[en] No-carrier-added 4-[18F]fluoro-N-[2-[1-(2-methoxyphenyl)-1 piperazinyl]ethyl-N-2-pyridinyl-benzamide (p-[18F]MPPF) was synthesized by nucleophilic substitution of the corresponding nitro compound in the presence of Kryptofix 222 and K2CO3 by microwave heating (3 min, 500 W) using a remotely controlled radiosynthesis. Baseline separation of p-[18F]MPPF from the nitro derivative was performed on a semipreparative HPLC C18 column. After Sep-Pak formulation, the radiopharmaceutical was obtained with a radiochemical yield of 25% (EOS) in about 70 min. Specific radioactivity averaged between 1-5 Ci/micromol EOS. Labelling of the ortho and meta derivatives was also attempted. Brain uptake of p-[18F]MPPF was studied with PET on fluothane-anesthetized cats. Following intravenous injection of p-[18F]MPPF, high accumulation of radioactivity was observed in the hippocampus and cerebral cortex. Low levels of radioactivity were observed in cerebellum. At 30 min, the mean hippocampus/cerebellum and cortex/cerebellum ratios were 5 and 3.8, respectively. The accumulation of the tracer was blocked by prior administration of reference WAY-100635, demonstrating the specificity of the ligand.
Research center :
GIGA CRC (Cyclotron Research Center) In vivo Imaging-Aging & Memory - ULiège CERMEP Lyon
Disciplines :
Radiology, nuclear medicine & imaging
Author, co-author :
Le Bars, Didier; Centre d'Exploration et de Recherche Médicales par Émission de Positons - CERMEP (Lyon)
Lemaire, Christian ; Université de Liège - ULiège > Centre de recherches du cyclotron
Ginovart, N.
Plenevaux, Alain ; Université de Liège - ULiège > Centre de recherches du cyclotron
Aerts, Joël ; Université de Liège - ULiège > Centre de recherches du cyclotron
Brihaye, C.
Hassoun, W.
Leviel, V.
Mekhsian, P.
Weissmann, D.
Pujol, J. F.
Luxen, André ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie organique de synthèse - Centre de recherches du cyclotron
Brihaye C., Lemaire C. and Luxen A. (1995, October) Robot-assisted synthesis of radiopharmaceuticals labeled with high activity positron emitters. Proceedings ISLAR 95 (International Symposium on Laboratory Automation and Robotics). Plaza Hotel, Boston, MA.
Cowen P. J. The effect of tryptophan on brain 5-HT function - a review. Hum. Psychopharmacol. Clin. Exp. 9:1994;371-376.
Fletcher A., Cliffe I. A., Dourish C. T. Silent 5-HT1A receptor antagonist Utility as research tools and therapeutic agents . Trends Pharmacol. Sci. 14:1993;441-448.
Fletcher A., Bill D. J., Cliffe I. A., Forster E. A., Reilly Y. A pharmacological profile of WAY-100635, a potent and highly selective 5-HT1A antagonist. Br. J. Pharmacol. 112:1994;91P.
Glenon R. A., Maiman N. A., Lyon R. A., Titeler M. Arylpiperazine derivatives as high affinity 5-HT1A serotonin ligands. J. Med. Chem. 31:1988;1968-1971.
Gozlan H., El Mestikaway S., Pichat L., Glowinski J., Hamon M. Identification of pre-synaptic serotonin autoreceptors using a new ligand, 3H-PAT. Nature. 305:1983;140-141.
Hume S. P., Ashworth S., Opacka-Juffry J., Ahier R. G., Lamertsmaa A. A., Pike V. W., et al. Evaluation of [O-methyl-3H]WAY-100635 as an in vivo radioligand for 5-HT1A receptors in rat brains. Eur. J. Pharmacol. 271:1994;515-523.
Humpfrey P. P. A., Hartig P., Hoyer D. A proposed new nomenclature for 5-HT receptors. Trends Pharmacol. Sci. 14:1993;223-236.
Kuipers W., Vanwijngaarden I., Kruse C. G., Ter-Horst-van Amstel M., Tulp H. T. M., Ijzerman A. P. N-4 unsubstituted N-1 arylpiperazine as high affinity 5-HT1A receptor ligand. J. Med. Chem. 38:1995;1942-1954.
Kuipers W., Kruse C. G., Van Wijngaarden I., Standaar P. J., Tulp M. T. M., Veldman N., et al. 5-HT1A-versus D2-receptor selectivity of flesinoxan and analogous N4-Substituted N1-arylpiperazines. J. Med. Chem. 40:1997;300-312.
Kung M., Zhuang Z., Frederic D., Kung H. F. In vivo binding of [123I] 4-(2′-methoxyphenyl)-1-[2′-[N-2″-pyridinyl]-p-iodobenzamido]- ethyl piperazine p-MPPI to 5-HT1A receptors in rat brain. Synapse. 18:1994;359-366.
Kung H. F., Frederick D., Kim H. J., McElgin W., Kung M-P., Mu M., et al. In vivo SPECT imaging of 5HT1A receptors with [123I]p-MPPI in nonhuman primates. Synapse. 24:1996;273-281.
Lemaire C., Guillaume M., Cantineau R., Christiaens L. No-carrier-added regioselective preparation of 6-[18F]fluoro-L-dopa. J. Nucl. Med. 31:1990;1247-1251.
Lemaire C., Cantineau R., Guillaume M., Plenevaux A., Christiaens L. Fluorine-18-altanserin A radioligand for the study of serotonin receptors with PET: Radiolabeling and in vivo biologic behavior in rats . J. Nucl. Med. 32:1991;2266-2272.
Lemaire C., Plenevaux A., Del Fiore G., Aerts J., Luxen A., Le Bars D., et al. Sep-Pak as alternative to rotary evaporators for radiopharmaceutical formulation. J. Label. Compd. Radiopharm. 37:1995;723-725.
McCarron J. A., Turton D. R., Pike V. W., Poole K. G. Remotely controlled production of the 5HT1A receptor radioligand [carbonyl-11C]WAY-100635, via 11C-carboxylation of an immobilized grignard reagent. J. Label. Compd. Radiopharm. 38:1996;941-953.
Mathis C. A., Simpson N. R., Mahmoud K., Kinahan P. E., Mintun M. A. [11C]WAY-100635 A radioligand for imaging 5HT1A receptors with positron emission tomography . Life Sci. 55:1994;403-407.
Middlemiss D., Fozard J. R. 8-Hydroxy-2-(di-n-propylamino)-tetralin discriminates between subtypes of the 5-HT1 recognition site. Eur. J. Pharmacol. 90:1983;151-153.
Modica M., Santagati M., Russo F., Parotti L., De Gioia L., Selvaggini C., et al. [[(Arylpiperazinyl)alkyl]thio]thieno[2,3-d]pyrimidinone derivatives as high-affinity, selective 5HT1A receptor ligands. J. Med. Chem. 40:1997;574-585.
Mokrosz J. L., Paluchowska M. H., Chojnacka-Wojcik E., Filip M., Chavakchieva-Minol S., DerenWerolk A., et al. Structure activity relationship studies of central nervous system agents 13. 4-[3-(benzotriazol-1-yl)propyl]-1-(2-methoxy)piperazine, a new putative 5-HT1A receptor antagonist, and its analogues . J. Med. Chem. 37:1994;2754-2760.
Osman S., Lundkvist C., Pike V. W., Halldin C., McCarron J., Swahn C. G., et al. Characterization of the radioactive metabolites of the 5-HT1A receptors radioligand [O-methyl-11C]WAY-100635 in monkey and human plasma by HPLC Comparison of the behaviour of an identified radioactive metabolite with parent radioligand in monkey using PET . Nucl. Med. Biol. 23:1996;627-634.
Palacios J. M., Pazos A. and Hoyer D. (1987) In: Brain 5HT1A Receptors (Edited by Dourish C. T., Ahlenius S., and Hutson P. H.), pp. 67-81. Ellis Horwood: Chichester, UK.
Pike V. W., McCarron J., Hume S. P., Ashworth S., Opacka-Juffry J., Osman S., et al. Preclinical development of a radioligand for studies of central 5-HT1A receptors in vivo-[11C]WAY-100635. Med. Chem. Res. 5:1994;208-227.
Pike V. W., McCarron J., Lamertsmaa A. A., Osman S., Hume S. P., Sargent P., et al. Exquisite delineation of 5-HT1A receptors in human brain with PET and · carbonyl-11C]WAY-100635. Eur. J. Pharmacol. 301:1996;R5-R7.
Peroutka S. J. Serotonin receptors subtypes Their evolution and clinical relevance . CNS Drugs. 4:(suppl.1):1995;18-28.
Plenevaux A., Lemaire C., Aerts J., Del Fiore G., Luxen A. Fast quality control of short-lived radiopharmaceutical compounds with a photodiode array detector. J. Label. Compd. Radiopharm. 37:1995;695-696.
Plenevaux A., Aerts J., Lemaire C., Brihaye C., Le Bars D., Mekhsian P., et al. Evaluation of p-[18F]MPPF, 5HT1A antagonist in rats Tissue distribution, autoradiography and metabolism . J. Nucl. Med. 5S:1997;56P.
Russo F., Romeo G., Guccione S., De Blasi A. Pyrimido [5,4-b]indole derivatives 1. A new class of potent and selective α1 adrenoreceptor ligands . J. Med. Chem. 34:1991;1850-1854.
Saudou F., Hen R. 5-Hydroxytryptamine receptor subtypes in vertebrates and invertebrates. Neurochem. Int. 25:1994;503-532.
Schiue C. Y., Schiue G. G., Zhuang Z., Kung M., Kung H. F. Synthesis of no-carrier-added 4-(2′-methoxyphenyl)-1-[2′-[N-2″-pyridinyl]-p[ 18F]fluorobenza mido]-ethyl piperazine 2b as a potential 5-HT1A receptor ligand for PET studies. J. Nucl. Med. 5S:1995;252P.
Schiue C. Y., Schiue G. G., Mozley P. D., Kung M., Zhuang Z., Kim H. J., et al. p-[18F]MPPF A potential radioligand for PET studies of 5-HT1A receptor in humans . Synapse. 25:1997;147-154.
Schmall B., Lang L., Jagoda E., Channing M., Sassaman M., Eckelman W. C. Antagonists for 5HT1A and 5HT2a receptors. J. Nucl. Med. 5S:1996;204P.
Wilson A. A., Da Silva J. N., Houle S. [18F]Fluoroalkyl analogues of the potent 5-HT1A antagonist WAY-100635 Radiosynthesis and in vivo evaluation . Nucl. Med. Biol. 23:1996;487-490.
Zhuang Z., Kung M., Kung H. F. 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. 37:1994;1406-1407.