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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on December 9, 2005; DOI: 10.1124/jpet.105.096792

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Received for publication October 12, 2005.
Revised December 3, 2005.
Accepted for publication December 5, 2005.

Pharmacological characterization of (E)-N-(4-fluorobut-2- enyl)-2{beta}-carbomethoxy-3{beta}-(4'-tolyl)nortropane (LBT-999) as a highly promising fluorinated ligand for the dopamine transporter

Sylvie Chalon 1*, Hakan Hall 2, Wadad Saba 3, Lucette Garreau 1, Frederic Dolle 3, Christer Halldin 2, Patrick Emond 1, Michel Bottlaender 3, Jean-Bernard Deloye 4, Julie Helfenbein 5, Jean-Claude Madelmont 6, Sylvie Bodard 1, Zoia Mincheva 7, Jean-Claude Besnard 1, Denis Guilloteau 1

1 Inserm U619; Universite Francois-Rabelais de Tours 2 Karolinska Institute 3 SHFJ, CEA/DSV 4 Cyclopharma 5 Orphachem 6 Inserm U484 7 Inserm U619; Universite Francois Rabelais de Tours

* Address correspondence to: E-mail: chalon{at}univ-tours.fr

Abstract

In the aim to develop an efficient fluorinated probe for 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{beta}-carbomethoxy-3{beta}-(4'-tolyl)nortropane (LBT-999). In vitro on rat striatal membrane, [3H]LBT-999 bound to a single site with a Kd of 9 nM, Bmax of 17 pmol/mg protein, and a very high selectivity for the DAT (IC50 for GBR 12909 and PE2I: 2.4 and 18 nM, respectively; IC50 for paroxetine, citalopram, MADAM, nisoxetine and desipramine > 1 µM). In vitro on post-mortem human brain section, 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 a striatum/cerebellum radioactivity ratio of 18 and 25 at 30 and 60 min post-injection, respectively. This accumulation was strongly prevented by a pre-injection of GBR 12909 whereas paroxetine and nisoxetine had no effect. In vivo kinetic PET study in a Baboon showed a fast and very high uptake in the striatum, with a plateau at 30 min post-injection 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.


Key words: PET, autoradiography, brain imaging, monoamine transpoter, rat, striatum




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