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 Chalon, Sylvie
A1 Hall, Hakan
A1 Saba, Wadad
A1 Garreau, Lucette
A1 Dollé, Frédéric
A1 Halldin, Christer
A1 Emond, Patrick
A1 Bottlaender, Michel
A1 Deloye, Jean-Bernard
A1 Helfenbein, Julie
A1 Madelmont, Jean-Claude
A1 Bodard, Sylvie
A1 Mincheva, Zoïa
A1 Besnard, Jean-Claude
A1 Guilloteau, Denis
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