title: Cerebral 5-HT release correlates with [11C]Cimbi36 PET measures of 5-HT2A receptor occupancy in the pig brain.
abstract: Positron emission tomography (PET) can, when used with appropriate radioligands, non-invasively generate temporal and spatial information about acute changes in brain neurotransmitter systems. We for the first time evaluate the novel 5-HT2Areceptor agonist PET radioligand, [11C]Cimbi-36, for its sensitivity to detect changes in endogenous cerebral 5-HT levels, as induced by different pharmacological challenges. To enable a direct translation of PET imaging data to changes in brain 5-HT levels, we calibrated the [11C]Cimbi-36 PET signal in the pig brain by simultaneous measurements of extracellular 5-HT levels with microdialysis and [11C]Cimbi-36 PET after various acute interventions (saline, citalopram, citalopram + pindolol, fenfluramine). In a subset of pigs, para-chlorophenylalanine pretreatment was given to deplete cerebral 5-HT. The interventions increased the cerebral extracellular 5-HT levels to 2-11 times baseline, with fenfluramine being the most potent pharmacological enhancer of 5-HT release, and induced a varying degree of decline in [11C]Cimbi-36 binding in the brain, consistent with the occupancy competition model. The observed correlation between changes in the extracellular 5-HT level in the pig brain and the 5-HT2Areceptor occupancy indicates that [11C]Cimbi-36 binding is sensitive to changes in endogenous 5-HT levels, although only detectable with PET when the 5-HT release is sufficiently high.
authors.affiliation: 1 Neurobiology Research Unit, Rigshospitalet, Copenhagen, Denmark.|2 Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Louise M
authors.initials: LM
authors.lastname: Jørgensen
authors.affiliation: 3 The Laboratory of Neuropsychiatry, Department of Neuroscience and Pharmacology, University of Copenhagen, Denmark.|4 Psychiatric Centre Copenhagen, University of Copenhagen, Denmark.
authors.forename: Pia
authors.initials: P
authors.lastname: Weikop
authors.affiliation: 1 Neurobiology Research Unit, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Jonas
authors.initials: J
authors.lastname: Villadsen
authors.affiliation: 3 The Laboratory of Neuropsychiatry, Department of Neuroscience and Pharmacology, University of Copenhagen, Denmark.|5 Center for Excellence in Translational Medicine, University of Tartu, Estonia.
authors.forename: Tanel
authors.initials: T
authors.lastname: Visnapuu
authors.affiliation: 1 Neurobiology Research Unit, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Ettrup
authors.affiliation: 1 Neurobiology Research Unit, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Hanne D
authors.initials: HD
authors.lastname: Hansen
authors.affiliation: 6 Research Center for Advanced Imaging, Hospital of Køge and Roskilde, Roskilde, Denmark.
authors.forename: Anders O
authors.initials: AO
authors.lastname: Baandrup
authors.affiliation: 7 PET and Cyclotron Unit, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Flemming L
authors.initials: FL
authors.lastname: Andersen
authors.affiliation: 8 Department of Neurosurgery, Aalborg University Hospital, Denmark.
authors.forename: Carsten R
authors.initials: CR
authors.lastname: Bjarkam
authors.affiliation: 2 Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.|9 Department of Radiology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Carsten
authors.initials: C
authors.lastname: Thomsen
authors.affiliation: 10 Department of Neurosurgery, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Bo
authors.initials: B
authors.lastname: Jespersen
authors.affiliation: 1 Neurobiology Research Unit, Rigshospitalet, Copenhagen, Denmark.|2 Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
authors.forename: Gitte M
authors.initials: GM
authors.lastname: Knudsen
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000032:analysis / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000032:analysis / Q000378:metabolism; D005260:Female; D005277:Fenfluramine / Q000494:pharmacology; D010627:Phenethylamines / Q000032:analysis / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D044402:Receptor, Serotonin, 5-HT2A / Q000032:analysis / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000032:analysis / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology; D013552:Swine
chemical_list: D001596:Benzylamines; D002250:Carbon Radioisotopes; C586246:Cimbi-36; D010627:Phenethylamines; D044402:Receptor, Serotonin, 5-HT2A; D058826:Serotonin 5-HT2 Receptor Agonists; D018490:Serotonin Agents; D005277:Fenfluramine; D012701:Serotonin
keywords: 5-HT; Positron emission tomography; brain imaging; kinetic modelling; neurosurgery
references.citation: Eur J Pharmacol. 1995 Nov 14;286(2):213-7
references.pmid: 8605960
references.citation: Life Sci. 1994;55(3):163-7
references.pmid: 8007758
references.citation: Psychopharmacology (Berl). 2015 Nov;232(21-22):4129-57
references.pmid: 25921033
references.citation: J Cereb Blood Flow Metab. 2004 Sep;24(9):1037-45
references.pmid: 15356424
references.citation: Brain Res. 1989 Mar 20;482(2):261-70
references.pmid: 2468397
references.citation: Brain Res. 1992 Jul 3;584(1-2):322-4
references.pmid: 1515949
references.citation: Depress Anxiety. 2009;26(5):411-8
references.pmid: 19180583
references.citation: Psychopharmacology (Berl). 1999 Jun;144(3):279-81
references.pmid: 10435395
references.citation: Mol Psychiatry. 2014 Mar;19(3):302-10
references.pmid: 23439486
references.citation: J Neurochem. 2003 Jul;86(1):13-24
references.pmid: 12807420
references.citation: Eur J Pharmacol. 1992 Dec 8;229(1):101-3
references.pmid: 1282104
references.citation: Mol Psychiatry. 2012 Dec;17 (12 ):1254-60
references.pmid: 22665264
references.citation: Brain Res. 1989 Dec 18;504(2):258-63
references.pmid: 2480833
references.citation: Neuroimage. 2012 Feb 15;59(4):3922-32
references.pmid: 21996132
references.citation: Bioorg Med Chem Lett. 2015 Mar 1;25(5):1053-6
references.pmid: 25655720
references.citation: Neuroimage. 2001 Nov;14(5):1089-96
references.pmid: 11697940
references.citation: Neuropharmacology. 2008 Nov;55(6):1006-14
references.pmid: 18761360
references.citation: Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2569-74
references.pmid: 9122236
references.citation: Eur J Pain. 2005 Apr;9(2):117-21
references.pmid: 15737798
references.citation: Nucl Med Biol. 2009 Nov;36(8):961-5
references.pmid: 19875053
references.citation: Anal Chem. 1993 Apr 15;65(8):1017-22
references.pmid: 8494171
references.citation: J Neurosci Methods. 1996 Sep;68(1):39-47
references.pmid: 8884611
references.citation: Behav Brain Res. 2003 Feb 17;139(1-2):21-9
references.pmid: 12642173
references.citation: J Pharmacol Exp Ther. 2000 Aug;294(2):571-9
references.pmid: 10900234
references.citation: Neuroscience. 1988 Nov;27(2):473-96
references.pmid: 2975361
references.citation: J Cereb Blood Flow Metab. 2010 Jan;30(1):46-50
references.pmid: 19738632
references.citation: Trends Neurosci. 1996 Sep;19(9):378-83
references.pmid: 8873352
references.citation: Neurosci Lett. 2006 Jan 9;392(1-2):129-34
references.pmid: 16213658
references.citation: J Nucl Med. 2014 Apr;55(4):640-6
references.pmid: 24566002
references.citation: Eur J Pharmacol. 2002 Jun 7;445(1-2):69-81
references.pmid: 12065196
references.citation: Neuropsychopharmacology. 2005 Sep;30(9):1624-31
references.pmid: 15827572
references.citation: Brain Res. 1999 Sep 11;841(1-2):160-9
references.pmid: 10546998
references.citation: Synapse. 2006 Jan;59(1):18-26
references.pmid: 16237679
references.citation: J Cereb Blood Flow Metab. 2009 Jan;29(1):186-96
references.pmid: 18797470
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 1991 Mar;343(3):237-44
references.pmid: 1714040
references.citation: J Pharmacol Exp Ther. 1990 Jan;252(1):410-8
references.pmid: 2137177
references.citation: J Neurochem. 2007 Nov;103(3):1111-20
references.pmid: 17666043
references.citation: Am J Psychiatry. 2007 Apr;164(4):622-9
references.pmid: 17403976
references.citation: Synapse. 2011 Feb;65(2):136-45
references.pmid: 20560131
references.citation: Synapse. 2004 Jun 1;52(3):188-208
references.pmid: 15065219
references.citation: Int J Neuropsychopharmacol. 2008 Feb;11(1):79-92
references.pmid: 17559709
references.citation: Eur J Pharmacol. 1994 Nov 14;265(1-2):103-6
references.pmid: 7883021
references.citation: Brain Res. 1997 Nov 7;774(1-2):94-105
references.pmid: 9452197
references.citation: J Cereb Blood Flow Metab. 2000 Mar;20(3):423-51
references.pmid: 10724107
references.citation: J Cereb Blood Flow Metab. 2014 Jul;34(7):1188-96
references.pmid: 24780897
references.citation: Br J Pharmacol. 1995 Jul;115(6):1064-70
references.pmid: 7582504
references.citation: J Cereb Blood Flow Metab. 2010 Oct;30(10 ):1682-706
references.pmid: 20664611
references.citation: J Cereb Blood Flow Metab. 2012 Apr;32(4):685-95
references.pmid: 22167236
references.citation: Neuropsychopharmacology. 2008 Jan;33(2):279-89
references.pmid: 17406650
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 1996 May;353(6):641-7
references.pmid: 8738297
references.citation: J Neural Transm (Vienna). 2007;114(11):1433-42
references.pmid: 17541696
references.citation: Neuroimage. 2009 Feb 1;44(3):1001-7
references.pmid: 19007894
references.citation: Biol Psychiatry. 2005 Nov 15;58(10 ):779-86
references.pmid: 16018986
references.citation: Synapse. 1997 Jan;25(1):1-14
references.pmid: 8987142
references.citation: Sleep. 2012 Dec 01;35(12):1615-23
references.pmid: 23204604
references.citation: Int J Neuropsychopharmacol. 2013 Aug;16(7):1577-86
references.pmid: 23351590
references.citation: Synapse. 2012 Oct;66(10 ):880-4
references.pmid: 22730164