Abstract
NNC 12-0722 (1-[2-(bis(4-fluorophenyl)methoxy)ethyl]-4-methyl piperazine) is a new selective inhibitor of the dopamine transporter. [11C]NNC 12-0722 was prepared by N-methylation of the desmethyl compound with [11C]methyl iodide. The total radiochemical yield of [11C]NNC 12-0722 was 40%–50% with an overall synthesis time of 30–35 min. The radiochemical purity was higher than 99% and the specific radioactivity about 1500 Ci/mmol (55 GBq/μmol). Autoradiographic examination of [11C]NNC 12-0722 binding on whole hemisphere cryosections from human brain post mortem demonstrated specific binding in the caudate nucleus and putamen. In a positron emission tomographic examination of [11C]NNC 12-0722 in a cynomolgus monkey there was a rapid uptake of radioactivity in the brain. In the striatum, a region with a high density of dopamine transporters, the radioactivity was two times higher than in the cerebellum. These results indicate that [11C]NNC 12-0722 may be a useful radioligand for labelling of the dopamine transporter in man.
Similar content being viewed by others
References
Kuhar MJ, Sanchez-Roa PM, Wong DF, Dannals RE Grigoriadis DE, Lew R, Milberger M. Dopamine transporter: biochemistry. pharmacology and imaging. Eur Neurol 1990; 30: 15–20
Carlsson A. Does dopamine have a role in schizophrenia? Biol Psychiatry 1978; 13: 3–21
van der Zee P, Koger HS, Gootjes J, Hespe N. Aryl 1,4-dialk(en)-ylpiperazines as selective and very potent inhibitors of dopamine uptake. Eur J Med Chem 1980; 15: 363–370
Andersen PH. The dopamine uptake inhibitor GBR 12909: selectivity and molecular mechanism of action. Eur J Pharmacol 1989; 166: 493–504
Andersen PH, Jansen JA, Nielsen EB. [3H]GBR 12935 binding in vivo in mouse brain: labelling of a piperazine acceptor site. Eur J Pharmacol 1987; 144: 1–6
Marcusson J, Eriksson K. [3H]GBR 12935 binding to dopamine uptake sites in the human brain. Brain Res 1988; 457:122–129
Berger P, Janowsky A, Vocci F, Skolnick P, Schweri M, Paul S. [3H]GBR 12935: a specific high affinity ligand for labeling the dopamine transport complex. Eur J Pharmacol 1985; 107: 289–290
Kilbourn MR, Carey JE, Koeppe RE, Haka MS, Hutchins GD, Sherman PS, Kuhl DE. Biodistribution, dosimetry, metabolism and monkey PET studies of [18F]GBR 13119. Imaging the dopamine uptake system in vivo. Nucl Med Biol 1989; 16: 569–576
Müller L, Foged C, Halldin C, Hall H, Hohlweg R, Farde L. Preparation of [C-11]NNC 12–0722, a potential radioligand for the dopamine uptake system [abstract]. J Nucl Med Biol 1992; 33: 931
Halldin C, Farde L, Högberg T, Hall H, Sedvall G. Carbon-11 labelling of eticlopride in two different positions — a selective high affinity ligand for the study of dopamine D-2 receptors using PET. Appl Radiat Isot 1990; 41: 669–674
Landa ME, Sanchez-Roa PM, Jaim-Etcheverry G. The neurotoxic compound DSP depletes endogenous norepinephrine and enhances the release of [3H]-norepinephrine from rat cortical slice. J Pharmacol Exp Ther 1984; 231: 131
Cohen ML, Wiley KS. Neuronal uptake inhibitors, nisoxetine and fluoxetine on rat vascular concentrations. Eur J Pharmacol 1977; 44:219–229
Hall H, Farde L, Sedvall G. Human dopamine receptor subtypes in vitro binding analysis using 3H-SCH 23390 and 3H-raclopride. J Neural Transm 1988; 73: 7–21
Persson A, d'Argy R, Gillberg P-G, Halldin C, Litton J-E, Swahn C-G, Sedvall G. Autoradiography with saturation experiments of [11C]Ro 15–1788 binding to human brain sections. J Neurosci Methods 1991; 36: 53–61
Hall H, Halldin C, Sedvall G. Binding of [3H]SCH 39166 to human post mortem brain tissue. Pharmacol Toxicol 1993; 72: 152–158
Hall H, Litton J-E, Halldin C, Kopp J, Sedvall G. Studies on the binding of [3H]flumazenil and [3H]sarmazenil in post mortem human brain. Hum Psychopharmacol 1992; 7: 367–377
Litton J-E, Holte S, Eriksson L. Evaluation of the Karolinska new positron camera system; the Scanditronix PC2048–15B. IEEE Trans Nucl Sci 1990; 37: 743–748
Halldin C, Swahn CG, Farde L, Litton JE, Sedvall G. Determination of [11C]SCH 23390 and its radioactive metabolites in plasma by HPLC [abstract]. Eur J Nucl Med 1991; 18: 526
Halldin C, Någren K, Swahn C-G, Långström B, Nybäck H. (S)- and (R)-[11C]nicotine and the metabolite (R/S)-[11C]cotinine. Preparation, metabolite studies and in vivo distribution in the human brain using PET. Nucl Med Biol 1992; 19: 871–880
Swahn CG, Farde L, Halldin C, Sedvall G. Ligand metabolites in plasma during PET studies with 11C-labelled dopamine antagonists, raclopride, SCH 23390 and N-methylspiroperidol. Hum Psychopharmacol 1992; 7: 97–103
Swahn CG, Halldin C, Lundström J, Erixson E, Farde L. A rapid and efficient HPLC-method for determination of ligand metabolism during PET-studies — exemplified with [11C]racopride. J Labelled Comp 1993; 32: 284–285
Swahn CG, Halldin C, Farde L, Sedvall G. Metabolism of the PET ligand [11C]SCH 23390. Identification of two metabolites with HPLC. Human Psychopharmacol 1993; (in press)
Aquilonius S-M, Bergström K, Eckernäs S-Å, Hartvig P, Leenders KL, Lundquist H, Antoni G, Gee A, Rimland A, Uhlin J, Långström B. In vivo evaluation of striatal dopamine reuptake sites using [11C]nomifensine and positron emission tomography. Acta Neurol Scand 1987; 76: 283–287
Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, MacGregor RR, Hitzemann R, Logan J, Bendriem B, Gatley SJ, Christman D. Mapping cocaine binding sites in human and baboon brain in vivo. Synapse 1989; 4: 371–377
Volkow ND, Fowler JS, Wolf AP, Wang G-J, Logan J, MacGregor R, Dewey SL, Schlyer D, Hitzemann R. Distribution and kinetics of carbon-ll-cocaine in the human body measured with PET. J Nucl Med 1992; 33: 521–525
Wong DF, Shaya EK, Yung B, Sheffel U, Dannals RE, Ricaurte GA, Chen C, Neumeyer JL, Wagner Jr HN, Kuhar MJ. C-11 WIN 35,428 imaging of the dopamine transporter site in living human brain. J Nucl Med 1992; 33: 964
Halldin C, Farde L, Müller L, Karlsson P, Neumeyer JL, Gao Y, Milius R, Hall H, Swahn C-G. Preparation of [11C]β-CIT, a new ligand for imaging cocaine binding sites in vivo by PET. Eur J Nucl Med 1992; 19: 592
Müller L, Halldin C, Farde L, Karlsson P, Hall H, Swahn C-G, Neumeyer J, Gao Y, Milius R. [11C]β-CIT, a cocaine analogue. Preparation, autoradiography and preliminary PET investigations. Nucl Med Biol 1993; 20: 249–255
Farde L, Eriksson L, Blomquist G, Halldin C. Kinetic analysis of 11C-raclopride binding to D2-dopamine receptors studied by PET — a comparison to the equilibrium analysis. J Cereb Blood Flow Metab 1989: 9: 696–708
Author information
Authors and Affiliations
Additional information
Correspondence to: C. Halldin
Rights and permissions
About this article
Cite this article
Müller, L., Halldin, C., Foged, C. et al. Preparation of a potential positron emission tomographic radioligand for the dopamine transporter. Eur J Nucl Med 21, 131–137 (1994). https://doi.org/10.1007/BF00175760
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00175760