11C]LBT-999: a suitable radioligand for investigation of extra-striatal dopamine transporter with PET.

CEA, Service Hospitalier Frédéric Joliot, DRM/DSV, Orsay, France. wadad.saba@cea.fr

Synapse (New York, N.Y.) 2007 Jan

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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.

Citation

Wadad Saba, Héric Valette, Marie-Anne Schöllhorn-Peyronneau, Christine Coulon, Michele Ottaviani, Sylvie Chalon, Frédéric Dolle, Patrick Emond, Christer Halldin, Julie Helfenbein, Jean-Claude Madelmont, Jean-Bernard Deloye, Denis Guilloteau, Michel Bottlaender. 11C]LBT-999: a suitable radioligand for investigation of extra-striatal dopamine transporter with PET. Synapse (New York, N.Y.). 2007 Jan;61(1):17-23