title: Synthesis and biodistribution of [18F]FE@CIT, a new potential tracer for the dopamine transporter.
abstract: In the last decade radiolabeled tropane analogs based on beta-CIT have proven indispensable for the imaging of the dopamine transporter. However, further improvements in their pharmacodynamic and pharmacokinetic features are desirable. An important improvement, yielding in higher affinity to the dopamine transporter (DAT) vs. serotonin transporter (SERT), can be achieved by a simple replacement of the carboxylic methyl ester group in beta-CIT by a fluoroethyl ester. The preparation and ex vivo evaluation of this new beta-CIT-analog ([18F]FE@CIT) is presented here. Precursor and standard were prepared from beta-CIT and analyzed by spectroscopic methods. Yields of precursor and standard preparation were 61% and 42%, respectively. [18F]FE@CIT was prepared by distillation of [18F]bromofluoroethane ([18F]BFE) and reaction with (1R-2-exo-3-exo)8-methyl-3-(4-iodo-phenyl)-8-azabicyclo[3.2.1] octane-2-carboxylic acid. After 10 min at 150 degrees C the product was purified using a C-18 SepPak. The radiosynthesis evinced radiochemical yields of >90% (based on [18F]BFE), the specific radioactivity was >416 GBq/micromol. An average 30 microAh cyclotron irradiation yielded more than 2.5 GBq [18F]FE@CIT. For the ex vivo bioevaluation, 20 male Sprague-Dawley rats were sacrificed at 5, 15, 30, 60, and 120 min after injection. Organs were removed, weighed, and counted. For autoradiographic experiments, transverse brain slices of about 100 microm were prepared. The ex vivo evaluation showed highest brain uptake in striatal regions, followed by thalamus and cerebellum. The highest striatum to cerebellum ratio was 3.73 and the highest thalamus to cerebellum ratio was 1.65. Autoradiographic images showed a good and differentiated uptake in striatal regions with a good target-to-background ratio.
authors.affiliation: Department of Nuclear Medicine, Medical University of Vienna, Austria. markus.mitterhauser@meduniwien.ac.at
authors.forename: Markus
authors.initials: M
authors.lastname: Mitterhauser
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wadsak
authors.forename: Leonhard-Key
authors.initials: LK
authors.lastname: Mien
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoepping
authors.forename: Helmut
authors.initials: H
authors.lastname: Viernstein
authors.forename: Robert
authors.initials: R
authors.lastname: Dudczak
authors.forename: Kurt
authors.initials: K
authors.lastname: Kletter
mesh_terms: D000818:Animals; D001345:Autoradiography / Q000379:methods; D001921:Brain / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002855:Chromatography, Thin Layer; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009662:Nortropanes / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D011854:Radiochemistry / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D013696:Temperature; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D005462:Fluorine Radioisotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C097058:N-(2-fluoroethyl)-2-carbomethoxy-3-(4-iodophenyl)nortropane; D009419:Nerve Tissue Proteins; D009662:Nortropanes; C493216:Slc6a3 protein, rat