[en] 4,2'-(Methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-fluorobenzamido]ethylpiperazine (F-18-MPPF) is a radiotracer used in clinical PET studies for the visualization of serotonin-1A (5-HT1A) receptors. In a previous study, we demonstrated that a rapid enhancement of extracellular serotonin concentrations influences F-18-MPPF-specific binding. Because endogenous serotonin is significantly decreased in some pathologies, the aim of this study was to determine whether F-18-MPPF is sensitive to depletion of this neurotransmitter. Methods: Using the beta-microprobe, an original beta(+)-sensitive intracerebral probe, and micro-dialysis, the effect of decreased serotonin on the specific binding of F-18-MPPF to 5-HT1A receptors was investigated in the hippocampus of the anesthetized rat. Extracellular serotonin was pharmacologically decreased in the hippocampus after a single injection of p-ethynylphenylalanine ([p-EPA] 5 mg/kg), a new tryptophan hydroxylase inhibitor. Results: Our results showed that the F-18-MPPF-specific binding was significantly enhanced after the decrease of extracellular serotonin. These results were confirmed by the F-18-MPPF distribution in cerebral tissues (hippocampus-to-cerebellum ratio) and by the decrease of the extracellular F-18-MPPF collected in hippocampal dialysates. Conclusion: This study further supports the view that 18F-MPPF binding potential is increased in the hippocampus if the endogenous serotonin is pharmacologically decreased after a p-EPA injection. This phenomenon will be an additional factor in the interpretation of the results from F-18-MPPF clinical PET studies.
Research Center/Unit :
GIGA CRC (Cyclotron Research Center) In vivo Imaging-Aging & Memory - ULiège
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Zimmer, L.; CERMEP
Rbah, L.
Giacomelli, Fabrice ; Université de Liège - ULiège > Centre de recherches du cyclotron
Le Bars, D.; CERMEP
Renaud, B.
Language :
English
Title :
A reduced extracellular serotonin level increases the 5-HT1A PET ligand F-18-MPPF binding in the rat hippocampus
Publication date :
September 2003
Journal title :
Journal of Nuclear Medicine
ISSN :
0161-5505
eISSN :
1535-5667
Publisher :
Society of Nuclear Medicine, Reston, United States - Virginia
Kostowski W, Plaznik A, Archer T. Possible implication of 5-HT 1A function for the etiology and treatment of depression. New Trends Exp Clin Psychiatry. 1989;5:91-116
Saxena PR. Serotonin receptors: subtypes, functional responses and therapeutic relevance. Pharmacol Ther. 1995;66:339-368.
Pike V, Halldin C, Wikström H Radioligands for the study of brain 5-HT1A receptors in vivo. In: King FD, Oxford AW, eds. Progress in Medicinal Chemistry. Amsterdam. The Netherlands: Elsevier Science, 2001:189-247.
Shiue CY, Shiue GG, Mozley PD, et al. P-18F-MPPF: a potential radioligand for PET studies of 5-HT1A receptors in humans. Synapse 1997;25:147-154.
Ginovart N, Hassoun W, Le Bars D, Weissmann D, Leviel V. in vivo characterization of p-18F-MPPF, a flouro analog of WAY-100635 for visualization of 5-HT1A receptors. Synapse. 2000;35:192-200.
Le Bars D, Lemaire C, Ginovart N, et al. High-yield radiosynthesis and preliminary in vivo evaluation of p-18F-MPPF, a fluoro analog of WAY-100635. Nucl Med Biol. 1998;25:343-350.
Plenevaux A, Weissmann D, Aerts J, et al. Tissue distribution, autoradiography, and metabolism of 4-(2′-methoxyphenyl)-1-[2′-[N- 2″-pyridinyl)-p-18F-fluorobenzamido]ethyl]piperazine p- 18F-MPPF), anew serotonin 5-HT1A antagonist for positron emission tomography: an in vivo study in rats. J Neurochem. 2000;75: 803-811.
Plenevaux A, Lemairc C, Aerts J, et al [18F]p-MPPF a radiolabelled antagonist for the study of 5-HT1A receptors with PET. Nucl Med Biol. 2000;27:467-471.
Zimmer L, Mauger G, Le Bars D, Bonmarchand G, Luxen A, Pujol JF. Effect of endogenous serotonin on the binding of the 5-HT1A PET ligand 18F-MPPF in the rat hippocampus: kinetic beta measurements combined with microdialysis J Neurochem. 2002;80:278-286
Curzon G. Serotonergic mechanisms of depression Clin Neuropharmacol. 1988; 11(suppl 2):S11-S20.
Stockmeier CA, Shapiro LA, Dilley GE, Kolli TN, Friedman L, Rajkowska G. Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression: postmortem evidence for decreased serotonin activity. J Neurosci 1998;18:7394-7401.
Udo de Haes JI, Bosker FJ, Van Waarde A, et al. 5-HT1A receptor imaging in the human brain: effect of tryptophan depletion and infusion on [18F]MPPF binding. Synapse. 2002;46:108-115.
Zimmer L, Luxen A, Giacomelli F, Pujol JF. Short and long-term effects of p-ethynylphenylalanine on brain serotonin levels. Neurochem Res 2002;27:269-275.
Kayser B, Altman J, Beck W. Alkyne bridged alpha-amino acids by palladium mediated coupling of alkynes with N-t-Boc-4-iodophenylalanine methyl ester. Tetrahedron. 1997;53:2475-2484.
Le Bars D, Bonmarchand G, Alvarez JM, Lemaire C, Mosdzianowski C. New automation of 18F-MPPF using a coincidence synthesizer [abstract] J Labelled Compds Radiopharm. 2001;44(suppl):S1045.
Paxinos G, Watson C The Rat Brain in Stereotaxic Coordinates New York, NY: Academic Press; 1986:24-38.
Zimmer L, Hassoun W, Pain F, et al SIC, an intracerebral β+-range-sensitive probe for radiopharmacology investigations in small laboratory animals: binding studies with 11C-raclopride. J Nucl Med. 2002;43:227-233.
Benveniste H. Brain microdialybis J Neurochem 1989;52:1667-1679
Passchier J, van Waarde A, Pieterman RM, et al In vivo delineation of 5-HT1A receptors in human brain with 18F-MPPF J Nucl Med. 2000;41:1830-1835.
Passchier J, van Waarde A, Pieterman RM, et al. Quantitative imaging of 5-HT1A receptor binding in healthy volunteers with 18F-p-MPPF. Nucl Med Biol. 2000; 27:473-476.
Passchier J, van Waarde A, Vaalburg W, Willemsen AT. On the quantification of [18F]MPPF binding to 5-HT1A receptors in the human brain. J Nucl Med 2001; 42:1025-1031.
Costes N, Merlet I, Zimmer L, et al Modeling 18F-MPPF positron emission tomography kinetics for the determination of 5-hydroxytryptamine(1A) receptor concentration with multiinjection. J Cereb Blood Flow Metab. 2002;22:753-765.
Stokes AH, Xu Y, Daunais JA, et al. p-Ethynylphenylalanine: a potent inhibitor of tryptophan hydroxylase J Neurochem. 2000;74:2067-2073.
Datla KP, Curzon G. Effect of p-chlorophenylalanine at moderate dosage on 5-HT and 5-HIAA concentrations in brain regions of control and p-chloroamphetamine treated rats. Neuropharmacology. 1996;35:315-320.
Harro J, Tonissaar M, Eller M, Kask A, Oreland L Chronic variable stress and partial 5-HT denervation by parachloroamphetamine treatment in the rat: effects on behavior and monoamine neurochemistry. Brain Res. 2001;899:227-239.
Zimmer L, Pain F, Mauger G, et al. The potential of the Beta-Microprobe, an intracerebral radiosensitive probe, to monitor the 18F-MPPF binding in the rat dorsal raphe nucleus. Eur J Nucl Med. 2002;29:1237-1247.
Gunn RN, Sargent PA, Bench CJ, et al. Tracer kinetic modeling of the 5-HT1A receptor ligand [carbonyl-11C]WAY-100635 for PET Neuroimage. 1998;8:426-440.
Rice OV, Gatley SJ, Shen J, et al. Effects of endogenous neurotransmitters on the in vivo binding of dopamine and 5-HT radiotracers in mice. Neuropsychophar-macology. 2001;25:679-689.
Maeda J, Suhara T, Ogawa M, et al. In vivo binding properties of [carbonyl-11C]WAY-100635: effect of endogenous serotonin. Synapse. 2001;40:122-129.
Seeman P, Guan HC, Niznik HB. Endogenous dopamine lowers the dopamine D2 receptor density as measured by 3H-raclopride: implications for positron emission tomography of the human brain. Synapse. 1989;3:96-97.
Zhuang ZP, Rung MP, Kung HF Synthesis and evaluation of 4-(2′-methoxyphenyl)-1-[2′-[N-(2″-pyridinyl)-p-iodobenzamido] ethyl]piperazine (p-MPPI): a new iodinated 5-HT1A ligand. J Med Chem. 1994;37:1406-1407
van Wijngaarden I, Tulp MT, Soudijn W The concept of selectivity in 5-HT receptor research Eur J Pharmacol. 1990;188:301-312
Mathis C, Simpson N, Price J, Mahmood K, Bowman K, Mintun M. Evaluation of [C-11]WAY 100635: a potent serotonin 5-HT1A receptor antagonist [abstract]. J Nucl Med. 1995;36(suppl):162P
Parsey RV, Hwang DR, Simpson N, et al. PET studies of competition between [11C]carbony-WAY 100635 and endogenous serotonin [abstract]. J Nucl Med. 2001;40(suppl):29P
Hume S, Hirani E, Opacka-Juffry J, et al. Effect of 5-HT on binding of 11C-WAY 100635 to 5-HT1A receptors in rat brain, assessed using in vivo microdialysis and PET after fenfluramine. Synapse. 2001;41:150-159
Laruelle M Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J Cereb Blood Flow Metab 2000;20:423-451.