title: Development and automation of a novel NET-PET tracer: [11C]Me@APPI.
abstract: BACKGROUND
  The norepinephrine transporter (NET) is an important target for research in neurology and psychology and is involved in the pathophysiology of many neurodegenerative diseases such as Alzheimer's disease and attention deficient hyperactivity disorder. For visualization of NET abundance and deregulation, a novel PET tracer--[(11)C]Me@APPI--has been developed.
  
  
  METHODS
  For precursor synthesis, a 4-step synthesis starting from N-phenyl-o-phenylenediamine was set up. Radiosynthesis was established and optimized using standard methods and subsequently automated in a GE TRACERlabFx C Pro synthesizer. Preclinical testing was performed comprising affinity and selectivity testing on human membranes as well as stability and blood-brain-barrier-penetration using in-vitro models.
  
  
  RESULTS
  Precursor molecule (APPI:0) and reference compound (Me@APPI) were synthesized with 26.5% and 21.4% overall yield, respectively. So far, 1.25±0.72 GBq [(11)C]Me@APPI with 54.35±7.80 GBq/μmol specific activity were produced (n=11). Affinity of reference compounds was determined as 8.08±1.75 nM for Me@APPI and 19.31±2.91 nM for APPI:0, respectively (n≥9). IAM-chromatography experiments (n=3) revealed a P(m) value of 1.51±0.34 for Me@APPI. Stability testing using human liver microsomes revealed that 99.5% of the tracer was found to be still intact after 60 minutes (n=4).
  
  
  CONCLUSIONS
  Present data indicate that [(11)C]Me@APPI has promising properties to become a clinically useful NET-PET-tracer. Further in-vitro and in-vivo evaluations are currently under way.
authors.affiliation: Radiochemistry and Biomarker Development Unit, Department of Nuclear Medicine, Medical University of Vienna, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Mark
authors.forename: Birgit
authors.initials: B
authors.lastname: Bornatowicz
authors.forename: Markus
authors.initials: M
authors.lastname: Mitterhauser
authors.forename: Matthias
authors.initials: M
authors.lastname: Hendl
authors.forename: Lukas
authors.initials: L
authors.lastname: Nics
authors.forename: Daniela
authors.initials: D
authors.lastname: Haeusler
authors.forename: Rupert
authors.initials: R
authors.lastname: Lanzenberger
authors.forename: Michael L
authors.initials: ML
authors.lastname: Berger
authors.forename: Helmut
authors.initials: H
authors.lastname: Spreitzer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wadsak
mesh_terms: D001331:Automation; D001562:Benzimidazoles / Q000737:chemistry* / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D002250:Carbon Radioisotopes; D004355:Drug Stability; D006801:Humans; D007553:Isotope Labeling; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D011786:Quality Control; D011854:Radiochemistry
chemical_list: C582421:1-(3-(methylamino)-1-phenylpropyl)-3-phenyl-1H-benzo(d)imidazol-2(3H)-one; D001562:Benzimidazoles; D002250:Carbon Radioisotopes; D050484:Norepinephrine Plasma Membrane Transport Proteins; C031000:benzimidazole