Pharmacological Characterization of<i>N</i>,<i>N</i>-Dimethyl-2-(2-amino-4-methylphenyl thio)benzylamine as a Ligand of the Serotonin Transporter with High Affinity and Selectivity

Chalon, Sylvie; Tarkiainen, Jari; Garreau, Lucette; Hall, Håkan; Emond, Patrick; Vercouillie, Johnny; Farde, Lars; Dasse, Philippe; Varnäs, Katarina; Besnard, Jean‐Claude; Halldin, Christer; Guilloteau, Denis

doi:10.1124/jpet.102.042226

Cited by 49 publications

(23 citation statements)

References 35 publications

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“…[ 3 H]MADAM, [ 123 I]ADAM, and [ 11 C]DASB did not display species differences in receptor affinity. The K d values obtained (0.11, 0.05, and 0.34 nM, respectively) were in accordance with previously published results reporting K d values in the rat brain of 0.06, 0.15, and 0.54 nM at 228C, respectively (Chalon et al, 2003;Choi et al, 2000;Lundquist et al, 2005). The K d (0.25 nM) and B max (105 fmol/mg protein) values obtained with [ 11 C]DASB in the monkey cortex are concordant with another study, where a K d value of 0.20 nM and a B max value of 66 fmol/mg protein have been obtained with [ 3 H]DASB binding in tissue homogenates of rhesus monkey frontal cortex (Zeng et al, 2006 I]ADAM contra 100-170 fmol/ mg protein with the other radioligands).…”

Section: Species Differencessupporting

confidence: 92%

Neuroimaging of the serotonin reuptake site requires high‐affinity ligands

Elfving¹,

Madsen²,

Knudsen³

2007

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Numerous attempts have been made to develop suitable radiolabeled tracers for positron emission tomography or single photon emission computed tomography imaging of the serotonin transporter (SERT), but most often, negative outcomes are reported. The aim of this study is to define characteristics of a good SERT radioligand and to investigate species differences. We examined seven different selective serotonin reuptake inhibitors (SSRIs) and that except for one all have been previously tested as emission tomography ligands. The outcome of the ligands as emission tomography tracers was compared in relation with receptor density (Bmax) and/or ligand affinity (Kd) in rat and monkey cerebrum and cerebellum (reference region) membranes. [3H]-(S)-Citalopram and [3H]-(+)-McN5652 display statistically significantly lower affinity, whereas [3H]paroxetine displays statistically significantly higher affinity for SERT in monkey cortex when compared with the rat cerebrum. The affinity of [3H]MADAM, [123I]ADAM, and [11C]DASB for SERT obtained with rat cerebrum and monkey cortex are similar. In monkey cortex, Kd and Bmax could not be determined with [3H]fluoxetine. Of the seven SSRIs, [3H]-(S)-citalopram, [3H]MADAM, and [11C]DASB displayed significant specific binding to SERT in monkey cerebellum, with Bmax cortex:cerebellum ratios being 17, 3, and 4, respectively. In rat brain tissue the ratios were 12, 6, and 3, respectively. In conclusion, it can be estimated that imaging of the human SERT in a high-density region requires radioligands with Kd values between 0.03 and a maximum of 0.3 nM (at 37 degrees C). The differential specific cerebellar binding raises the question of the suitability of cerebellum as a reference region for nonspecific binding.

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Section: Species Differencessupporting

confidence: 92%

Neuroimaging of the serotonin reuptake site requires high‐affinity ligands

Elfving¹,

Madsen²,

Knudsen³

2007

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“…After demonstrating promising characteristics in nonhuman primate PET studies, [ 11 C]MADAM ( N,N ‐dimethyl‐2‐(2‐amino‐4‐methylphenylthio)benzylamine) was tested in humans . The brain accumulation pattern was consistent with human postmortem SERT binding with [ 3 H]MADAM as well as [ 3 H]imipramine, [ 3 H]paroxetine, and [ 3 H]citalopram . In a test–retest study, [ 11 C]MADAM had excellent reproducibility when done several weeks apart .…”

Section: Current Radioligands For Imaging the 5‐ht Systemsupporting

confidence: 70%

5‐HT radioligands for human brain imaging with PET and SPECT

Paterson

Kornum

Nutt

et al. 2011

Medicinal Research Reviews

145

129

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The serotonergic system plays a key modulatory role in the brain and is the target for many drug treatments for brain disorders either through reuptake blockade or via interactions at the 14 subtypes of 5-HT receptors. This review provides the history and current status of radioligands used for positron emission tomography (PET) and single photon emission computerized tomography (SPECT) imaging of human brain serotonin (5-HT) receptors, the 5-HT transporter (SERT), and 5-HT synthesis rate. Currently available radioligands for in vivo brain imaging of the 5-HT system in humans include antagonists for the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 receptors, and for SERT. Here we describe the evolution of these radioligands, along with the attempts made to develop radioligands for additional serotonergic targets. We describe the properties needed for a radioligand to become successful and the main caveats. The success of a PET or SPECT radioligand can ultimately be assessed by its frequency of use, its utility in humans, and the number of research sites using it relative to its invention date, and so these aspects are also covered. In conclusion, the development of PET and SPECT radioligands to image serotonergic targets is of high interest, and successful evaluation in humans is leading to invaluable insight into normal and abnormal brain function, emphasizing the need for continued development of both SPECT and PET radioligands for human brain imaging.

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“…This explanation is however unlikely as in vitro binding studies using rat cortex homogenate at 22°C have demonstrated that citalopram and other SSRIs inhibit all specific binding of [ 3 H]MADAM and that the inhibition is best described by a one-site binding model (Chalon et al 2003 (Quelch et al 2012). It can thus not be ruled out that incomplete inhibition of [ 11 C]MADAM by escitalopram and citalopram may partly be due to a cellular redistribution of SERT which affects escitalopram and citalopram binding differently than [ 11 C]MADAM binding.…”

Section: Discussionmentioning

confidence: 92%

Serotonin transporter occupancy by escitalopram and citalopram in the non-human primate brain: a [11C]MADAM PET study

et al. 2015

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Escitalopram or citalopram doses nearly saturated SERT in previous monkey studies which examined serotonin sensitivity of receptor radioligands. PET-measured cross-species differential effects of SSRI on cortical serotonin concentration may thus be related to SSRI dose. Future monkey studies using SSRI doses inducing clinically relevant SERT occupancy may further illuminate the delayed onset of SSRI therapeutic effects.

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Pharmacological Characterization ofN,N-Dimethyl-2-(2-amino-4-methylphenyl thio)benzylamine as a Ligand of the Serotonin Transporter with High Affinity and Selectivity

Cited by 49 publications

References 35 publications

Neuroimaging of the serotonin reuptake site requires high‐affinity ligands

Neuroimaging of the serotonin reuptake site requires high‐affinity ligands

5‐HT radioligands for human brain imaging with PET and SPECT

Serotonin transporter occupancy by escitalopram and citalopram in the non-human primate brain: a [11C]MADAM PET study

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