RT Journal Article
SR Electronic
T1 Pharmacological Characterization of (<em>E</em>)-<em>N</em>-(4-Fluorobut-2-enyl)-2β-carbomethoxy-3β-(4′-tolyl)nortropane (LBT-999) as a Highly Promising Fluorinated Ligand for the Dopamine Transporter
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 147
OP 152
DO 10.1124/jpet.105.096792
VO 317
IS 1
A1 Sylvie Chalon
A1 Hakan Hall
A1 Wadad Saba
A1 Lucette Garreau
A1 Frédéric Dollé
A1 Christer Halldin
A1 Patrick Emond
A1 Michel Bottlaender
A1 Jean-Bernard Deloye
A1 Julie Helfenbein
A1 Jean-Claude Madelmont
A1 Sylvie Bodard
A1 Zoïa Mincheva
A1 Jean-Claude Besnard
A1 Denis Guilloteau
YR 2006
UL http://jpet.aspetjournals.org/content/317/1/147.abstract
AB 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)-2β-carbomethoxy-3β-(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 1-{2-[bis-(4-fluorophenyl)-methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR 12909) and (E)-N-(3-iodoprop-2-enyl)-2β-carbomethoxy-3β-(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 &gt;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. The American Society for Pharmacology and Experimental Therapeutics