[en] Several studies have demonstrated the potential of p-[F-18]MPPF as a radiophanilaceutical to study the 5-HT1A receptor family in animals and humans. A structural modification leading to a higher radioactive signal at an equipotent dose would greatly enhance this potential. With this goal, the desmethylated 4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p-fluorobenzamidolethyl]-piperazine (p-MPPF), identified as p-DMPPF, was synthesized, labeled with fluorine-18 and evaluated through ex vivo tissue distribution in rats. The new compounds p-DMPPF, p-DMPPNO2, MEM-p-MPPF and MEM-p-MPPNO2 were isolated and fully identified (H-1 and C-13 NMR, LC-MS). The final compound, p-[F-18]DMPPF, was obtained ready for injection, with an overall radiochemical yield of 10% (EOB corrected) within 90 min and a specific activity of 62 GBq/mu mol. Tissue distributions showed that the carbon-fluorine bond was stable in vivo and that this compound could cross the blood-brain barrier. For kidney, lung, heart, spleen, bone, testicle, liver and muscle, the percentage of injected dose per gram of tissue obtained with p-[F-18]DMPPF was of the same order of magnitude as that of p-[F-18]MPPF. The amount of radioactivity reaching the brain was much higher (approximately fivefold at 60 min) for p-[F-18]DMPPF compared with p-[F-18]MPPF, which was taken as reference. The distribution and specificity were in total agreement with the known localization of 5-HT1A receptors in rats. The radioactivity increase was more important for specific tissues (hippocampus and frontal cortex) than for cerebellum or striatum, leading to better contrast (hippocampus/cerebellum=5.8 at 60 min). The levels of metabolites found in plasma showed that p-[F-18]DMPPF appears to be less metabolized than p-[F-18]MPPF. p-[F-18]DMPPF deserves further evaluation as a radiopharmaceutical candidate. (c) 2006 Elsevier Inc. All rights reserved.
Research center :
GIGA CRC (Cyclotron Research Center) In vivo Imaging-Aging & Memory - ULiège
Disciplines :
Radiology, nuclear medicine & imaging
Author, co-author :
Defraiteur, Caroline
Lemaire, Christian ; Université de Liège - ULiège > Centre de recherches du cyclotron
Luxen, André ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie organique de synthèse - Centre de recherches du cyclotron
Plenevaux, Alain ; Université de Liège - ULiège > Centre de recherches du cyclotron
Language :
English
Title :
Radiochemical synthesis and tissue distribution of p-[F-18]DMPPF, a new 5-HT1A ligand for PET, in rats
Publication date :
July 2006
Journal title :
Nuclear Medicine and Biology
ISSN :
0969-8051
Publisher :
Elsevier Science Inc, New York, United States - New York
Kung H.F., Stevenson D.A., Zhuang Z.-P., Kung M.-P., Frederick D., and Hurt S.D. New 5-HT1A receptor antagonist: p-[3H]MPPF. Synapse 23 (1996) 344-346
Plenevaux A., Weissmann D., Aerts J., Lemaire C., Brihaye C., Degueldre C., et al. Tissue distribution, autoradiography and metabolism of 4-(2′-methoxyphenyl)-1-[N-(2″-pyridinyl)-p-[18F]fluorobenzamido]ethyl]piperazine (p-[18F]MPPF), a new serotonin 5-HT1A antagonist for positron emission tomography: an in vivo study in rats. J Neurochem 75 (2000) 803-811
Zhuang Z.-P., Kung M.-P., and 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
Van Wijngaarden I., Tulp M., and Soudijn W. The concept of selectivity in 5-HT receptor research. Eur J Pharmacol 188 (1990) 301-312
Zimmer L., Mauger G., Le Bars D., Bonmarchand G., Luxen A., and Pujol J.-F. Effect of endogenous serotonin on the binding of the 5-HT1A PET ligand [18F]MPPF in the rat hippocampus: kinetic β measurements combined with microdialysis. J Neurochem 80 (2002) 278-286
Zimmer L., Rbah L., Giacomelli F., Le Bars D., and Renaud B. A reduced extracellular serotonin level increases the 5-HT1A PET ligand [18F]MPPF binding in the rat hippocampus. J Nucl Med 44 (2003) 1495-1501
Passchier J., Van Waarde A., Pieterman R.M., Elsinga P.H., Hendrikse H.N., Pruim J., et al. Delineation of serotonin 5-HT1A receptors in human brain with [18F]MPPF. J Nucl Med 40 (1999) 29P
Plenevaux A., Lemaire C., Salmon E., Laureys S., Fuchs S., Maquet P., et al. 5-HT1A receptors visualization with p-[18F]MPPF in healthy volunteers. J Label Compd Radiopharm 42 (1999) S60-S62
Passchier J., Van Waarde A., Pieterman R.M., Elsinga P.H., Pruim J., Hendrikse H.N., et al. In vivo delineation of 5-HT1A receptors in human brain with [18F]MPPF. J Nucl Med 41 (2000) 1830-1835
Passchier J., Van Waarde A., Vaalburg W., and Willemsen A.T. On the quantification of [18F]MPPF binding to 5-HT1A receptors in human brain. J Nucl Med 42 (2001) 1025-1031
Costes N., Merlet I., Zimmer L., Lavenne F., Cinotti L., Delforge J., et al. Modelling [18F]MPPF positron emission tomography kinetics for the determination of 5-hydroxytryptamine(1A) receptor concentration with multiinjection. J Cereb Blood Flow Metab 22 (2002) 753-765
Sanabria-Bohorquez S.M., Biver F., Damhaut P., Wikler D., Veraart C., and Goldman S. Quantification of 5-HT1A receptors in human brain using p-MPPF kinetic modelling and PET. Eur J Nucl Med Mol Imaging 29 (2002) 76-81
Merlet I., Ostrowsky K., Costes N., Ryvlin P., Isnard J., Faillenot I., et al. 5-HT1A receptor binding and intracerebral activity in temporal lobe epilepsy: an [18F]MPPF-PET study. Brain 127 (2004) 900-913
Praschak-Reider N., Hussey D., Wilson A.A., Carella A., Lee M., Dunn E., et al. Tryptophan depletion and serotonin loss in selective serotonin reuptake inhibitor-treated depression: an [18F]MPPF positron emission tomography study. Biol Psychiatry 56 (2004) 587-591
Mathis C., Simpson N., Mahmood K., Kinahan P., and Mintun M. [11C]WAY100635: a radioligand for imaging 5-HT1A receptors with positron emission tomography. Life Sci 55 (1994) 403-407
Pike V.W., Halldin C., McCarron J.A., Lundkvist C., Hirani E., Olsson H., et al. [carbonyl-11C]Desmethyl-WAY100635 (DWAY) is a potent and selective radioligand for central 5-HT1A receptors in vitro and in vivo. Eur J Nucl Med Mol Imaging 25 (1998) 338-346
Andrée B., Halldin C., Pike V.W., Gunn R.N., Olsson H., and Farde L. The PET radioligand [carbonyl-11C]desmethyl-WAY100635 binds to 5-HT1A receptors and provides a higher radioactive signal than [carbonyl-11C]WAY100635 in the human brain. J Nucl Med 43 (2002) 292-303
Crouzel C., Clark J.C., Brihaye C., Langström B., Lemaire C., Meyer G.J., et al. Radiochemistry automation for PET. In: Stöcklin G., and Pike V.W. (Eds). Radiopharmaceuticals for positron emission tomography. Methodological aspects (1993), Kluwer Academic Publishers, Dordrecht 45-79
Le Bars D., Lemaire C., Ginovart N., Plenevaux A., Aerts J., Brihaye C., et al. High yield radiosynthesis and preliminary in vivo evaluation of p-[18F]MPPF, a fluoro analog of WAY-100635. Nucl Med Biol 25 (1998) 343-350
Corey E., Gras J.-L., and Ulrich P. A new general method for protection of the hydroxyl function. Tetrahedron Lett 17 (1976) 809-812
Lemaire C., Damhaut P., Lauricella B., Mosdzianowski C., Morelle J.-L., Monclus M., et al. Fast [18F]FDG synthesis by alkaline hydrolysis on a low polarity phase support. J Label Compd Radiopharm 45 (2002) 435-447
Lemaire C., Gillet S., Guillouet S., Plenevaux A., Aerts J., and Luxen A. Highly enantioselective synthesis of no-carrier-added 6-[18F]fluoro-L-dopa by chiral phase-transfer alkylation. Eur J Org Chem (2004) 2899-2904
MacLean M.R., Clayton R.A., Templeton A.G., and Morecroft I. Evidence for 5-HT1-like-receptor-mediated vasoconstriction in human pulmonary artery. Br J Pharmacol 119 (1996) 277-282
Cattaneo M.G., Fesce R., and Vicentini L.M. Mitogenic effect of serotonin in human cell lung carcinoma cells via both 5-HT1A and 5-HT1D receptors. Eur J Pharmacol 291 (1995) 209-211
Kia H.K., Miquel M.C., Brisorgueil M.J., Daval G., Riad M., el Mestikawy S., et al. Immunocytochemical localization of serotonin 1A receptors in the rat central nervous system. J Comp Neurol 365 (1996) 289-305
Hamon M., Lanfumey L., el Mestikawy S., Boni C., Miquel M.C., Bolanos F., et al. The main features of central 5-HT1 receptors. Neuropsychopharmacology 3 (1990) 349-360
Khawaja X. Quantitative autoradiographic characterisation of the binding of [3H]WAY-100635, a selective 5-HT1A receptor antagonist. Brain Res 673 (1995) 217-225
Vergé D., Daval G., Marcinkiewicz M., Patey A., el Mestikawy S., Gozlan H., et al. Quantitative autoradiography of multiple 5-HT1 receptor subtypes in brain of control or 5,7-dihydroxytryptamine-treated rats. J Neurosci 6 (1986) 3474-3482
Dishino D., Welch M., Kilbourn M., and Raichle M. Relationship between lipophilicity and brain extraction of 11C-labeled radiopharmaceuticals. J Nucl Med (1983) 1030-1038
Eckelman W. Sensitivity of new radiopharmaceuticals. Nucl Med Biol 25 (1998) 169-173
Habgood M., Begley D., and Abbott N. Determinants of passive drug entry into the central nervous system. Cell Mol Neurobiol 20 (2000) 231-253
Schinkel A.H. P-Glycoprotein, a gatekeeper in the blood-brain barrier. Adv Drug Deliv Rev 36 (1999) 179-194
Naito M., and Tsuruo T. Role of P-glycoprotein in the blood-brain barrier. In: Gupta S., and Tsuruo T. (Eds). Multidrug resistance in cancer cells (1996), John Willey and Sons, Chichester 321-333
Tsuji A., and Tamai I. Blood-brain barrier function of P-glycoprotein. Adv Drug Deliv Rev 25 (1997) 287-298
Plenevaux A., Lacan G., Defraiteur C., Gillet S., Way B., Rubins D., et al. Influence of P-glycoprotein on the tissue distribution in rats of the 5-HT1A antagonist p-[18F]MPPF. Society for Neuroscience 32nd annual meeting. Orlando FL (2002)
Passchier J., Van Waarde A., Doze P., Elsinga P.H., and Vaalburg W. Influence of P-glycoprotein on brain uptake of [18F]MPPF in rats. Eur J Pharmacol 407 (2000) 273-280