[11C]MDL 100907, a radioligand for selective imaging of 5-HT2A receptors with positron emission tomography

doi:10.1016/0024-3205(96)00013-6

Life Sciences

Volume 58, Issue 10, 2 February 1996, Pages 187-192

https://doi.org/10.1016/0024-3205(96)00013-6 Get rights and content

Abstract

The highly selective 5-HT_2A receptor antagonist, MDL 100907 ((R)-(+)-4-(1-hydroxy-1-(2,3-dimethoxyphenyl)methyl)-N-2-(4-fluorophenylethyl)piperidine), was labeled with ¹¹C for Positron Emission Tomography (PET) studies. After i.v. injection of (R)-(+)-[3-OCH₃-¹¹C]MDL 100907 ([¹¹C]MDL 100907) in Cynomolgus monkeys a marked accumulation in the 5-HT_2A receptor rich neocortical regions was obtained with a neocortex to cerebellum ratio of 3.5–4.5 after 60–80 minutes. In the neocortical regions a transient equilibrium occured within 40–60 minutes. Radioactivity in the neocortex, but not in the cerebellum, was reduced after injection of ketanserin, indicating that neocortical radioactivity following injection of [¹¹C]MDL 100907 represents specific binding to 5-HT_2A receptors. There was no evident effect on neocortical binding after pretreatment with raclopride or SCH 23390. [¹¹C]MDL 100907 has potential to become the first selective radioligand for PET-quantitation of 5-HT_2A receptors in the human brain in vivo.

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Development of novel chiral capillary electrophoresis methods for the serotonin receptor (5-HT<inf>2A</inf>) antagonist MDL 100,907 (volinanserin) and for its key intermediate compound
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Citation Excerpt :
Its R-enantiomer binds to its receptor with higher affinity (Ki ∼ 0.4 nM) than its racemic form (Ki ∼ 2.1 nM) [2]. MDL 100,907 has about 100-fold or greater selectivity for 5-HT2A than for the other 5-HT receptor subtypes [3,4]. This drug is widely used in the investigation of the 5-HT2A receptor function [1,5–8].
Enantioselective capillary electrophoretic methods were elaborated for the determination of the enantiomeric purity of (R)-MDL 100,907 and its preparatively resolved key intermediate compound during the synthesis route. The pK_a values of the intermediate compound and the end product determined by CE were 10.5 ± 0.1 and 9.0 ± 0.1, respectively. The enantiopurity of the intermediate compound can be monitored in fully protonated state by applying 15 mM sulfobutylether-β-cyclodextrin at pH 5 when the peak belonging to the impurity migrates before the main component. The fact that the consecutive steps of the synthesis do not affect the enantiomeric purity was verified by the other, newly developed CE method. The enantiomers of rac-MDL 100,907 were resolved by 15 mM carboxymethyl-γ-cyclodextrin at pH 3. The applicability (selectivity, LOD, LOQ, repeatability, precision and accuracy) of the methods was studied as well.
Characterization of [<sup>11</sup>C]Cimbi-36 as an agonist PET radioligand for the 5-HT<inf>2A</inf> and 5-HT<inf>2C</inf> receptors in the nonhuman primate brain
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Citation Excerpt :
PET studies examining 5-HT2A receptors have been conducted to evaluate the role of 5-HT2A receptors in physiology (Erritzoe et al., 2009) and neuropsychiatric disorders (Adams et al., 2005; Haugbol et al., 2007). A limitation of the available 5-HT2A receptor PET radioligands, e.g. [18F]altanserin (Biver et al., 1994; Lemaire et al., 1991) or [11C]MDL 100907 (Ito et al., 1998; Lundkvist et al., 1996), is that they are antagonists. Classical receptor binding assay studies have demonstrated that 5-HT2A receptors exist in two affinity states for agonists (Fitzgerald et al., 1999; Lopez-Gimenez et al., 2001c; Song et al., 2005), similar as for other G protein-coupled receptors.
Only recently the first successful serotonin 2A (5-HT_2A) receptor agonist PET radioligands have been described, with [¹¹C]Cimbi-36 reported as the most promising in the pig brain so far. Agonist radioligands may target specifically the G protein-coupled state of the receptors and thereby provide a more meaningful assessment of available receptors than antagonist radioligands. In the current study we characterized [¹¹C]Cimbi-36 receptor binding in the primate brain.
On five experimental days, a total of 14 PET measurements were conducted in three female rhesus monkeys. On each day, PET measurements were conducted after intravenous injection of [¹¹C]Cimbi-36 during baseline conditions and after intravenous infusion of the 5-HT₂ receptor antagonist ketanserin (n = 3) or the 5-HT_2C receptor antagonist SB 242084 (n = 2). On four of the experimental days an additional baseline PET measurement was conducted after injection of [¹¹C]MDL 100907. All PET measurements were performed for 2 h in a HRRT PET system and arterial blood was obtained for measurement of the [¹¹C]Cimbi-36 input function. Quantification of [¹¹C]Cimbi-36 receptor binding was performed using kinetic and graphical analysis.
After injection of [¹¹C]Cimbi-36 the regional distribution of radioactivity in brain was in accordance with the known 5-HT₂ receptor distribution. The two-tissue compartment model was superior for the description of the time–radioactivity curves of all examined brain regions. BP_ND values obtained with reference tissue models correlated with corresponding values obtained with kinetic modeling. Administration of ketanserin decreased the binding in all brain regions but did not affect the cerebellar distribution volume. The BP_ND of [¹¹C]Cimbi-36 was 56 ± 8% of [¹¹C]MDL 100907 across cortical regions, but higher in other brain regions including choroid plexus. After administration of SB 242084, [¹¹C]Cimbi-36 binding was nearly completely inhibited in the choroid plexus, partly reduced in several subcortical regions (e.g. hippocampus), but not affected in the cortical regions.
In conclusion, the receptor binding of [¹¹C]Cimbi-36 can be quantified using kinetic modeling and the cerebellum was found to be a suitable reference region. The difference between [¹¹C]Cimbi-36 and [¹¹C]MDL 100907 binding in the choroid plexus is related to 5-HT_2C receptor binding of [¹¹C]Cimbi-36. [¹¹C]Cimbi-36 is the first agonist radioligand suitable for examination of 5-HT_2A receptors in the cortical regions and of 5-HT_2C receptors in the choroid plexus of the primate brain.

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Pharmacology letter accelerated communication[11C]MDL 100907, a radioligand for selective imaging of 5-HT2A receptors with positron emission tomography

Abstract

Int. J. Radiat. Appl. Inst. Part B

Appl. Radiat. Isot.

Neuroscience

Brain Res.

Nucl. Med. Biol.

Science

Schizophr. Bull.

Psychopharmacology

Schizophr. Bull.

Psychopharmacology

Eur. J. Nucl. Med.

Pharmacology letter accelerated communication
[¹¹C]MDL 100907, a radioligand for selective imaging of 5-HT_2A receptors with positron emission tomography