Abstract
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 >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.
Footnotes
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This work was supported by the French “Réseau National de Technologies pour la Santé” under the RNTS 03B243 FLUOPARK program and by a grant from Biotechnocenter (Région Centre, France).
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This study was funded in part by the EC-FP6 project Diagnostic Molecular Imaging (DiMI), LSHB-CT-2005-512146-3.
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Partial results were presented as abstracts [Dollé F, Emond P, Saba W, Chalon S, Demphel S, Halldin C, Mavel S, Garreau L, Coulon C, Ottaviani M, et al. (2003) Radiosynthesis of [11C]LBT-999, a selective radioligand for the visualization of the dopamine transporter with PET, J Label Compd Radiopharm46:S145; and Hassoun W, Chalon S, Valette H, Dollé F, Garreau L, Emond P, Halldin C, Deloye J-B, Bottlaender M, and Guilloteau D (2004) [11C]LBT-999, a new radioligand to study the dopamine transporter with PET: preclinical characterization. Eur J Nucl Med31:28].
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doi:10.1124/jpet.105.096792.
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ABBREVIATIONS: DAT, dopamine transporter; FPCIT, N-3-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane; PET, positron emission tomography; FPCBT, N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-bromophenyl)nortropane; CFT, 2β-carbomethoxy-3β-(4-fluorophenyl)tropane; FPCT, 2β-carbomethoxy-3β-(4-chlorophenyl)-8-(3-fluoropropyl)nortropane; FECNT, N-2-fluoroethyl-2β-carbomethoxy-3β-(4-chlorophenyl)-nortropane; PE2I, (E)-N-(3-iodoprop-2-enyl)-2β-carbomethoxy-3β-(4′-methylphenyl)nortropane; LBT-999, (E)-N-(4-fluorobut-2-enyl)-2β-carbomethoxy-3β-(4′-tolyl)nortropane; HPLC, high-performance liquid chromatography; MADAM, N,N-dimethyl-2-(2-amino-4-methylphenyl thio)benzylamine; GBR12935, 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)-piperazine; ID, injected dose; ROI, region of interest; GBR 12909, 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine.
- Received October 7, 2005.
- Accepted December 5, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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