Review[18F]MPPF as a tool for the in vivo imaging of 5-HT1A receptors in animal and human brain
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.
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2020, Handbook of Behavioral NeuroscienceCitation 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).
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