title: [11C]LBT-999: a suitable radioligand for investigation of extra-striatal dopamine transporter with PET.
abstract: A new tropane derivative, (E)-N-(4-fluorobut-2-enyl)-2beta-carbomethoxy-3beta-(4'-tolyl)nortropane (LBT-999), was evaluated in baboons as a carbon-11 radioligand for studies of the dopamine transporter (DAT) using positron emission tomography (PET). Brain uptake was high in the striatum (17 and 13% ID/100 mL tissue in the putamen and the caudate, respectively), moderate in the midbrain and thalamus (5 and 3% ID/100 mL tissue, respectively), and low in the cortex and cerebellum (2% ID/100 mL tissue) at 30 min post injection. The striatum-to-cerebellum ratio was high (30 at 110 min post injection). Specific binding was completely blocked following pretreatment with the DAT antagonists GBR12909 (5 mg/kg i.v.) or PE2I (1 mg/kg i.v.). The [(11)C]LBT-999 uptake was decreased by these antagonists in the putamen (-79 and -92%, respectively), caudate (-80 and -91%, respectively), midbrain (-73 and -78%, respectively), and thalamus (-34 and -46%, respectively). The serotonin transporter (SERT) antagonist citalopram (5 mg/kg i.v.) or the norepinephrine transporter antagonist maprotiline (5 mg/kg i.v.) had no effect on LBT specific binding. Pharmacological challenge with PE2I (1 mg/kg i.v.) induced a rapid and almost complete decrease of the specific binding in the putamen (-97%), caudate (-96%), midbrain (-96%), and thalamus (-81%), confirming the reversibility of [(11)C]LBT-999 binding. The high brain uptake of [(11)C]LBT-999 together with its low nonspecific binding (reflected by the very high brain structure-to-cerebellum ratio) indicate that this radiotracer is an excellent candidate for in vivo quantification of the DAT, especially in extrastriatal structures, such as the midbrain.
authors.affiliation: CEA, Service Hospitalier Frédéric Joliot, DRM/DSV, Orsay, France. wadad.saba@cea.fr
authors.forename: Wadad
authors.initials: W
authors.lastname: Saba
authors.forename: Héric
authors.initials: H
authors.lastname: Valette
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Schöllhorn-Peyronneau
authors.forename: Christine
authors.initials: C
authors.lastname: Coulon
authors.forename: Michele
authors.initials: M
authors.lastname: Ottaviani
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chalon
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dolle
authors.forename: Patrick
authors.initials: P
authors.lastname: Emond
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Julie
authors.initials: J
authors.lastname: Helfenbein
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Madelmont
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Deloye
authors.forename: Denis
authors.initials: D
authors.lastname: Guilloteau
authors.forename: Michel
authors.initials: M
authors.lastname: Bottlaender
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes; D002421:Caudate Nucleus / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives; D003342:Corpus Striatum / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D004952:Esters / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000378:metabolism; D009662:Nortropanes / Q000378:metabolism; D048530:Papio anubis; D049268:Positron-Emission Tomography / Q000379:methods*; D011699:Putamen / Q000378:metabolism; D013788:Thalamus / Q000378:metabolism
chemical_list: C508666:8-((E)-4-fluoro-but-2-enyl)-3beta-p-tolyl-8-aza-bicyclo(3.2.1)octane-2beta-carboxylic acid methyl ester; D002250:Carbon Radioisotopes; D050483:Dopamine Plasma Membrane Transport Proteins; D004952:Esters; C113010:N-(3-iodoprop-2-enyl)-2-beta-carbomethoxy-3-(4-methylphenyl)nortropane; D009662:Nortropanes; D003042:Cocaine