [(18)F]-FHUb and [(18)F]-FHUc). Initial biological evaluation included in vitro autoradiography in rat with competition with an AChE inhibitor at different concentrations, and microPET-scan on anesthetized rats. In vivo PET studies in anesthetized cat focused on [(18)F]-FHUa.
  
  
  CONCLUSIONS
  Although radiosynthesis of these huprine analogs was straightforward, they showed poor brain penetration potential, partially reversed after pharmacological inhibition of P-glycoprotein. These results indicated that current huprine analogs are not suitable for PET mapping of brain AChE receptors, but require physicochemical modulation in order to increase brain penetration.
authors.affiliation: Advanced Accelerator Applications, Saint-Genis-Pouilly, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Da Costa Branquinho
authors.forename: Guillaume
authors.initials: G
authors.lastname: Becker
authors.forename: Cédric
authors.initials: C
authors.lastname: Bouteiller
authors.forename: Ludovic
authors.initials: L
authors.lastname: Jean
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Renard
authors.forename: Luc
authors.initials: L
authors.lastname: Zimmer
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry*; D000818:Animals; D001345:Autoradiography; D002415:Cats; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D019295:Computational Biology; D054879:Halogenation; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D064847:Multimodal Imaging / Q000379:methods*; D011786:Quality Control; D011849:Radioactive Tracers; D011854:Radiochemistry; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000634:Aminoquinolines; D002800:Cholinesterase Inhibitors; D011849:Radioactive Tracers; D000110:Acetylcholinesterase