Elsevier

Neuropharmacology

Volume 52, Issue 3, March 2007, Pages 695-707
Neuropharmacology

Review
[18F]MPPF as a tool for the in vivo imaging of 5-HT1A receptors in animal and human brain

https://doi.org/10.1016/j.neuropharm.2006.09.023Get rights and content

Abstract

Serotonin (5-hydroxytryptamine, 5-HT) and its various receptors are involved in numerous CNS functions and psychiatric disorders. 5-HT1A, the best-characterized subtype of currently known 5-HT receptors, is tightly implicated in the pathogenesis of depression, anxiety, epilepsy and eating disorders. It thus represents an important target for drug therapy. Specific radioligands and positron emission tomography (PET) allow for a quantitative imaging of brain 5-HT1A receptor distribution in living animals and humans. Recently, the selective 5-HT1A receptor antagonist, MPPF, has been successfully labeled with [18F]fluorine ([18F]MPPF), and an increasing number of academic and industry centres have used this radiotracer in preclinical and clinical studies. After a brief account of some of the structural, distributional and electrophysiological characteristics of brain 5-HT1A receptors, this review focuses on studies conducted with [18F]MPPF, with emphasis on preclinical results illustrating the actual and potential value of this PET radioligand for clinical research and drug development.

Section snippets

Introduction: the brain serotonin system

Serotonin (5-hydroxytryptamine, 5-HT) acts as a neurotransmitter and neuromodulator in the central nervous system (CNS). It regulates a broad spectrum of functions and behaviours in the adult, and also contributes to brain development (Lauder and Krebbs, 1978, Whitaker-Azmitia, 1991, Whitaker-Azmitia, 2001, Gross et al., 2002, Gaspar et al., 2003). Impairment of the 5-HT system has been reported in a number of major psychiatric disorders including anxiety (Heisler et al., 1998, Parks et al.,

5-HT1A receptors

Since the introduction of radioligand binding techniques, followed by the advent of molecular cloning approaches, at least 14 5-HT receptor subtypes have been identified in mammalian CNS. The 5-HT1A receptors were the first to be cloned, in human (Fargin et al., 1988) and then in rat (Albert et al., 1990). Owing to the availability of highly selective agonists such as 8-OH-DPAT (Arvidsson et al., 1981, Gozlan et al., 1983, Hall et al., 1985), of antagonists such as WAY-100635 (Laporte et al.,

WAY-100635

The 5-HT1A receptor possesses a high affinity for 5-HT and for many synthetic selective agonists and antagonists, some of which have been successfully used in brain imaging. One of the best known 5-HT1A receptor agonist is aminotetralin, 8-OH-DPAT (Gozlan et al., 1983), which has been extensively used in pharmacological studies (Hamon, 1997) and more recently found to act also as a 5-HT7 agonist (Bonaventure et al., 2002). Other compounds acting on 5-HT1A receptors exhibit more complex

Preclinical studies in vitro

In experiments performed on rat brain homogenates, the tissue distribution of [18F]MPPF in rats was characterized by a high initial uptake in all brain regions followed by a rapid decline of the radioactivity (Shiue et al., 1997, Plénevaux et al., 2000a). Differential washout rates were observed for cortex, striatum, hippocampus, and cerebellum, and disappearance rates were slower in 5-HT1A-rich regions, such as hippocampus in comparison with cerebellum or striatum. Thirty minutes after

Preclinical studies of [18F]MPPF displacement by 5-HT

The classical occupancy model (Seeman et al., 1989) predicts an association between changes in endogenous neurotransmitter levels and changes in in vivo binding parameters of radiotracers. Several studies combining the use of a radiosensitive probe (β-microprobe) and microdialysis in the brain of anesthetized rats have reported modifications in [18F]MPPF binding after pharmacologically induced changes in extracellular 5-HT (Zimmer et al., 2002a, Zimmer et al., 2002b, Zimmer et al., 2003a).

Toward imaging 5-HT1A autoreceptor internalization in human

Brain imaging and measurement of the decrease in [18F]MPPF binding associated with 5-HT1A receptor internalization in NRD at the onset of SSRI treatment could have far reaching implications for future research on depression and its treatment in human. There is considerable evidence from animal studies indicating that a 3–4 week period of treatment is needed to achieve maximal desensitization of 5-HT1A autoreceptors, a return to normal firing and release of 5-HT neurons, and hence the increase

Conclusion

[18F]MPPF is a radiopharmaceutical that is relatively simple to synthesize, making it readily accessible to most PET centres dedicated to research and also to hospitals. Preclinical studies have convincingly shown that the binding of [18F]MPPF reflects the density of 5-HT1A receptors in animal and human brain, but also that it can be modified by extracellular 5-HT levels, internalization of 5-HT1A and the expression of P-glycoproteins. All available evidence support the need to continue

Acknowledgments

The authors are extremely grateful to Prof. Laurent Descarries for his meticulous revision and numerous suggestions. N. Aznavour is recipient of a postdoctoral fellowship from the Swiss National Science Foundation.

References (169)

  • Y. Claustre et al.

    5-HT1A receptor agonists inhibit carbachol-induced stimulation of phosphoinositide turnover in the rat hippocampus

    European Journal of Pharmacology

    (1988)
  • I.A. Cliffe

    A retrospect on the discovery of WAY-100635 and the prospect for improved 5-HT1A receptor PET radioligands

    Nuclear Medicine and Biology

    (2000)
  • A. Coppen et al.

    Potentiation of the antidepressive effect of a monoamine-oxidase inhibitor by tryptophan

    Lancet

    (1963)
  • C. Derry et al.

    Increased serotonin receptor availability in human sleep: evidence from an [18F]MPPF PET study in narcolepsy

    NeuroImage

    (2006)
  • L. Descarries et al.

    Ultrastructural evidence for diffuse transmission by monoamine and acetylcholine neurons of the central nervous system

    Progress in Brain Research

    (2000)
  • S. El Mestikawy et al.

    Production of specific anti-rat 5-HT1A receptor antibodies in rabbits injected with a synthetic peptide

    Neuroscience Letters

    (1990)
  • M.B. Emerit et al.

    Physical evidence of the coupling of solubilized 5-HT1A binding sites with G regulatory proteins

    Biochemical Pharmacology

    (1990)
  • E.A. Forster et al.

    A pharmacological profile of the selective silent 5-HT1A receptor antagonist, WAY-100635

    European Journal of Pharmacology

    (1995)
  • R.A. Glennon

    Serotonin receptors: clinical implications

    Neuroscience and Biobehavioural Reviews

    (1990)
  • H. Gozlan et al.

    The selective 5-HT1A antagonist radioligand [3H]WAY 100635 labels both G-protein-coupled and free 5-HT1A receptors in rat brain membranes

    European Journal of Pharmacology

    (1995)
  • M.A. Harrington et al.

    5-Hydroxytryptamine1A receptors are linked to a Gi-adenylate cyclase complex in rat hippocampus

    European Journal of Pharmacology

    (1988)
  • J.G. Hensler

    Differential regulation of 5-HT1A receptor-G protein interactions in brain following chronic antidepressant administration

    Neuropsychopharmacology

    (2002)
  • F. Héry et al.

    In vivo release of serotonin in two raphe nuclei (raphe dorsalis and magnus) of the cat

    Brain Research Bulletin

    (1982)
  • B.Y. Ho et al.

    The role of conserved aspartate and serine residues in ligand binding and in function of the 5-HT1A receptor: a site-directed mutation study

    FEBS Letters

    (1992)
  • J.P. Hornung

    The human raphe nuclei and the serotonergic system

    The Journal of Chemical Neuroanatomy

    (2003)
  • D. Hoyer et al.

    Serotonin receptors in the human brain. I. Characterization and autoradiographic localization of 5-HT1A recognition sites. Apparent absence of 5-HT1B recognition sites

    Brain

    (1986)
  • D. Hoyer et al.

    Molecular, pharmacological and functional diversity of 5-HT receptors

    Pharmacology, Biochemistry, and Behavior

    (2002)
  • P.H. Hutson et al.

    Hippocampal 5-HT synthesis and release in vivo is decreased by infusion of 8-OHDPAT into the nucleus raphe dorsalis

    Neuroscience Letters

    (1989)
  • L.S. Kegeles et al.

    In vivo imaging of neurotransmitter systems using radiolabeled receptor ligands

    Neuropsychopharmacology

    (1997)
  • G.A. Kennett et al.

    Single administration of 5-HT1A agonists decreases 5-HT1A presynaptic, but not postsynaptic receptor-mediated responses: relationship to antidepressant-like action

    European Journal of Pharmacology

    (1987)
  • H. Kusserow et al.

    Reduced anxiety-related behaviour in transgenic mice overexpressing serotonin 1A receptors

    Brain Research. Molecular Brain Research

    (2004)
  • L. Lanfumey et al.

    Further assessment of the antagonist properties of the novel and selective 5-HT1A receptor ligands (+)-WAY 100 135 and SDZ 216-525

    European Journal of Pharmacology

    (1993)
  • A.M. Laporte et al.

    Selective in vivo labeling of brain 5-HT1A receptors by [3H]WAY 100635 in the mouse

    European Journal of Pharmacology

    (1994)
  • D. Le Bars et al.

    High-yield radiosynthesis and preliminary in vivo evaluation of p-[18F]MPPF, a fluoro analog of WAY-100635

    Nuclear Medicine and Biology

    (1998)
  • E. Le Poul et al.

    Differential adaptation of brain 5-HT1A and 5-HT1B receptors and 5-HT transporter in rats treated chronically with fluoxetine

    Neuropharmacology

    (2000)
  • Y.F. Liu et al.

    Stimulation of cAMP synthesis by Gi-coupled receptors upon ablation of distinct Galphai protein expression. Gi subtype specificity of the 5-HT1A receptor

    Journal of Biological Chemistry

    (1999)
  • C. Luscher et al.

    G protein-coupled inwardly rectifying K+ channels (GIRKs) mediate postsynaptic but not presynaptic transmitter actions in hippocampal neurons

    Neuron

    (1997)
  • M. Marcinkiewicz et al.

    Autoradiographic evidence for the heterogeneity of 5-HT1 sites in the rat brain

    Brain Research

    (1984)
  • R. Andrade et al.

    A G protein couples serotonin and GABAB receptors to the same channels in hippocampus

    Science

    (1986)
  • L.E. Arvidsson et al.

    8-Hydroxy-2-(di-n-propylamino)tetralin, a new centrally acting 5-hydroxytryptamine receptor agonist

    Journal of Medicinal Chemistry

    (1981)
  • M. Beer et al.

    A single dose of 8-OH-DPAT reduces raphe binding of [3H]8-OH-DPAT and increases the effect of raphe stimulation on 5-HT metabolism

    European Journal of Pharmacology

    (1990)
  • P. Blier et al.

    Modification of 5-HT neuron properties by sustained administration of the 5-HT1A agonist gepirone: electrophysiological studies in the rat brain

    Synapse

    (1987)
  • P. Bonaventure et al.

    Reconsideration of 5-hydroxytryptamine (5-HT) (7) receptor distribution using [(3)H]5-carboxamidotryptamine and [(3)H]8-hydroxy-2-(di-n-propylamino)tetraline: analysis in brain of 5-HT (1A) knockout and 5-HT (1A/1B) double-knockout mice

    The Journal of Pharmacology and Experimental Therapeutics

    (2002)
  • M.C. Buhot et al.

    Role of serotonin in memory impairment

    Annals of Medicine

    (2000)
  • P.K. Chanda et al.

    Identification of residues important for ligand binding to the human 5-hydroxytryptamine1A serotonin receptor

    Molecular Pharmacology

    (1993)
  • Y. Chaput et al.

    Effects of the 5-hydroxytryptamine receptor antagonist, BMY 7378, on 5-hydroxytryptamine neurotransmission: electrophysiological studies in the rat central nervous system

    The Journal of Pharmacology and Experimental Therapeutics

    (1988)
  • A. Charest et al.

    Cloning and differentiation-induced expression of a murine serotonin1A receptor in a septal cell line

    The Journal of Neuroscience

    (1993)
  • A. Chattopadhyay et al.

    Solubilization of serotonin1A receptors heterologously expressed in Chinese hamster ovary cells

    Cellular and Molecular Neurobiology

    (2004)
  • D.C. Chugani

    Serotonin in autism and pediatric epilepsies

    Mental Retardation and Developmental Disabilities Research Reviews

    (2004)
  • W.P. Clarke et al.

    Lack of 5-hydroxytryptamine1A-mediated inhibition of adenylyl cyclase in dorsal raphe of male and female rats

    The Journal of Pharmacology and Experimental Therapeutics

    (1996)
  • Cited by (75)

    • Constitutive activity of 5-HT receptors: Factual analysis

      2020, Neuropharmacology
      Citation Excerpt :

      5-HT1AR is a seven-transmembrane receptor. It is mainly expressed in limbic and cortical regions of mammalian brain (Aznavour and Zimmer, 2007; Ginovart et al., 2000; Hamon et al., 1990; Kumar et al., 2013; Laporte et al., 1994; Miquel et al., 1992; Vidal et al., 2016). It is also expressed at the level of 5-HT cell bodies in midbrain raphe nuclei (Miquel et al., 1992; Riad et al., 2000).

    • Molecular neuroimaging of the serotonergic system with Positron Emission Tomography

      2020, Handbook of Behavioral Neuroscience
      Citation Excerpt :

      Moreover, [18F]MPPF, [18F]4-(2-Methoxyphenyl)-1-[2-(N-2-pyridinyl)-p-fluorobenzamido)-ethyl]piperazine, another reversible antagonist 5-HT1A tracer (KD = 0.3 nM) with the structural skeleton of WAY100635, has been demonstrated to possess low nonspecific binding and good correlation to binding patterns obtained from postmortem human brain studies (Passchier et al., 2000). A large number of animal and human studies (Aznavour & Zimmer, 2007), a normative database in men and women with age-related binding variables (Costes et al., 2005), and reliable test–retest data (Costes et al., 2007) validated the use of [18F]MPPF in molecular imaging of the 5-HT1A receptor. A major advantage of [18F]MPPF is that it can be produced in a simple one-step procedure giving high yield (Le Bars et al., 1998).

    View all citing articles on Scopus
    View full text