Skip to main content
Hauptrubriken
CME Facharzt-Training Webinare Zeitschriften Bücher e.Medpedia Podcast
Service
Jobbörse Info & Hilfe
Fachgebiete
Anästhesiologie Allgemeinmedizin Arbeitsmedizin Augenheilkunde Chirurgie Dermatologie Gynäkologie und Geburtshilfe HNO Innere Medizin Kardiologie Neurologie Onkologie und Hämatologie Orthopädie und Unfallchirurgie Pädiatrie Pathologie Psychiatrie Radiologie Rechtsmedizin Urologie Zahnmedizin
Themen
Klimawandel und Gesundheit Neues aus dem Markt COVID-19 Praxis und Beruf Seltene Erkrankungen GOÄ & EBM Panorama
Sammlungen
Kasuistiken Algorithmen & Infografiken Blickdiagnosen Arthropedia FlapFinder (für Dermatochirurgen) Videos Kongressberichterstattung Medizin für Apothekerinnen und Apotheker Für Ärztinnen und Ärzte in Weiterbildung Für Medizinstudierende

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Konkret geht es um den Diabetes-Patienten mit kardiovaskulären Erkrankungen oder Risiken, die Herzinsuffizienz sowie die kardiovaskuläre Primär- und Sekundärprävention. Sind Sie hier schon auf dem neuesten Stand? Unsere Experten beleuchten, wo und warum das bisherige Procedere geändert werden soll und was in der Praxis sinnvoll ist. Holen Sie sich Ihr Update und 2 CME-Punkte beim MMW-Webinar am 24. April von 17.30 bis 19 Uhr. 
Erweiterte Suche
Anmelden
nach oben
European Journal of Nuclear Medicine and Molecular Imaging
Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging 4/2011

01.04.2011 | Original Article

Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT2A agonist PET tracers

verfasst von: Anders Ettrup, Martin Hansen, Martin A. Santini, James Paine, Nic Gillings, Mikael Palner, Szabolcs Lehel, Matthias M. Herth, Jacob Madsen, Jesper Kristensen, Mikael Begtrup, Gitte M. Knudsen

Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging | Ausgabe 4/2011

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Positron emission tomography (PET) imaging of serotonin 2A (5-HT2A) receptors with agonist tracers holds promise for the selective labelling of 5-HT2A receptors in their high-affinity state. We have previously validated [11C]Cimbi-5 and found that it is a 5-HT2A receptor agonist PET tracer. In an attempt to further optimize the target-to-background binding ratio, we modified the chemical structure of the phenethylamine backbone and carbon-11 labelling site of [11C]Cimbi-5 in different ways. Here, we present the in vivo validation of nine novel 5-HT2A receptor agonist PET tracers in the pig brain.

Methods

Each radiotracer was injected intravenously into anaesthetized Danish Landrace pigs, and the pigs were subsequently scanned for 90 min in a high-resolution research tomography scanner. To evaluate 5-HT2A receptor binding, cortical nondisplaceable binding potentials (BPND) were calculated using the simplified reference tissue model with the cerebellum as a reference region.

Results

After intravenous injection, all compounds entered the brain and distributed preferentially into the cortical areas, in accordance with the known 5-HT2A receptor distribution. The largest target-to-background binding ratio was found for [11C]Cimbi-36 which also had a high brain uptake compared to its analogues. The cortical binding of [11C]Cimbi-36 was decreased by pretreatment with ketanserin, supporting 5-HT2A receptor selectivity in vivo. [11C]Cimbi-82 and [11C]Cimbi-21 showed lower cortical BPND, while [11C]Cimbi-27, [11C]Cimbi-29, [11C]Cimbi-31 and [11C]Cimbi-88 gave rise to cortical BPND similar to that of [11C]Cimbi-5.

Conclusion

[11C]Cimbi-36 is currently the most promising candidate for investigation of 5-HT2A receptor agonist binding in the living human brain with PET.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Gonzalez-Maeso J, Weisstaub NV, Zhou M, et al. Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior. Neuron. 2007;53:439–52.PubMedCrossRef
2.
Abbas A, Roth BL. Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders. Expert Opin Pharmacother. 2008;9:3251–9.PubMedCrossRef
3.
Pinborg LH, Adams KH, Svarer C, et al. Quantification of 5-HT2A receptors in the human brain using [18F]altanserin-PET and the bolus/infusion approach. J Cereb Blood Flow Metab. 2003;23:985–96.PubMedCrossRef
4.
Ito H, Nyberg S, Halldin C, Lundkvist C, Farde L. PET imaging of central 5-HT2A receptors with carbon-11-MDL 100,907. J Nucl Med. 1998;39:208–14.PubMed
5.
Fitzgerald LW, Conklin DS, Krause CM, et al. High-affinity agonist binding correlates with efficacy (intrinsic activity) at the human serotonin 5-HT2A and 5-HT2C receptors: evidence favoring the ternary complex and two-state models of agonist action. J Neurochem. 1999;72:2127–34.PubMedCrossRef
6.
Song J, Hanniford D, Doucette C, et al. Development of homogeneous high-affinity agonist binding assays for 5-HT2 receptor subtypes. Assay Drug Dev Technol. 2005;3:649–59.PubMedCrossRef
7.
Cornea-Hebert V, Watkins KC, Roth BL, et al. Similar ultrastructural distribution of the 5-HT(2A) serotonin receptor and microtubule-associated protein MAP1A in cortical dendrites of adult rat. Neuroscience. 2002;113:23–35.PubMedCrossRef
8.
Peddie CJ, Davies HA, Colyer FM, Stewart MG, Rodriguez JJ. Colocalisation of serotonin2A receptors with the glutamate receptor subunits NR1 and GluR2 in the dentate gyrus: an ultrastructural study of a modulatory role. Exp Neurol. 2008;211:561–73.PubMedCrossRef
9.
Cumming P, Wong DF, Gillings N, Hilton J, Scheffel U, Gjedde A. Specific binding of [(11)C]raclopride and N-[(3)H]propyl-norapomorphine to dopamine receptors in living mouse striatum: occupancy by endogenous dopamine and guanosine triphosphate-free G protein. J Cereb Blood Flow Metab. 2002;22:596–604.PubMedCrossRef
10.
Braden MR, Parrish JC, Naylor JC, Nichols DE. Molecular interaction of serotonin 5-HT2A receptor residues Phe339(6.51) and Phe340(6.52) with superpotent N-benzyl phenethylamine agonists. Mol Pharmacol. 2006;70:1956–64.PubMedCrossRef
11.
Nichols DE, Frescas SP, Chemel BR, Rehder KS, Zhong D, Lewin AH. High specific activity tritium-labeled N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (INBMeO): a high-affinity 5-HT2A receptor-selective agonist radioligand. Bioorg Med Chem. 2008;16:6116–23.PubMedCrossRef
12.
Ettrup A, Palner M, Gillings N, Santini MA, Hansen M, Kornum BR, et al. Radiosynthesis and evaluation of 11C-CIMBI-5 as a 5-HT2A receptor agonist radioligand for PET. J Nucl Med. 2010;51:1763–70.PubMedCrossRef
13.
Narendran R, Mason NS, Laymon CM, et al. A comparative evaluation of the dopamine D(2/3) agonist radiotracer [11C](-)-N-propyl-norapomorphine and antagonist [11C]raclopride to measure amphetamine-induced dopamine release in the human striatum. J Pharmacol Exp Ther. 2010;333:533–9.PubMedCrossRef
14.
Narendran R, Hwang DR, Slifstein M, et al. In vivo vulnerability to competition by endogenous dopamine: comparison of the D2 receptor agonist radiotracer (-)-N-[11C]propyl-norapomorphine ([11C]NPA) with the D2 receptor antagonist radiotracer [11C]-raclopride. Synapse. 2004;52:188–208.PubMedCrossRef
15.
Paterson LM, Tyacke RJ, Nutt DJ, Knudsen GM. Measuring endogenous 5-HT release by emission tomography: promises and pitfalls. J Cereb Blood Flow Metab. 2010;30:1682–706.PubMedCrossRef
16.
Shulgin A, Shulgin A. PIHKAL, a chemical love story. Berkeley, CA: Transform Press; 1991. p. 1–978.
17.
Nichols DE, Frescas S, Marona-Lewicka D, et al. 1-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)-2-aminopropane: a potent serotonin 5-HT2A/2C agonist. J Med Chem. 1994;37:4346–51.PubMedCrossRef
18.
Monte AP, Marona-Lewicka D, Parker MA, Wainscott DB, Nelson DL, Nichols DE. Dihydrobenzofuran analogues of hallucinogens. 3. Models of 4-substituted (2,5-dimethoxyphenyl)alkylamine derivatives with rigidified methoxy groups. J Med Chem. 1996;39:2953–61.PubMedCrossRef
19.
Herth MM, Kramer V, Piel M, et al. Synthesis and in vitro affinities of various MDL 100907 derivatives as potential 18F-radioligands for 5-HT2A receptor imaging with PET. Bioorg Med Chem. 2009;17:2989–3002.PubMedCrossRef
20.
Sureau FC, Reader AJ, Comtat C, et al. Impact of image-space resolution modeling for studies with the high-resolution research tomograph. J Nucl Med. 2008;49:1000–8.PubMedCrossRef
21.
Watanabe H, Andersen F, Simonsen CZ, Evans SM, Gjedde A, Cumming P. MR-based statistical atlas of the Gottingen minipig brain. Neuroimage. 2001;14:1089–96.PubMedCrossRef
22.
Kornum BR, Lind NM, Gillings N, Marner L, Andersen F, Knudsen GM. Evaluation of the novel 5-HT4 receptor PET ligand [11C]SB207145 in the Gottingen minipig. J Cereb Blood Flow Metab. 2009;29:186–96.PubMedCrossRef
23.
Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. Neuroimage. 1996;4:153–8.PubMedCrossRef
24.
Gillings N. A restricted access material for rapid analysis of [11C]-labeled radiopharmaceuticals and their metabolites in plasma. Nucl Med Biol. 2009;36:961–5.PubMedCrossRef
25.
Meyer PT, Bhagwagar Z, Cowen PJ, Cunningham VJ, Grasby PM, Hinz R. Simplified quantification of 5-HT2A receptors in the human brain with [11C]MDL 100,907 PET and non-invasive kinetic analyses. Neuroimage. 2010;50:984–93.PubMedCrossRef
26.
Kristiansen H, Elfving B, Plenge P, Pinborg LH, Gillings N, Knudsen GM. Binding characteristics of the 5-HT2A receptor antagonists altanserin and MDL 100907. Synapse. 2005;58:249–57.PubMedCrossRef
27.
Marazziti D, Rossi A, Giannaccini G, et al. Distribution and characterization of [3H]mesulergine binding in human brain postmortem. Eur Neuropsychopharmacol. 1999;10:21–6.PubMedCrossRef
28.
Innis RB, Cunningham VJ, Delforge J, et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab. 2007;27:1533–9.PubMedCrossRef
29.
Guo Q, Brady M, Gunn RN. A biomathematical modeling approach to central nervous system radioligand discovery and development. J Nucl Med. 2009;50:1715–23.PubMedCrossRef
30.
Ewald AH, Fritschi G, Maurer HH. Metabolism and toxicological detection of the designer drug 4-iodo-2,5-dimethoxy-amphetamine (DOI) in rat urine using gas chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;857:170–4.PubMedCrossRef
31.
Theobald DS, Putz M, Schneider E, Maurer HH. New designer drug 4-iodo-2,5-dimethoxy-beta-phenethylamine (2C-I): studies on its metabolism and toxicological detection in rat urine using gas chromatographic/mass spectrometric and capillary electrophoretic/mass spectrometric techniques. J Mass Spectrom. 2006;41:872–86.PubMedCrossRef
Metadaten
Titel
Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT2A agonist PET tracers
verfasst von
Anders Ettrup
Martin Hansen
Martin A. Santini
James Paine
Nic Gillings
Mikael Palner
Szabolcs Lehel
Matthias M. Herth
Jacob Madsen
Jesper Kristensen
Mikael Begtrup
Gitte M. Knudsen
Publikationsdatum
01.04.2011
Verlag
Springer-Verlag
Erschienen in
European Journal of Nuclear Medicine and Molecular Imaging / Ausgabe 4/2011
Print ISSN: 1619-7070
Elektronische ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-010-1686-8

Weitere Artikel der Ausgabe 4/2011

European Journal of Nuclear Medicine and Molecular Imaging 4/2011 Zur Ausgabe

Original Article

Renal uptake of different radiolabelled peptides is mediated by megalin: SPECT and biodistribution studies in megalin-deficient mice

Original Article

The use of a portable gamma camera for preoperative lymphatic mapping: a comparison with a conventional gamma camera

Original Article

Binding of [123I]iodobenzamide to the rat D2 receptor after challenge with various doses of methylphenidate: an in vivo imaging study with dedicated small animal SPECT

Book Review

Henry N. Wagner Jr: Brain Imaging: the Chemistry of Mental Activity

Original Article

PET functional volume delineation: a robustness and repeatability study

Review Article

In vivo imaging of embryonic stem cell therapy