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NEUROPHARMACOLOGY

Pharmacological Characterization of (E)-N-(4-Fluorobut-2-enyl)-2-carbomethoxy-3-(4'-tolyl)nortropane (LBT-999) as a Highly Promising Fluorinated Ligand for the Dopamine Transporter

Institut National de la Sante et de la Recherche Medicale U619 (S.C., L.G., P.E., S.B., Z.M., J.-C.B., D.G.) and Université François-Rabelais de Tours (S.C., L.G., P.E., S.B., Z.M., J.-C.B., D.G.), Tours, France; Karolinska Institutet, Stockholm, Sweden (H.H., C.H.); Service Hospitalier Frédéric Joliot, CEA/DSV, Orsay, France (W.S., F.D., M.B.); Laboratoires Cyclopharma, Saint-Beauzire, France (J.-B.D.); Orphachem, Clermont-Ferrand, France (J.H.); and Institut National de la Sante et de la Recherche Medicale U484, Clermont-Ferrand, France (J.-C.M.)

In the aim to develop an efficient fluorinated probe for positron emission tomography (PET) exploration of the dopamine transporter (DAT), we studied several in vitro and in vivo characteristics of the phenyltropane derivative (E)-N-(4-fluorobut-2-enyl)-2-carbomethoxy-3-(4'-tolyl)nortropane (LBT-999). In vitro on rat striatal membrane, [³H]LBT-999 bound to a single site with a K_d of 9 nM, B_max of 17 pmol/mg protein, and a very high selectivity for the DAT [IC₅₀ for 1-{2-[bis-(4-fluorophenyl)-methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR 12909) and (E)-N-(3-iodoprop-2-enyl)-2-carbomethoxy-3-(4'-methylphenyl)nortropane (PE2I): 2.4 and 18 nM, respectively; IC₅₀ for paroxetine, citalopram, N,N-dimethyl-2-(2-amino-4-methylphenyl thio)benzylamine, nisoxetine, and desipramine >1 µM]. In vitro on post-mortem human brain sections, LBT-999 bound with high intensity to the caudate-putamen, weakly to the thalamus, and not in the neocortex and cerebellum. This binding was totally abolished in the presence of PE2I. Ex vivo cerebral biodistribution of [¹¹C]LBT-999 in rats showed striatum/cerebellum radioactivity ratios of 18 and 25 at 30 and 60 min postinjection, respectively. This accumulation was strongly prevented by preinjection of GBR 12909, whereas paroxetine and nisoxetine had no effect. An in vivo kinetic PET study in three baboons showed a fast and very high uptake in the striatum, with a plateau at 30 min postinjection and a maximal putamen/cerebellum ratio of 30. Taken together, these findings demonstrate that LBT-999 is a highly promising agent for in vivo exploration of the DAT. This probe is currently labeled with ¹⁸F for further characterizations.

Address correspondence to: Sylvie Chalon, INSERM U619, Université François-Rabelais de Tours, UFR Pharmacie, 31 avenue Monge, 37200, Tours, France. E-mail: chalon{at}univ-tours.fr