Tissue distribution of radioiodinated FAUC113

O. Prante; C. Hocke; S. Löber; H. Hübner; P. Gmeiner; T. Kuwert

doi:10.1055/s-0038-1623933

Nuklearmedizin - NuclearMedicine, Table of Contents

Nuklearmedizin 2006; 45(01): 41-48
DOI: 10.1055/s-0038-1623933

Original Article

Schattauer GmbH

Tissue distribution of radioiodinated FAUC113

Assessment of a pyrazolo(1,5-α)pyridine based dopamine D4 receptor radioligand candidateBioverteilung von Radioiodmarkiertem FAUC 113Bewertung eines potenziellen Radioliganden für den Dopamin D4-Rezeptor mit Pyrazolo(1,5-α)-pyridin-Grundkörper

Authors

O. Prante

¹Laboratory of Molecular Imaging, Clinic of Nuclear Medicine (Head: Prof. Dr. T. Kuwert)
C. Hocke

¹Laboratory of Molecular Imaging, Clinic of Nuclear Medicine (Head: Prof. Dr. T. Kuwert)
S. Löber

²Department of Medicinal Chemistry (Head: Prof. Dr. P. Gmeiner), Friedrich-Alexander University Erlangen, Germany
H. Hübner

²Department of Medicinal Chemistry (Head: Prof. Dr. P. Gmeiner), Friedrich-Alexander University Erlangen, Germany
P. Gmeiner

²Department of Medicinal Chemistry (Head: Prof. Dr. P. Gmeiner), Friedrich-Alexander University Erlangen, Germany
T. Kuwert

¹Laboratory of Molecular Imaging, Clinic of Nuclear Medicine (Head: Prof. Dr. T. Kuwert)

Abstract

Summary

Aim: Disturbances of the D4 receptor subtype have been implicated in the genesis of a broad range of psychiatric disorders. In order to assess the suitability of a radioiodinated analogue of the D4-selective ligand FAUC 113 for tracer studies in vivo, we investigated the in-vivo stability, biodistribution and brain-uptake of 7-¹³¹I-FAUC 113 in Sprague-Dawley rats. Methods: Radiolabelling was carried out with high radiochemical yield and specific activity. After intravenous injection, blood and tissue samples, taken at designated time intervals, were collected for analysis. Analyses of metabolites were performed by radiohplc and radio-tlc. For in-vivo evaluation, sagittal cryo-sections of the rat brain were investigated by in-vitro and exvivo autoradiography on a μ-Imager system. Results: 7-¹³¹I-FAUC 113 was rapidly cleared from blood. Highest uptake was observed in kidney (0.603±0.047% ID/g, n=4) and liver (0.357±0.070% ID/g, n=4) at 10 min p.i.; 7-¹³¹I-FAUC 113 displayed rapid uptake (0.21-0.26% ID/g) and fast clearance in various brain regions consistent with the determined logP-value of 2.36±0.15 (n=4). In-vivo stability of 7-¹³¹I-FAUC 113 was confirmed in the frontal cortex (>95%). Ex-vivo autoradiography revealed a frontal cortex-to-cerebellum ratio of 1.57±0.13 at 10 min p.i. (n=6). Coinjection with L-750667 could not suppress any putative specific binding of 7-¹³¹I-FAUC 113. In-vitro autoradiography using authentic 7-iodo-FAUC 113 or L-750667 failed to cause significant displacement of the radioligand. Conclusions: Radioiodinated FAUC 113 does not allow imaging of D4 receptors in the rat brain in vivo nor in vitro. Further work should aim at the development of selective dopamine D4 radioligands with improved tracer characteristics, such as receptor affinity and subtype selectivity, specific activity or blood-brainbarrier permeability.

Zusammenfassung

Ziel: Für eine Vielzahl psychiatrischer Erkrankungen wird eine Implikation des Dopamin-D4-Rezeptorsubtyps diskutiert. Um die Eignung eines radioiodierten Analogons des D4-selektiven Liganden FAUC 113 für Tracerstudien in vivo zu beurteilen, haben wir die in-vivo-Stabilität, Bioverteilung sowie die Hirnaufnahme von 7-¹³¹I-FAUC 113 in Sprague-Dawley-Ratten untersucht. Methoden: Die Radiomarkierung lieferte den Tracer in hoher radiochemischer Ausbeute und spezifischer Aktivität. Nach intravenöser Injektion wurden die zu bestimmten Zeitpunkten entnommenen Blut- und Gewebeproben zur Radio-HPLC/Radio-DC Metabolitenanalyse gesammelt. Für die in-vivo Evaluierung wurden sagittale Kryo-Gewebeschnitte des Rattenhirns mit Hilfe der in-vitro- und ex-vivo-Autoradiographie an einem μ-Imager untersucht. Ergebnisse: 7-¹³¹I-FAUC 113 wurde schnell aus dem Blut ausgeschieden. Die höchste Aufnahme wurde in der Niere (0.603±0.047% ID/g, n=4) und Leber (0.357±0.070% ID/g, n=4) 10 min p.i. beobachtet. 7-¹³¹I-FAUC 113 zeigte in verschiedenen Hirnregionen eine schnelle Aufnahme (0.21-0.26% ID/g) sowie Auswaschung. Dies stimmt mit dem ermittelten LogP-Wert von 2.36±0.15 (n=4) überein. Die in-vivo- Stabilität von 7-¹³¹I-FAUC 113 im frontalen Cortex wurde bestätigt (>95%). Die ex-vivo Autoradiographie zeigte ein Cortex/Cerebellum-Verhältnis von 1.57±0.13, 10 min p.i. (n=6). Eine Coinjektion mit L-750667 konnte die vermeintlich spezifische Bindung von 7-¹³¹I-FAUC 113 im Gehirn nicht unterdrücken. In der in-vitro-Autoradiographie unter Verwendung von 7-iodo-FAUC 113 oder L-750667 erfolgte keine signifikante Deplazierung des Radioliganden. Schlussfolgerung: Das radioiodierte FAUC 113 erlaubt in vivo sowie in vitro keine Darstellung des D4-Rezeptors im Rattenhirn. Weiterführende Studien sollten auf die Entwicklung von D4-selektiven Radioliganden mit verbesserten Eigenschaften, wie Rezeptoraffinität und Subtypselektivität, spezifische Aktivität oder Blut-Hirn-Schranken- Durchgängigkeit, abzielen.

Keywords

D4 receptor - radioligand - autoradiography

Schlüsselwörter

D4-Rezeptor - Radioligand - Autoradiographie

Full Text

References

References
1 Ariano MA, Wang J, Noblett KL. et al. Cellular distribution of the rat D4 dopamine receptor protein in the CNS using anti-receptor antisera. Brain Res 1997; 752: 26-34.
2 Bartenstein P. PET in neuroscience. Nuklearmedizin 2004; 43: 33-42.
3 Boy C, Klimke A, Holschbach M. et al. Imaging dopamine D4 receptors in the living primate brain: a positron emission tomography study using the novel D1/D4 antagonist [11C]SDZ GLC 756. Synapse 1998; 30: 341-50.
4 Boyfield I, Brown TH, Coldwell MC. et al. Design and synthesis of 2-naphthoate esters as selective dopamine D4 antagonists. J Med Chem 1996; 39: 1946-8.
5 Charon Y, Laniece P, Tricoire H. Radio-imaging for quantitative autoradiography in biology. Nucl Med Biol 1998; 25: 699-704.
6 Defagot MC, Falzone TL, Low MJ. et al. Quantitative analysis of the dopamine D4 receptor in the mouse brain. J Neurosci Res 2000; 59: 202-8.
7 Defagot MC, Malchiodi EL, Villar MJ. et al. Distribution of the D4 dopamine receptor in rat brain with sequence-specific antibodies. Mol Brain Res 1997; 45: 1-12.
8 Eskola O, Bergman J, Lehikoinen P. et al. Synthesis of 3-[[4-(4-[¹⁸F]fluorophenyl)piperazin- 1-yl]methyl]-1H-pyrrolo[2,3-b]pyridine. J Label Compd Radiopharm 2002; 45: 687-96.
9 Helmeste DM, Tang SW, Bunney WE. et al. Decrease in sigma but no increase in striatal dopamine D4 sites in schizophrenic brains. Eur J Pharmacol 1996; 314: R3-5.
10 Holschbach MH, Olsson RA, Bier D. et al. Synthesis and evaluation of no-carrier-added 8-cyclopentyl- 3-(3-¹⁸F-fluoropropyl)-1-propylxanthine (¹⁸F-CPFPX): a potent and selective A1-adenosine receptor antagonist for in vivo imaging. J Med Chem 2002; 45: 5150-6.
11 Hübner H, Kraxner J, Gmeiner P. Cyanoindole derivatives as highly selective dopamine D4 receptor partial agonists: Solid-phase synthesis, binding assays, and functional experiments. J Med Chem 2000; 43: 4563-9.
12 Kulagowski JJ, Broughton HB, Curtis NR. et al. 3-[4-(4-Chlorophenyl)piperazin-1-yl]methyl-1Hpyrrolo( 2,3-b)pyridine: an antagonist with high affinity and selectivity for the human dopamine D4 receptor. J Med Chem 1996; 39: 1941-2.
13 Lahti RA, Roberts RC, Tamminga CA. D2 family receptor distribution in human postmortem tissue: an autoradiographicstudy. Neuroreport 1995; 6: 2505-12.
14 Lahti RA, Roberts RC, Cochrane EV. et al. Direct determination of dopamine D4 receptors in normal and schizophrenic postmortem brain tissue: a [3H]NGD-94–1 study. Mol Psychiatry 1998; 3: 528-33.
15 Langer O, Halldin C, Chou Y. et al. Carbon-11 PB-12: an attempt to visualize the dopamine D4 receptor in the primate brain with positron emission tomography. Nucl Med Biol 2000; 27: 707-14.
16 Lanig H, Utz W, Gmeiner P. Comparative molecular field analysis of dopamine D4 receptor antagonists including 3-[4-(4-Chlorophenyl)piperazin- 1-ylmethyl]pyrazolo(1,5-a)pyridine (FAUC 113), 3-[4-(4-Chlorophenyl)piperazin-1-ylmethyl]- 1H-pyrrolo(2,3-b)pyridine (L-745,870), and clozapine. J Med Chem 2001; 44: 1151-7.
17 Lidow MS, Wang F, Cao Y. et al. Layer V neurons bear the majority of mRNAs encoding the five distinct dopamine receptor subtypes in the primate prefrontal cortex. Synapse 1998; 28: 10-20.
18 Löber S, Hübner H, Gmeiner P. Azaindole derivatives with high affinity for the dopamine D4 receptor: synthesis, ligand binding studies and comparison of molecular electrostatic potential maps. Bioorg Med Chem Lett 1999; 9: 97-102.
19 Löber S, Hübner H, Utz W. et al. Rationally based efficacy tuning of selective dopamine D4 receptor ligands leading to the complete antagonist 2-[4-(4-chlorophenyl)piperazin-1-ylmethyl] pyrazolo(1,5-a])pyridine (FAUC 213). J Med Chem 2001; 4417: 2691-4.
20 Löber S, Aboul-Fadl T, Hübner H. et al. Di- and trisubstituted pyrazolo[1,5-a]pyridine derivatives: synthesis, dopamine receptor binding and ligand efficacy. Bioorg Med Chem Lett 2002; 12: 633-36.
21 Matarrese M, Soloviev D, Moresco RM. et al. Synthesis and in vivo evaluation of 3-11C-methyl- (3-methoxy-naphthalen)-2-yl-(1-benzylpiperidin)- 4-yl-acetate (SB-235753), as a putative dopamine D4 receptors antagonist for PET. J Label Compd Radiopharm 2000; 43: 359-74.
22 Matulenko MA, Surber B, Fan L. et al. Synthesis and activity of 2-[4-(4-3H-2-cyanophenyl)piperazinyl]- N-(2,4,6-3H-3-3-methylphenyl)acetamide: a selective dopamine D4 receptor agonist and radioligand. Bioorg Med Chem Lett 2004; 14: 5095-8.
23 Meador-Woodruff JH, Damask SP, Wang J. et al. Dopamine receptor mRNA expression in human striatum and neocortex. Neuropsychopharmacology 1996; 15: 17-29.
24 Mrzljak L, Bergson C, Pappy M. et al. Localisation of dopamine D4 receptors in GABAergic neurons of the primate brain. Nature 1996; 381: 245-8.
25 O‘Malley KL, Harmon S, Tang L. et al. The rat dopamine D4 receptor: sequence, gene structure, and demonstration of expression in the cardiovascular system. New Biol 1992; 4: 137-46.
26 Oak JN, Oldenhof J, Van Tol HHM. The dopamine D4 receptor: one decade of research. Eur J Pharmacol 2000; 405: 303-27.
27 Oh SJ, Lee KC, Lee SY. et al. Synthesis and evaluation of fluorine-substituted 1H-pyrrolo 2,3-bpyridine derivatives for dopamine D4 receptor imaging. Bioorg Med Chem 2004; 12: 5505-13.
28 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), a new serotonin 5-HT1A antagonist for positron emission tomography: An in vivo study in rats. J Neurochem 2002; 75: 803-11.
29 Prante O, Löber S, Hübner H. et al. Synthesis and in vitro evaluation of iodine labelled pyrazolo( 1,5-a)pyridines as highly selective dopamine D4 receptor ligands. J Label Compd Radiopharm 2001; 44: 849-58.
30 Primus RJ, Thurkauf A, Xu J. et al. Localization and characterization of dopamine D4 binding sites in rat and human brain by use of the novel, D4 receptor- selective ligand 3H-NGD 94-1. J Pharmacol Exp Ther 1997; 282: 1020-7.
31 Reynolds GP, Mason SL. Absence of detectable striatal dopamine D4 receptors in drug-treated schizophrenia. Eur J Pharmacol 1995; 281: R5-R6.
32 Seeman P, Guan HC, Van Tol HHM. Dopamine D4 receptors elevated in schizophrenia. Nature 1993; 365: 441-5.
33 Staley JK, Tamagnan G, Baldwin RM. et al. SPECT imaging with the D4 receptor antagonist L-750667 in nonhuman primate brain. Nucl Med Biol 2000; 27: 547-56.
34 Van Tol HHM, Bunzow JR, Guan HC. et al. Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 1991; 350: 610-4.
35 Wong AHC, Van Tol HHM. The dopamine D4 receptors and mechanisms of antipsychotic atypicality. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27: 1091-9.
36 Zhang MR, Haradahira T, Maeda J. et al. Syntheses and pharmacological evaluation of two potent antagonists for dopamine D4 receptors: 11C-YM- 50001 and N-2-[4-(4-chlorophenyl)piperazin- 1- yl]ethyl-3-11C-methoxybenzamide. Nucl Med Biol 2002; 29: 233-41.