Synthesis and biological evaluation in rat and cat of [ F]12ST05 as a

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Nuclear Medicine and Biology 34 (2007) 995 – 1002
www.elsevier.com/locate/nucmedbio
Synthesis and biological evaluation in rat and cat of [ 18 F]12ST05 as a
potential 5-HT6 PET radioligand☆
Sandrine Tang a,1 , Mathieu Verdurand b,c,1 , Benoît Joseph a , Laëtitia Lemoine b,c , Alexia Daoust c ,
Thierry Billard a , Guy Fournet a , Didier Le Bars a,c , Luc Zimmer b,c,⁎
a
Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, UMR CNRS 5246, Université Lyon 1, Université de Lyon, Lyon, 69677 (Cermep), France
b
Laboratoire de Neuropharmacologie, FRE CNRS 3006, Université Lyon 1, Université de Lyon, Lyon, 69373 (FRE CNRS 3006), France
c
CERMEP-Imagerie du Vivant, PET Department, Lyon, 69622 (ICBMS), France
Received 6 April 2007; received in revised form 18 June 2007; accepted 2 July 2007
Abstract
Introduction: 5-hydroxytryptamine (5-HT)6 receptors represent one of the more recently discovered serotoninergic receptor family.
However, no 5-HT6 positron emission tomography (PET) radiotracer is currently used in clinical imaging studies. The purpose of this study
was to propose the first fluorinated PET radiotracer for this brain receptor.
Methods: A new compound presenting in vitro high affinity towards the serotoninergic 5-HT6 receptor, N-[2-(1-[(4-fluorophenyl)sulfonyl]1H-indol-4-yloxy)ethyl]-N,N-dimethylamine, was labelled with fluorine 18 via a nitro-/fluoronucleophilic substitution. Biological
evaluations included (i) in vitro and ex vivo autoradiographies in rat brain and (ii) a PET scan on anaesthetized cat.
Results and Conclusion: Although the radioligand showed excellent brain penetration, it did not reveal any specific binding to the 5-HT6
receptors indicating that this radiotracer is not suitable for mapping 5-HT6 receptors using PET.
© 2007 Elsevier Inc. All rights reserved.
Keywords: 5-HT6 receptors; Radioligand; Positron emission tomography; Rat; Cat
1. Introduction
Serotonin [5-hydroxytryptamine (5-HT)] is a central
neurotransmitter involved in a great variety of physiological
functions, as well as neurological and pathological disorders
such as depression, eating disorders and Alzheimer's disease
[1]. Pharmacological studies allowed identification of
numerous 5-HT receptor families and subtypes. These
receptors have been classified by structural, functional and
pharmacological criteria into seven distinct receptor classes
(5-HT1-7) [2,3].
☆
Sandrine Tang was supported by a grant from Région Rhône-Alpes
“Bourse Prospective.” Mathieu Verdurand was supported by a CIFRE grant
with Advanced Accelerator Applications.
⁎ Corresponding author. CERMEP-Imagerie du Vivant, PET Department, F-69006 Lyon, France.
E-mail address: [email protected] (L. Zimmer).
1
S.T. and M.V. contributed equally to this article.
0969-8051/$ – see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.nucmedbio.2007.07.002
5-HT6 receptors represent one of the more recently
discovered serotoninergic receptor family. The 5-HT6
receptor mRNA appears to be almost exclusively present
in the brain with little evidence for its presence in peripheral
tissues [4,5]. Immunocytochemistry studies in rats agreed
well with that seen with 5-HT6 mRNA and have shown that
5-HT6 receptors are localized in striatum, olfactory tubercles,
nucleus accumbens, cerebral cortex, hippocampus, hypothalamus and amygdala [6,7]. These data are largely supported
by in vitro autoradiographic studies with the selective 5-HT6
radioligands [125I]SB-258585 and [3H]Ro 63-0563 [8–10].
The 5-HT6 receptor messenger RNA is mainly located in the
5-HT projection fields, suggesting that the receptor is located
postsynaptically [11]. According to its brain distribution, the
5-HT6 receptors have been implicated in diverse central
nervous system pathophysiologies, and several atypical
antipsychotics have high affinity for it [12,13].
Although few human postmortem studies are available,
the distribution of 5-HT6 receptors appears to be similar to
that in rats [14,15].