title: Imaging of α7 nicotinic acetylcholine receptors in brain and cerebral vasculature of juvenile pigs with [(18)F]NS14490.
abstract: BACKGROUND
  The α7 nicotinic acetylcholine receptor (nAChR) is an important molecular target in neuropsychiatry and oncology. Development of applicable highly specific radiotracers has been challenging due to comparably low protein expression. To identify novel ligands as candidates for positron emission tomography (PET), a library of diazabicyclononane compounds was screened regarding affinity and specificity towards α7 nAChRs. From these, [(18)F]NS14490 has been shown to yield reliable results in organ distribution studies; however, the radiosynthesis of [(18)F]NS14490 required optimization and automation to obtain the radiotracer in quantities allowing dynamic PET studies in piglets.
  
  
  METHODS
  Automated radiosynthesis of [(18)F]NS14490 has been performed by [(18)F]fluorination with the tosylate precursor in the TRACERlab™ FX F-N synthesis module (Waukesha, WI, USA). After optimization, the radiochemical yield of [(18)F]NS14490 was consistently approximately 35%, and the total synthesis time was about 90 min. The radiotracer was prepared with >92% radiochemical purity, and the specific activity at the end of the synthesis was 226 ± 68 GBq μmol(-1). PET measurements were performed in young pigs to investigate the metabolic stability and cerebral binding of [(18)F]NS14490 without and with administration of the α7 nAChR partial agonist NS6740 in baseline and blocking conditions.
  
  
  RESULTS
  The total distribution volume relative to the metabolite-corrected arterial input was 3.5 to 4.0 mL g(-1) throughout the telencephalon and was reduced to 2.6 mL g(-1) in animals treated with NS6740. Assuming complete blockade, this displacement indicated a binding potential (BPND) of approximately 0.5 in the brain of living pigs. In addition, evidence for specific binding in major brain arteries has been obtained.
  
  
  CONCLUSIONS
  [(18)F]NS14490 is not only comparable to other preclinically investigated PET radiotracers for imaging of α7 nAChR in brain but also could be a potential PET radiotracer for imaging of α7 nAChR in vulnerable plaques of diseased vessels.
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstr. 15, Leipzig 04318, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Rötering
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstr. 15, Leipzig 04318, Germany.
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.affiliation: Department of Nuclear Medicine, Friedrich-Alexander-Universität, Ulmenweg 18, Erlangen 91054, Germany ; Department of Pharmacology and Neuroscience, Copenhagen University, Blegdamsvej 3B, Copenhagen 2200, Denmark.
authors.forename: Paul
authors.initials: P
authors.lastname: Cumming
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstr. 15, Leipzig 04318, Germany.
authors.forename: Cornelius K
authors.initials: CK
authors.lastname: Donat
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstr. 15, Leipzig 04318, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Scheunemann
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstr. 15, Leipzig 04318, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Fischer
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-Universität, Marchioninistr. 15, Munich 83177, Germany.
authors.forename: Guoming
authors.initials: G
authors.lastname: Xiong
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstr. 15, Leipzig 04318, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.affiliation: DanPET AB, Rosenstigen 7, Malmö SE-21619, Sweden.
authors.forename: Dan
authors.initials: D
authors.lastname: Peters
authors.affiliation: Department of Nuclear Medicine, Universität Leipzig, Liebigstr. 18, Leipzig 04103, Germany.
authors.forename: Osama
authors.initials: O
authors.lastname: Sabri
authors.affiliation: Department of Nuclear Medicine, Maastricht University Medical Center, P. Debeylaan 25, Maastricht 6229, The Netherlands ; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, P. Debeylaan 25, Maastricht 6229, The Netherlands ; Department of Nuclear Medicine, University Hospital RWTH Aachen, Pauwelstr. 30, Aachen 52074, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Bucerius
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstr. 15, Leipzig 04318, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
keywords: Alpha7 nicotinic acetylcholine receptors; Alzheimer's disease; Blood-brain barrier; Cancer; Diazabicyclononane; Metabolism; PET; Stroke