title: Synthesis, radiosynthesis and first in vitro evaluation of novel PET-tracers for the dopamine transporter: [(11)C]IPCIT and [(18)F]FE@IPCIT.
abstract: BACKGROUND
  Present data indicate that merging beneficial structural elements from previously published DAT-ligands highest DAT affinity, selectivity and a suitable metabolic profile should be achieved. This combination led to the development of IPCIT and FE@IPCIT.
  
  
  METHODS
  Precursor synthesis was done starting from cocaine in a six step reaction. O-[(11)C]-methylation was established using [(11)C]methyl iodide, optimized and subsequently automated. Small scale (18)F-fluroroethylation as well as optimization of reaction parameters and automation were performed. Affinity and selectivity of the candidate substances were tested in standard binding experiments on human membranes. Metabolic stability and blood-brain-barrier (BBB) penetration were determined.
  
  
  RESULTS
  Precursor compound, IPCITacid, and reference compounds, IPCIT and FE@IPCIT, were obtained in 4.9%, 12.7% and 4.1% yield, respectively. Automated radiosynthesis of [(11)C]IPCIT yielded 1.9 ± 0.7 GBq (12.5 ± 4%, corrected for decay). Optimum parameters for (18)F-fluoroethylation were 110 °C for 15 min under TBAH catalysis, yielding 67 ± 16 % radiochemical incorporation. Affinity was determined as 1.7 ± 0.6 nM for IPCIT, 1.3 ± 0.2 nM for FE@IPCIT and 37 ± 13 nM for the precursor molecule, IPCIT-acid. Results from in vitro and in silico evaluations revealed high stability but also high lipophilicity.
  
  
  CONCLUSIONS
  Present data indicate high affinity and stability of both IPCIT and FE@IPCIT. Radiolabelling, optimization of reaction parameters and automation succeeded. On the other hand, data concerning BBB-penetration are not promising.
authors.affiliation: Division of Nuclear Medicine, Radiochemistry and Biomarker Development Unit, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria; Department of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Rami-Mark
authors.forename: Birgit
authors.initials: B
authors.lastname: Bornatowicz
authors.forename: Cornel
authors.initials: C
authors.lastname: Fink
authors.forename: Paul
authors.initials: P
authors.lastname: Otter
authors.forename: Johanna
authors.initials: J
authors.lastname: Ungersboeck
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Vraka
authors.forename: Daniela
authors.initials: D
authors.lastname: Haeusler
authors.forename: Lukas
authors.initials: L
authors.lastname: Nics
authors.forename: Helmut
authors.initials: H
authors.lastname: Spreitzer
authors.forename: Marcus
authors.initials: M
authors.lastname: Hacker
authors.forename: Markus
authors.initials: M
authors.lastname: Mitterhauser
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wadsak
mesh_terms: D002247:Carbon Isotopes; D003042:Cocaine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000032:analysis*; D005462:Fluorine Radioisotopes; D006801:Humans; D008968:Molecular Conformation; D049268:Positron-Emission Tomography; D011849:Radioactive Tracers
chemical_list: C000591622:2-fluoroethyl 8-(3-iodoprop-2-en-1-yl)-3-(4-iodophenyl)-8-azabicyclo(3.2.1)octane-2-carboxylate; D002247:Carbon Isotopes; D050483:Dopamine Plasma Membrane Transport Proteins; D005462:Fluorine Radioisotopes; D011849:Radioactive Tracers; C079213:RTI 121; D003042:Cocaine
keywords: Carbon-11; Dopamine; Fluorine-18; IPCIT; PET; Radiosynthesis; Transporter