PET tracers for 5-HT1A receptors and uses thereof

doi:10.1016/j.drudis.2007.07.008

Drug Discovery Today

Volume 12, Issues 17–18, September 2007, Pages 748-756

https://doi.org/10.1016/j.drudis.2007.07.008 Get rights and content

The serotonin 5-HT_1A receptor is implicated in the pathophysiology of major neuropsychiatric disorders, including depression, suicidal behavior, panic disorder, epilepsy, bulimia, schizophrenia, Parkinson's disease, and Alzheimer's disease and is, therefore, an important target for drug therapy. 5-HT_1A receptors are expressed as somatodendritic autoreceptors in serotonin neurons of the raphé nuclei (presynaptic) and as postsynaptic receptors in cortical and subcortical serotonin terminal fields in the brain. Due to the higher concentration and heterogeneous distribution of this receptor, it is an attractive target for quantification in vivo using positron emission tomography (PET) and single photon emission tomography (SPECT). Here, we review the PET radioligands employed for imaging 5-HT_1A receptors in living brain.

Section snippets

Antagonist radioligands

Currently available successful PET tracers for 5-HT_1A receptor binding are all antagonist radioligands and provide the measure of receptor number and affinity, but cannot distinguish the agonist high and low affinity conformations of the receptor (Figure 1).

[Carbonyl-¹¹C]WAY100635

N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY100635) is a potent and selective 5-HT_1A antagonist with high affinity for 5-HT_1A receptors (K_D = 0.2 nM) [21]. In vivo studies in mice and rats with [³H]WAY100635 revealed a specific distribution, consistent with the known distribution of 5-HT_1A receptors in human 22, 23. The originally designed [O-methyl-¹¹C]WAY100635 had a lipophilic metabolite [O-methyl-¹¹C]WAY100634 in primate brain that crosses the blood

[Carbonyl ¹¹C]DWAY

DWAY is a minor metabolite of WAY-100635, and has been labeled with carbon-11 by reaction of desmethyl-WAY-100634 with [carbonyl-¹¹C]cyclohexanecarbonyl chloride [62]. [Carbonyl-¹¹C]DWAY has hippocampus/cerebellum binding ratios of 22 and 6 in rat brain and monkey brain, respectively [62]. Studies with [carbonyl-¹¹C]DWAY in human volunteers has a substantially (∼75%) greater signal per unit of radioactive dose compared to [carbonyl-¹¹C]WAY100635 [63]. Although there are several reports on the

[¹⁸F]MPPF

4-(2-Methoxyphenyl)-1-[2-(N-2-pyridinyl)-p-fluorobenzamido)ethyl]piperazine (MPPF) is a selective 5-HT_1A antagonist (K_D = 0.34 nM), and a radiolabeled version ([¹⁸F]MPPF) was synthesized by [¹⁸F⁻]fluoride for nitro nucleophilic aromatic substitution [66]. An update of in vivo imaging of 5-HT_1A receptor in animal and human brain with [¹⁸F]MPPF is reviewed by Aznavour et al. [67]. In summary, nonhuman primate, rat and human studies show that [¹⁸F]MPPF binding to 5-HT_1A receptors is reversible, with

[¹⁸F]FCWAY

[¹⁸F]3-cis-FCWAY is an analogue of FCWAY and had the slowest [¹⁸F]defluorination of all FCWAY analogs in rats and human [77]. Lower 5-HT_1A receptor binding in the anterior and posterior cingulate cortices of patients with panic disorder was observed in a recent PET study using [¹⁸F]FCWAY [78]. A lower 5-HT_1A receptor binding and a higher plasma-free fraction of [¹⁸F]FCWAY were found in mesial temporal and insular cortex of TLE patients in comparison to control subjects 79, 80. However, no

[¹¹C]CPC-222

CPC-222, a structural analogue of WAY100635, in which the cyclohexyl ring has been replaced by a bicyclo[2,2,2]octane (adamantine) ring, designed to overcome the metabolic instability of [carbonyl-¹¹C)WAY100635 [84]. Radiosynthesis of [¹¹C]CPC-222 is achieved in high yield by a simple [¹¹C]-methylation of the corresponding desmethyl analogue. Biodistribution studies with [¹¹C]CPC-222 in rats show a hippocampus to cerebellum binding ratio of 10 at 45 min [29]. Pilot study with [¹¹C]CPC-222 in

[¹¹C](R)-RWAY

[¹¹C](R)-RWAY ([¹¹C]2,3,4,5,6,7-hexahydro-1{4-[1[4-(2-methoxyphenyl)piperazinyl]]-2-phenyl-butyry}-1H-azepine) is a reverse amide of WAY100635, designed to improve the issues of metabolite stability associated with WAY100635 [87]. [¹¹C](R)-RWAY has been shown to be a successful radioligand for 5-HT_1A receptor measurements in rodents and monkeys [88]. Despite promising results in rodents and nonhuman primates, interference of radioactive metabolite in brain result slow washout of activity from

[¹⁸F]MeFWAY

N-{2-[4-(2-Methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(4-¹⁸F-fluoromethyl-cyclohexane)carboxamide ([¹⁸F]MeFWAY), is an analogue of WAY100635, with comparable binding affinity [90]. The [¹⁸F] labeling of MeFWAY is performed on a primary carbon atom which makes the compound more stable to de[¹⁸F]fluorination. PET studies in rats and rhesus monkeys showed [¹⁸F]MeFWAY binding in 5-HT_1A receptor enriched brain areas with excellent selectivity and has potential as a PET agent for 5-HT_1A

Agonist radioligands

5-HT_1A receptors occur in high and low affinity agonist binding states. Antagonists bind to the high affinity (HA) and low affinity (LA) conformations of 5-HT_1A receptors with comparable affinity [93]. In contrast, agonists bind preferentially to the HA state of the receptor, which is coupled to G-proteins and therefore agonists provide a measure of functional 5-HT_1A receptors 94, 95. Hence, agonist ligands only compete with the binding of antagonist radiotracers to the HA subpopulation of

Conclusion

Although [carbonyl-¹¹C]WAY100635, [¹¹C]DWAY, [¹⁸F]FCWAY, and [¹⁸F]MPPF currently appear to be the most useful antagonist PET ligands for the quantification of 5-HT_1A receptors in human, the development of a new antagonist PET tracer that is easier, routinely and reliably, to radiolabel is still required for the facile quantitative measurements of these receptors in clinical studies. The research efforts in the field of antagonist tracers are now aimed at improvement of the metabolic stability

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ReviewPost ScreenPET tracers for 5-HT1A receptors and uses thereof

Section snippets

Antagonist radioligands

[Carbonyl-11C]WAY100635

[Carbonyl 11C]DWAY

[18F]MPPF

[18F]FCWAY

[11C]CPC-222

[11C](R)-RWAY

[18F]MeFWAY

Agonist radioligands

Conclusion

Pharmacol. Biochem. Behav.

Life Sci.

Neuropsychopharmacology

J. Psychiatric Res.

Biol. Psychiatry

Biol. Psychiatry

Brain Res.

Neurochem. Int.

Brain Res.

Brain Res.

Biol. Psychiatry

Brain Res.

Nucl. Med. Biol.

Progr. Med. Chem.

Brain Res.

Eur. J. Pharmacol.

Nucl. Med. Biol.

Brain Res.

Biol. Psychiatry

Brain Res.

Neuroimage

Neuropsychopharmacology

Biol. Psychiatry

Biol. Psychiatry

Brain Res.

Epilepsy Res.

Psychiatry Res. Neuroimaging

Biol. Psychiatry

Life Sci.

Neuropsychopharmacology

Biol. Psychiatry

Biol. Psychiatry

Neuropsychopharmacology

Nucl. Med. Biol.

Nucl. Med. Biol.

Appl. Rad. Isotop.

Neuropharmacology

J. Chem. Neuroanatomy

NeuroImage

Nucl. Med. Biol.

Bioorg. Med. Chem.

Nucl. Med. Biol.

Bioorg. Chem.

Eur. J. Pharmacol.

Life Sci.

Reduced serotonin type 1A receptor binding in panic disorder

J. Neurosci.

5-HT1A receptor binding and intracerebral activity in temporal lobe epilepsy: an [18F]MPPF-PET study

Brain

Serotonin1A receptors in the living brain of Alzheimer's disease patients

Proc. Natl. Acad. Sci.

Changes in sleep electroencephalogram and nocturnal hormone secretion after administration of the antidyskinetic agent sarizotan in healthy young male volunteers

Psychopharmacology

A retrospect on the discovery of WAY100635 and the prospect for improved 5-HT1A receptor PET radioligands

Nucl. Med. Biol.

Review
Post Screen
PET tracers for 5-HT_1A receptors and uses thereof

[Carbonyl-¹¹C]WAY100635

[Carbonyl ¹¹C]DWAY

[¹⁸F]MPPF

[¹⁸F]FCWAY

[¹¹C]CPC-222

[¹¹C](R)-RWAY

[¹⁸F]MeFWAY

5-HT_1A receptor binding and intracerebral activity in temporal lobe epilepsy: an [¹⁸F]MPPF-PET study

Serotonin_1A receptors in the living brain of Alzheimer's disease patients

A retrospect on the discovery of WAY100635 and the prospect for improved 5-HT_1A receptor PET radioligands