title: Synthesis and radiopharmacological characterization of 2beta-carbo-2'-[18F]fluoroethoxy-3beta-(4-bromo-phenyl)tropane ([18F]MCL-322) as a PET radiotracer for imaging the dopamine transporter (DAT).
abstract: The fluoroalkyl-containing tropane derivative 2beta-carbo-2'-fluoroethoxy-3beta-(4-bromo-phenyl)tropane (MCL-322) is a highly potent and moderately selective ligand for the dopamine transporter (DAT). The compound was labeled with the short-lived positron emitter (18)F in a single step by nucleophilic displacement of the corresponding tosylate precursor MCL-323 with no-carrier-added [(18)F]fluoride. The positron emission tomography (PET) radiotracer 2beta-carbo-2'-[(18)F]fluoroethoxy-3beta-(4-bromo-phenyl)tropane [(18)F]MCL-322 was obtained in decay-corrected radiochemical yields of 30-40% at a specific radioactivity of 1.6-2.4Ci/mumol (60-90GBq/mumol) at the end-of-synthesis (EOS). Small animal PET, ex vivo and in vivo biodistribution experiments in rats demonstrated a high uptake in the striatum (3.2% ID/g) 5min after injection, which increased to 4.2% ID/g after 60min. The uptake in the cerebellum was 1.8% ID/g and 0.6% ID/g after 5min and 60min post-injection, respectively. Specific binding to DAT of [(18)F]MCL-322 was confirmed by blocking experiments using the high affinity DAT ligand GBR 12909. The radiopharmacological characterization was completed with metabolite and autoradiographic studies confirming the selective uptake of [(18)F]MCL-322 in the striatum. It is concluded that the simple single-step radiosynthesis of [(18)F]MCL-322 and the promising radiopharmacological data make [(18)F]MCL-322 an attractive candidate for the further development of a PET radiotracer potentially suitable for clinical DAT imaging in the human brain.
authors.affiliation: Institut für Radiopharmazie, Forschungszentrum Dresden-Rossendorf, Postfach 510119, 01314 Dresden, Germany. f.wuest@fz-rossendorf.de
authors.forename: F
authors.initials: F
authors.lastname: Wuest
authors.forename: M
authors.initials: M
authors.lastname: Berndt
authors.forename: K
authors.initials: K
authors.lastname: Strobel
authors.forename: J
authors.initials: J
authors.lastname: van den Hoff
authors.forename: X
authors.initials: X
authors.lastname: Peng
authors.forename: J L
authors.initials: JL
authors.lastname: Neumeyer
authors.forename: R
authors.initials: R
authors.lastname: Bergmann
mesh_terms: D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive / Q000187:drug effects; D001711:Biotransformation; D001921:Brain / Q000000981:diagnostic imaging; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D007553:Isotope Labeling; D008279:Magnetic Resonance Imaging; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D014326:Tropanes / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: C521681:2beta-carbo-2'-(18F)fluoroethoxy-3beta-(4-bromo-phenyl)tropane; D050483:Dopamine Plasma Membrane Transport Proteins; D010879:Piperazines; D019275:Radiopharmaceuticals; D014326:Tropanes; C043425:vanoxerine