Advertisement

PET Imaging of the 5-HT2A Receptor System: A Tool to Study the Receptor’s In Vivo Brain Function

  • Matthias M. Herth
  • Gitte M. Knudsen
Chapter
Part of the The Receptors book series (REC, volume 32)

Abstract

The serotonergic 5-HT2A receptor system plays a key modulatory role for many brain functions such as regulation of mood, temperature, sex, appetite and emotions. The receptor is also involved in a number of brain disorders, for example, depression, Alzheimer’s disease or schizophrenia. This makes it an obvious target for many drugs.

This chapter describes how the in vivo imaging technique positron emission tomography (PET) can be used to investigate 5-HT2A receptors in humans in terms of neurobiology and brain disorders. It also highlights how PET can be used in drug development and in humans in terms of neurobiology and brain disorders. It also highlights how PET can be used in drug development and explains the basic methodology of PET. The chapter discusses currently used 5-HT2A receptor selective PET tracers. This chapter explains with the help of 5-HT2A receptor tracers how PET can be used in vivo to determine a drug’s receptor occupancy. Finally, the possibility of 5-HT2A receptor selective PET tracers imaging endogenous serotonin levels in the living brain is discussed.

Keywords

PET 5-HT2A [11C]MDL 100907 (R)-[18F]MH.MZ [18F]altanserin [11C]Cimbi-36 

Abbreviation

5-HT2AR

Serotonin 2A receptor, 5-hydroxytryptamine 2A receptor

5-HT2BR

Serotonin 2B receptor, 5-hydroxytryptamine 2B receptor

5-HT2CR

Serotonin 2C receptor, 5-hydroxytryptamine 2C receptor

AD

Alzheimer’s disease

As

Specific activity

Bavail

Concentration of receptors available for binding

BBB

Blood brain barrier

Bmax

Maximal concentration of receptors

BP

Binding potential

CNS

Central nervous system

D2

Dopamine receptor D2

DAG

Diacylglycerol

DOI

1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane

fND

The free fraction in the non-displaceable tissue compartment

HPLC

High-performance liquid chromatography

IP3

Inositol triphosphate

KD

Radioligand equilibrium dissociation constant

Ki

Inhibition constant

LSD

Lysergic acid diethylamide

MCI

Mild cognitive impairment

MDMA

3,4-methylenedioxymethamphetamine, “ecstasy”

NIGA

Non-invasive graphical analysis

PET

Positron emission tomography

PLC

Phospholipase C

PKC

Protein kinase

P-pg

P-glycoprotein

SPECT

Single photon emission computed tomography

SRTM

Simplified reference tissue model

SUV

Standard uptake value

TAC

Time-activity curve

TCM

Tissue compartment modeling

tBRtarget/off-target

Theoretical, observed binding ratio of the target to another off-target

References

  1. 1.
    Rosel P, Arranz B, San L, Vallejo J, Crespo JM, Urretavizcaya M et al (2000) Altered 5-HT2A binding sites and second messenger inositol trisphosphate (IP3) levels in hippocampus but not in frontal cortex from depressed suicide victims. Psychiat Res Neuroim 99(3):173–181CrossRefGoogle Scholar
  2. 2.
    Pazos A, Probst A, Palacios JM (1987) Serotonin receptors in the human-brain .4. Autoradiographic mapping of serotonin-2 receptors. Neuroscience 21(1):123–139PubMedCrossRefGoogle Scholar
  3. 3.
    Cornea-Hebert V, Riad M, Wu C, Singh SK, Descarries L (1999) Cellular and subcellular distribution of the serotonin 5-HT2A receptor in the central nervous system of adult rat. J Comp Neurol 409(2):187–209PubMedCrossRefGoogle Scholar
  4. 4.
    Hall H, Farde L, Halldin C, Lundkvist C, Sedvall G (2000) Autoradiographic localization of 5-HT2A receptors in the human brain using [3H]M100907 and [11C]M100907. Synapse 38(4):421–431PubMedCrossRefGoogle Scholar
  5. 5.
    Saulin A, Savli M, Lanzenberger R (2012) Serotonin and molecular neuroimaging in humans using PET. Amino Acids 42(6):2039–2057PubMedCrossRefGoogle Scholar
  6. 6.
    Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H et al (2007) Functional selectivity and classical concepts of quantitative pharmacology. J Pharmacol Exp Ther 320(1):1–13PubMedCrossRefGoogle Scholar
  7. 7.
    Leysen I, Van der Gucht E, Eysel UT, Huybrechts R, Vandesande F, Arckens L (2004) Time-dependent changes in the expression of the MEF2 transcription factor family during topographic map reorganization in mammalian visual cortex. Eur J Neurosci 20(3):769–780PubMedCrossRefGoogle Scholar
  8. 8.
    Meyer PT, Bhagwagar Z, Cowen PJ, Cunningham VJ, Grasby PM, Hinz R (2010) Simplified quantification of 5-HT2A receptors in the human brain with [11C]MDL 100907 PET and non-invasive kinetic analyses. NeuroImage 50(3):984–993PubMedCrossRefGoogle Scholar
  9. 9.
    Girgis RR, Slifstein M, Xu XY, Frankle WG, Anagnostou E, Wasserman S et al (2011) The 5-HT2A receptor and serotonin transporter in Asperger’s disorder: a PET study with [11C]MDL 100907 and [11C]DASB. Psychiat Res Neuroim 194(3):230–234CrossRefGoogle Scholar
  10. 10.
    Akash K, Balarama K, Paulose C (2008) Enhanced 5-HT2A receptor status in the hypothalamus and corpus striatum of ethanol-treated rats. Cell Mol Neurobiol 28(7):1017–1025PubMedCrossRefGoogle Scholar
  11. 11.
    Jones BJ, Blackburn TP (2002) The medical benefit of 5-HT research. Pharmacol Biochem Behav 71(4):555–568PubMedCrossRefGoogle Scholar
  12. 12.
    Landolt HP, Wehrle R (2009) Antagonism of serotonergic 5-HT2A/2C receptors: mutual improvement of sleep, cognition and mood? Eur J Neurosci 29(9):1795–1809PubMedCrossRefGoogle Scholar
  13. 13.
    Burnet PWJ, Eastwood SL, Harrison PJ (1996) 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schizophrenia. Neuropsychopharmacology 15(5):442–455PubMedCrossRefGoogle Scholar
  14. 14.
    Burnet PWJ, Chen CPLH, McGowan S, Franklin M, Harrison PJ (1996) The effects of clozapine and haloperidol on serotonin-1A, -2A and -2C receptor gene expression and serotonin metabolism in the rat forebrain. Neuroscience 73(2):531–540PubMedCrossRefGoogle Scholar
  15. 15.
    Erritzoe D, Rasmussen H, Kristiansen KT, Frokjaer VG, Haugbol S, Pinborg L et al (2008) Cortical and subcortical 5-HT2A receptor binding in neuroleptic-naive first-episode schizophrenic patients. Neuropsychopharmacology 33(10):2435–2441PubMedCrossRefGoogle Scholar
  16. 16.
    Erritzoe DF, Frokjaer VB, Christoffersen MV, Baare W, Ramsoy T, Svarer C et al (2008) Decreased serotonin-2A binding in MDMA and hallucinogen users: an [18F]altanserin PET study. NeuroImage 41:46CrossRefGoogle Scholar
  17. 17.
    Haahr MT, Erritzoe D, Lindqvist D, Baare W, Hojgaard L, Almdal T et al (2008) Obesity is associated with increased cortical 5-HT2A receptor binding and decreased serotonin transporter binding in humans: a pilot study. NeuroImage 41:152CrossRefGoogle Scholar
  18. 18.
    Naughton M, Mulrooney JB, Leonard BE (2000) A review of the role of serotonin receptors in psychiatric disorders. Hum Psychopharm Clin 15(6):397–415CrossRefGoogle Scholar
  19. 19.
    Popa D, Lena C, Fabre V, Prenat C, Gingrich J, Escourrou P et al (2005) Contribution of 5-HT2 receptor subtypes to sleep-wakefulness and respiratory control, and functional adaptations in knock-out mice lacking 5-HT2A receptors. J Neurosci 25(49):11231–11238PubMedCrossRefGoogle Scholar
  20. 20.
    Sheline YI, Mintun MA, Moerlein SM, Snyder AZ (2002) Greater loss of 5-HT2A receptors in midlife than in late life. Am J Psychiat 159(3):430–435PubMedCrossRefGoogle Scholar
  21. 21.
    Abbas A, Roth BL (2008) Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders. Expert Opin Pharmaco 9(18):3251–3259CrossRefGoogle Scholar
  22. 22.
    Hasselbalch SG, Madsen K, Svarer C, Pinborg LH, Holm S, Paulson OB et al (2008) Reduced 5-HT2A receptor binding in patients with mild cognitive impairment. Neurobiol Aging 29(12):1830–1838PubMedCrossRefGoogle Scholar
  23. 23.
    McKeith IG, Marshall EF, Ferrier IN, Armstrong MM, Kennedy WN, Perry RH et al (1987) 5-HT receptor-binding in postmortem brain from patients with affective-disorder. J Affect Disorders 13(1):67–74PubMedCrossRefGoogle Scholar
  24. 24.
    Meneses A (2007) Stimulation of 5-HT1A, 5-HT1B, 5-HT2A/2C, 5-HT3 and 5-HT4 receptors or 5-HT uptake inhibition: short- and long-term memory. Behav Brain Res 184(1):81–90PubMedCrossRefGoogle Scholar
  25. 25.
    Gonzalez-Maeso J, Sealfon SC (2009) Psychedelics and schizophrenia. Trends Neurosci 32(4):225–232PubMedCrossRefGoogle Scholar
  26. 26.
    Kaye WH, Frank GK, Bailer UF, Henry SE, Meltzer CC, Price JC et al (2005) Serotonin alterations, in anorexia and bulimia nervosa: new insights from imaging studies. Physiol Behav 85(1):73–81PubMedCrossRefGoogle Scholar
  27. 27.
    Leysen JE (2004) 5-HT2 receptors. Curr Drug Targets CNS Neurol Disord 3:11–26PubMedCrossRefGoogle Scholar
  28. 28.
    Nordstrom AL, Farde L, Halldin C (1993) High 5-HT2 receptor occupancy in clozapine treated patients demonstrated by PET. Psychopharmacology 110(3):365–367PubMedCrossRefGoogle Scholar
  29. 29.
    Grunder G, Yokoi F, Offord SJ, Ravert HT, Dannals RF, Salzmann JK et al (1997) Time course of 5-HT2A receptor occupancy in the human brain after a single oral dose of the putative antipsychotic drug MDL 100907 measured by positron emission tomography. Neuropsychopharmacology 17(3):175–185PubMedCrossRefGoogle Scholar
  30. 30.
    Meltzer HY, Bastani B, Ramirez L, Matsubara S (1989) Clozapine—new research on efficacy and mechanism of action. Eur Arch Psychiatry Neurol Sci 238(5–6):332–339PubMedCrossRefGoogle Scholar
  31. 31.
    Halberstadt AL (2015) Recent advances in the neuropsychopharmacology of serotonergic hallucinogens. Behav Brain Res 277:99–120PubMedCrossRefGoogle Scholar
  32. 32.
    Liechti ME, Geyer MA, Hell D, Vollenwieder FX (2000) MDMA (“ecstasy”) effects on sensorimotor gating after selective pretreatments in humans. Biol Psychiatry 47(8):148CrossRefGoogle Scholar
  33. 33.
    Liechti ME, Vollenweider FX (2000) Acute psychological and physiological effects of MDMA (“Ecstasy”) after haloperidol pretreatment in healthy humans. Eur Neuropsychopharmacol 10(4):289–295PubMedCrossRefGoogle Scholar
  34. 34.
    Geyer MA, Vollenweider FX (2008) Serotonin research: contributions to understanding psychoses. Trends Pharmacol Sci 29(9):445–453PubMedCrossRefGoogle Scholar
  35. 35.
    Gonzalez-Maeso J, Weisstaub NV, Zhou MM, Chan P, Ivic L, Ang R et al (2007) Hallucinogens recruit specific cortical 5-HT2A receptor-mediated signaling pathways to affect behavior. Neuron 53(3):439–452PubMedCrossRefGoogle Scholar
  36. 36.
    Massoud TF, Gambhir SS (2003) Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev 17(5):545–580PubMedCrossRefGoogle Scholar
  37. 37.
    Antoni GKT, Langström B (2003) 11C-Labeling chemistry and labeled compounds. In: Vértes A, Nagy S, Klencsár Z, Lovas RG, Rösch F (eds) Handbook of nuclear chemistry, vol 4. Kluwer Academic Publishers, Dordrecht, pp 119–165Google Scholar
  38. 38.
    Lanzenberger R, Wadsak W, Spindelegger C, Mitterhauser M, Akimova E, Mien LK et al (2010) Cortisol plasma levels in social anxiety disorder patients correlate with serotonin-1A receptor binding in limbic brain regions. Int J Neuropsychopharmacol 13(9):1129–1143PubMedCrossRefGoogle Scholar
  39. 39.
    Spindelegger C, Lanzenberger R, Wadsak W, Mien LK, Stein P, Mitterhauser M et al (2009) Influence of escitalopram treatment on 5-HT1A receptor binding in limbic regions in patients with anxiety disorders. Mol Psychiatry 14(11):1040–1050PubMedCrossRefGoogle Scholar
  40. 40.
    Farde L, Nordstrom AL (1992) PET analysis indicates atypical central dopamine receptor occupancy in clozapine-treated patients. Br J Psychiatry 160:30–33Google Scholar
  41. 41.
    Paterson LM, Kornum BR, Nutt DJ, Pike VW, Knudsen GM (2013) 5-HT radioligands for human brain imaging with PET and SPECT. Med Res Rev 33(1):54–111PubMedCrossRefGoogle Scholar
  42. 42.
    Herth MM, Andersen VL, Lehel S, Madsen J, Knudsen GM, Kristensen JL (2013) Development of a 11C-labeled tetrazine for rapid tetrazine-trans-cyclooctene ligation. Chem Commun 49(36):3805–3807CrossRefGoogle Scholar
  43. 43.
    Herth MM, Barz M, Moderegger D, Allmeroth M, Jahn M, Thews O et al (2009) Radioactive Labeling of Defined HPMA-Based Polymeric Structures Using [18F]FETos for In Vivo Imaging by Positron Emission Tomography. Biomacromolecules 10(7):1697–1703PubMedCrossRefGoogle Scholar
  44. 44.
    Herzog HRF (2005) PET- und SPECT-Technik. Pharm Unserer Zeit 34(6):468–473PubMedCrossRefGoogle Scholar
  45. 45.
    Saha G (2010) The basics of PET imaging. Springer, New York. 978-1-4419-0804-9CrossRefGoogle Scholar
  46. 46.
    Piel M, Vernaleken I, Rosch F (2014) Positron emission tomography in CNS drug discovery and drug monitoring. J Med Chem 57(22):9232–9258PubMedCrossRefGoogle Scholar
  47. 47.
    Innis RB, Cunningham VJ, Delforge J, Fujita M, Giedde A, Gunn RN et al (2007) Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cerebr Blood Flow Metab 27(9):1533–1539CrossRefGoogle Scholar
  48. 48.
    Wernick MN, Aarsvold JN (eds) (2004) Emission tomography: the fundamentals of PET and SPECT. Academic Press, San Diego. ISBN: 978-0127444826Google Scholar
  49. 49.
    Salinas C, Weinzimmer D, Searle G, Labaree D, Ropchan J, Huang Y et al (2013) Kinetic analysis of drug-target interactions with PET for characterization of pharmacological hysteresis. J Cereb Blood Flow Metab 33(5):700–707PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Watabe H, Ikoma Y, Kimura Y, Naganawa M, Shidahara M (2006) PET kinetic analysis—compartmental model. Ann Nucl Med 20(9):583–588PubMedCrossRefGoogle Scholar
  51. 51.
    Wong DF (2003) Predicting the success of a radiopharmaceutical for in vivo imaging of central nervous system neuroreceptor systems. Mol Imaging Biol 5(6):350–362PubMedCrossRefGoogle Scholar
  52. 52.
    Logan J (2000) Graphical analysis of PET data applied to reversible and irreversible tracers. Nucl Med Biol 27(7):661–670PubMedCrossRefGoogle Scholar
  53. 53.
    Marshall RC, Powers-Risius P, Huesman RH, Reutter BW, Taylor SE, Maurer HE et al (1998) Estimating glucose metabolism using glucose analogs and two tracer kinetic models in isolated rabbit heart. Am J Physiol 275(2):668–679Google Scholar
  54. 54.
    Patlak CS, Blasberg RG (1985) Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data—generalizations. J Cerebr Blood Flow Metab 5(4):584–590CrossRefGoogle Scholar
  55. 55.
    Patlak CS, Blasberg RG, Fenstermacher JD (1983) Graphical Evaluation of Blood-to-Brain Transfer Constants from Multiple-Time Uptake Data. J Cerebr Blood Flow Metab 3(1):1–7CrossRefGoogle Scholar
  56. 56.
    Varnas K, Halldin C, Hall H (2004) Autoradiographic distribution of serotonin transporters and receptor subtypes in human brain. Hum Brain Mapp 22(3):246–260PubMedCrossRefGoogle Scholar
  57. 57.
    Sullivan GM, Parsey RV, Kumar JSD, Arango V, Kassir SA, Huang YY et al (2007) PET Imaging of CRF1 with [11C]R121920 and [11C]DMP696: is the target of sufficient density? Nucl Med Biol 34(4):353–361PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Zeng ZZ, Chen TB, Miller PJ, Dean D, Tang YS, Sur C et al (2006) The serotonin transporter in rhesus monkey brain: comparison of DASB and citalopram binding sites. Nucl Med Biol 33(4):555–563PubMedCrossRefGoogle Scholar
  59. 59.
    Christian BT, Narayanan T, Shi B, Morris ED, Mantil J, Mukherjee J (2004) Measuring the in vivo binding parameters of [18F]fallypride in monkeys using a PET multiple-injection protocol. J Cereb Blood Flow Metab 24(3):309–322PubMedCrossRefGoogle Scholar
  60. 60.
    Farde L, Hall H, Ehrin E, Sedvall G (1986) Quantitative-Analysis of D2 Dopamine Receptor-Binding in the Living Human-Brain by Pet. Science 231(4735):258–261PubMedCrossRefGoogle Scholar
  61. 61.
    Lopez-Gimenez JF, Vilaro MT, Palacios JM, Mengod G (1998) [3H]MDL 100907 labels 5-HT2A serotonin receptors selectively in primate brain. Neuropharmacology 37(9):1147–1158PubMedCrossRefGoogle Scholar
  62. 62.
    Herth MM, Debus F, Piel M, Palner M, Knudsen GM, Luddens H et al (2008) Total synthesis and evaluation of [18F]MH.MZ. Bioorg Med Chem Lett 18(4):1515–1519PubMedCrossRefGoogle Scholar
  63. 63.
    Pazos A, Probst A, Palacios JM (1987) Serotonin Receptors in the Human-Brain 3. Autoradiographic Mapping of Serotonin-1 Receptors. Neuroscience 21(1):97–122PubMedCrossRefGoogle Scholar
  64. 64.
    Debus F, Herth MM, Piel M, Buchholz HG, Bausbacher N, Kramer V et al (2010) 18F-Labeling and evaluation of novel MDL 100907 derivatives as potential 5-HT2A antagonists for molecular imaging. Nucl Med Biol 37(4):487–495PubMedCrossRefGoogle Scholar
  65. 65.
    Lopez-Gimenez JF, Mengod G, Palacios JM, Vilaro MT (1997) Selective visualization of rat brain 5-HT2A receptors by autoradiography with [3H]MDL 100907. Naunyn Schmiedebergs Arch Pharmacol 356(4):446–454PubMedCrossRefGoogle Scholar
  66. 66.
    Malgouris C, Flamand F, Doble A (1993) Autoradiographic studies of RP 62203, a potent 5-HT2 receptor antagonist—pharmacological characterization of [3H]RP 62203 binding in the rat-brain. Eur J Pharmacol 233(1):37–45PubMedCrossRefGoogle Scholar
  67. 67.
    Hansen HD, Ettrup A, Herth MM, Dyssegaard A, Ratner C, Gillings N et al (2013) Direct comparison of [18F]MH.MZ and [18F]altanserin for 5-HT2A receptor imaging with PET. Synapse 67(6):328–337PubMedCrossRefGoogle Scholar
  68. 68.
    Kristiansen H, Elfving B, Plenge P, Pinborg LH, Gillings N, Knudsen GM (2005) Binding characteristics of the 5-HT2A receptor antagonists altanserin and MDL 100907. Synapse 58(4):249–257PubMedCrossRefGoogle Scholar
  69. 69.
    Pinborg LH, Adams KH, Svarer C, Holm S, Hasselbalch SG, Haugbol S et al (2003) Quantification of 5-HT2A receptors in the human brain using [18F]altanserin. PET and the bolus/infusion approach. J Cereb Blood Flow Metab 23(8):985–996PubMedCrossRefGoogle Scholar
  70. 70.
    Ito H, Nyberg S, Halldin C, Lundkvist C, Farde L (1998) PET imaging of central 5-HT2A receptors with [11C]MDL 100,907. J Nucl Med 39(1):208–214PubMedGoogle Scholar
  71. 71.
    Talvik-Lotfi M, Nyberg S, Nordstrom AL, Ito H, Halldin C, Brunner F et al (2000) High 5-HT2A receptor occupancy in MDL 100907 treated schizophrenic patients. Psychopharmacology 148(4):400–403PubMedCrossRefGoogle Scholar
  72. 72.
    Watabe H, Channing MA, Der MG, Adams HR, Jagoda E, Herscovitch P et al (2000) Kinetic analysis of the 5-HT2A ligand [11C]MDL 100907. J Cereb Blood Flow Metab 20(6):899–909PubMedCrossRefGoogle Scholar
  73. 73.
    Lundkvist C, Halldin C, Ginovart N, Nyberg S, Swahn CG, Carr AA et al (1996) [11C]MDL 100907, a radioligand for selective imaging of 5-HT2A receptors with positron emission tomography. Life Sci 58(10):Pl87–Pl92CrossRefGoogle Scholar
  74. 74.
    Maeshima T, Shutoh F, Hamada S, Senzaki K, Hamaguchi-Hamada K, Ito R et al (1998) Serotonin2A receptor-like immunoreactivity in rat cerebellar Purkinje cells. Neurosci Lett 252(1):72–74PubMedCrossRefGoogle Scholar
  75. 75.
    Johnson MP, Siegel BW, Carr AA (1996) [3H]MDL 100907: a novel selective 5-HT2A receptor ligand. Naunyn Schmiedebergs Arch Pharmacol 354(2):205–209PubMedCrossRefGoogle Scholar
  76. 76.
    Herth MM, Volk B, Pallagi K, Bech LK, Antoni FA, Knudsen GM et al (2012) Synthesis and in vitro evaluation of oxindole derivatives as potential radioligands for 5-HT7 receptor imaging with PET. ACS Chem Neurosci 3(12):1002–1007PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Marazziti D, Rossi A, Giannaccini G, Zavaglia KM, Dell'Osso L, Lucacchini A et al (1999) Distribution and characterization of [3H]mesulergine binding in human brain postmortem. Eur Neuropsychopharmacol 10(1):21–26PubMedCrossRefGoogle Scholar
  78. 78.
    Varnas K, Thomas DR, Tupala E, Tiihonen J, Hall H (2004) Distribution of 5-HT7 receptors in the human brain: a preliminary autoradiographic study using [3H]SB-269970. Neurosci Lett 367(3):313–316PubMedCrossRefGoogle Scholar
  79. 79.
    Grossisseroff R, Dillon KA, Fieldust SJ, Biegon A (1990) Autoradiographic analysis of alpha-1-noradrenergic receptors in the human brain postmortem—effect of suicide. Arch Gen Psychiatry 47(11):1049–1053CrossRefGoogle Scholar
  80. 80.
    DePaermentier F, Mauger JM, Lowther S, Crompton MR, Katona CLE, Horton RW (1997) Brain alpha-adrenoceptors in depressed suicides. Brain Res 757(1):60–68CrossRefGoogle Scholar
  81. 81.
    Boyson SJ, Mcgonigle P, Molinoff PB (1986) Quantitative autoradiographic localization of the D1 and D2 subtypes of dopamine-receptors in rat-brain. J Neurosci 6(11):3177–3188PubMedGoogle Scholar
  82. 82.
    Boyson SJ, Adams C (1991) A detailed quantitative autoradiographic study of D2 receptors in parkinsons-disease and progressive supranuclear palsy. Ann Neurol 30(2):256Google Scholar
  83. 83.
    Boyson SJ, Adams CE (1997) D1 and D2 dopamine receptors in perinatal and adult basal ganglia. Pediatr Res 41(6):822–831PubMedCrossRefGoogle Scholar
  84. 84.
    Boyson SJ, Adams C (1990) Receptors for dopaminergic and serotonergic drugs in human choroid-plexus. Ann Neurol 28(2):250Google Scholar
  85. 85.
    Hall H, Lundkvist C, Halldin C, Farde L, Pike VW, McCarron JA et al (1997) Autoradiographic localization of 5-HT1A receptors in the post-mortem human brain using [3H]WAY 100635 and [11C]WAY 100635. Brain Res 745(1–2):96–108PubMedCrossRefGoogle Scholar
  86. 86.
    Hall H, Halldin C, Farde L, Sedvall G (1998) Whole hemisphere autoradiography of the postmortem human brain. Nucl Med Biol 25(8):715–719PubMedCrossRefGoogle Scholar
  87. 87.
    Mo HP, Balko KM, Colby DA (2010) A practical deuterium-free NMR method for the rapid determination of 1-octanol/water partition coefficients of pharmaceutical agents. Bioorg Med Chem Lett 20(22):6712–6715PubMedCrossRefGoogle Scholar
  88. 88.
    OECD (1989) Guideline for testing of chemicals. OECD, ParisGoogle Scholar
  89. 89.
    Rowley M, Kulagowski JJ, Watt AP, Rathbone D, Stevenson GI, Carling RW et al (1997) Effect of plasma protein binding on in vivo activity and brain penetration of glycine/NMDA receptor antagonists. J Med Chem 40(25):4053–4068PubMedCrossRefGoogle Scholar
  90. 90.
    Bouchard G, Pagliara A, Carrupt PA, Testa B, Gobry V, Girault HH (2002) Theoretical and experimental exploration of the lipophilicity of zwitterionic drugs in the 1,2-dichloroethane/water system. Pharm Res 19(8):1150–1159PubMedCrossRefGoogle Scholar
  91. 91.
    Pike VW (2009) PET radiotracers: crossing the blood-brain barrier and surviving metabolism. Trends Pharmacol Sci 30(8):431–440PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Waring MJ (2010) Lipophilicity in drug discovery. Expert Opin Drug Dis 5(3):235–248CrossRefGoogle Scholar
  93. 93.
    Herth MM, Kramer V, Piel M, Palner M, Riss PJ, Knudsen GM et al (2009) Synthesis and in vitro affinities of various MDL 100907 derivatives as potential 18F-radioligands for 5-HT2A receptor imaging with PET. Bioorgan Med Chem 17(8):2989–3002CrossRefGoogle Scholar
  94. 94.
    Muehlhausen UEJ, Coenen HH (2008) Synthesis, labeling and first evaluation of [18F]R91150 as a serotonin 5-HT2A receptor antagonist for PET. J Label Compd Radiopharm 52(1):13–22CrossRefGoogle Scholar
  95. 95.
    Ettrup A, Hansen M, Santini MA, Paine J, Gillings N, Palner M et al (2011) Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT2A agonist PET tracers. Eur J Nucl Med Mol Imaging 38(4):681–693PubMedCrossRefGoogle Scholar
  96. 96.
    Reichel A, Begley DJ (1998) Potential of immobilized artificial membranes for predicting drug penetration across the blood-brain barrier. Pharm Res 15(8):1270–1274PubMedCrossRefGoogle Scholar
  97. 97.
    Vraka CNL, Hendl M, Zeilinger M, Savli M, Lanzenberger R, Mitterhauser M, Wadsak W (2013) Immobilized artificial membrane (IAM) chromatographie—ine geeignete, präklinische Methode zur Vorhersage der Bluthirnschranken Penetration? AGRR Abstract BookGoogle Scholar
  98. 98.
    Ishiwata K, Yanai K, Iwata R, Takahashi T, Hatazawa J, Ithoh M, Watabe T, Ido T (1996) Analysis of plasma metabolites during human PET-studies with three receptor ligands, [11C]YM-09151-2, [11C]doxepin and [11C]pyrilamine. Tohoku J Exp Med 178(2):129–136PubMedCrossRefGoogle Scholar
  99. 99.
    Wong DF, Gjedde A, Wagner HN (1986) Quantification of neuroreceptors in the living human-brain 1. Irreversible binding of ligands. J Cerebr Blood Flow Metab 6(2):137–146CrossRefGoogle Scholar
  100. 100.
    Doble A, Girdlestone D, Piot O, Allam D, Betschart J, Boireau A et al (1992) Pharmacological characterization of RP-62203, a novel 5-hydroxytryptamine 5-HT2 receptor antagonist. Br J Pharmacol 105(1):27–36PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Ashworth S, Hume SP, Lammertsma AA, OpackaJuffry J, Shah F, Pike VW (1996) Development of central 5-HT2A receptor radioligands for PET: comparison of [3H]RP 62203 and [3H]SR 46349B kinetics in rat brain. Nucl Med Biol 23(3):245–250PubMedCrossRefGoogle Scholar
  102. 102.
    Fajolles C, Boireau A, Ponchant M, Laduron PM (1992) [3H]RP-62203, a ligand of choice to label invivo brain 5-HT2 receptors. Eur J Pharmacol 216(1):53–57PubMedCrossRefGoogle Scholar
  103. 103.
    Baron JC, Samson Y, Comar D, Crouzel C, Deniker P, Agid Y (1985) An invivo study of central serotonin receptors in humans using 11C-labeled ketanserin and positron tomography. Rev Neurol 141(8–9):537–545PubMedGoogle Scholar
  104. 104.
    Moerlein SM, Perlmutter JS (1991) Central serotonergic S2 binding in Papio-Anubis measured invivo with N-omega-[18F]Fluoroethylketanserin and PET. Neurosci Lett 123(1):23–26PubMedCrossRefGoogle Scholar
  105. 105.
    Lyon RA, Titeler M, Frost JJ, Whitehouse PJ, Wong DF, Wagner HN et al (1986) [3H]3-N-methylspiperone labels D2 dopamine-receptors in basal ganglia and S2 serotonin receptors in cerebral-cortex. J Neurosci 6(10):2941–2949PubMedGoogle Scholar
  106. 106.
    Lever JR, Dannals RF, Wilson AA, Ravert HT, Scheffel U, Hoffman BJ et al (1989) Synthesis and invivo characterization of D-(+)-(N1-[11C]Methyl)-2-Br-Lsd—a radioligand for positron emission tomographic studies of Serotonin 5-HT2 receptors. Nucl Med Biol 16(7):697–704Google Scholar
  107. 107.
    Blin J, Pappata S, Kiyosawa M, Crouzel C, Baron JC (1988) [18F]Setoperone—a new high-affinity ligand for positron emission Tomography study of the serotonin-2 receptors in baboon brain invivo. Eur J Pharmacol 147(1):73–82PubMedCrossRefGoogle Scholar
  108. 108.
    Besret L, Dauphin F, Huard C, Lasne MC, Vivet R, Mickala P et al (1996) Specific in vivo binding in the rat brain of [18F]RP 62203: a selective 5-HT2A receptor radioligand for positron emission tomography. Nucl Med Biol 23(2):169–171PubMedCrossRefGoogle Scholar
  109. 109.
    Herth MM, Piel M, Debus F, Schmitt U, Luddens H, Rosch F (2009) Preliminary in vivo and ex vivo evaluation of the 5-HT2A imaging probe [18F]MH.MZ. Nucl Med Biol 36(4):447–454PubMedCrossRefGoogle Scholar
  110. 110.
    Kramer V, Herth MM, Santini MA, Palner M, Knudsen GM, Rosch F (2010) Structural combination of established 5-HT2A receptor ligands: new aspects of the binding mode. Chem Biol Drug Des 76(4):361–366PubMedCrossRefGoogle Scholar
  111. 111.
    Lemaire C, Cantineau R, Guillaume M, Plenevaux A, Christiaens L (1991) [18F]Altanserin—a radioligand for the study of serotonin receptors with PET—radiolabeling and invivo biologic behavior in rats. J Nucl Med 32(12):2266–2272PubMedGoogle Scholar
  112. 112.
    van Dyck CH, Malison RT, Seibyl JP, Laruelle M, Klumpp H, Zoghbi SS et al (2000) Age-related decline in central serotonin transporter availability with [123I]beta-CIT SPECT. Neurobiol Aging 21(4):497–501PubMedCrossRefGoogle Scholar
  113. 113.
    Herth MM, Knudsen GM (2015) Current radiosynthesis strategies for 5-HT2A receptor PET tracers. J Labelled Comp Radiopharm 58(7):265–273PubMedCrossRefGoogle Scholar
  114. 114.
    Ettrup A, Hansen M, Santini MA, Paine J, Gillings N, Palner M et al (2010) In vivo evaluation of a series of substituted 11C-phenetylamines as 5-HT2A agonist PET tracers. NeuroImage 52:48CrossRefGoogle Scholar
  115. 115.
    Tan PZ, Baldwin RM, Van Dyck CH, Al-Tikriti M, Roth B, Khan N et al (1999) Characterization of radioactive metabolites of 5-HT2A receptor PET ligand [18F]altanserin in human and rodent. Nucl Med Biol 26(6):601–608PubMedCrossRefGoogle Scholar
  116. 116.
    Biver F, Lotstra F, Monclus M, Dethy S, Damhaut P, Wikler D et al (1997) In vivo binding of [18F]altanserin to rat brain 5-HT2 receptors: a film and electronic autoradiographic study. Nucl Med Biol 24(4):357–360PubMedCrossRefGoogle Scholar
  117. 117.
    Hasler F, OF K, Krasikova RN, Cservenyak T, Quednow BB, Vollenweider FX et al (2009) GMP-compliant radiosynthesis of [18F]altanserin and human plasma metabolite studies. Appl Radiat Isot 67(4):598–601PubMedCrossRefGoogle Scholar
  118. 118.
    Smith GS, Price JC, Lopresti BJ, Huang YY, Simpson N, Holt D et al (1998) Test-retest variability of serotonin 5-HT2A receptor binding measured with positron emission tomography and [18F]altanserin in the human brain. Synapse 30(4):380–392PubMedCrossRefGoogle Scholar
  119. 119.
    Price JC, Lopresti BJ, Mason NS, Holt DP, Huang Y, Mathis CA (2001) Analyses of [18F]altanserin bolus injection PET data. I: consideration of radiolabeled metabolites in baboons. Synapse 41(1):1–10PubMedCrossRefGoogle Scholar
  120. 120.
    Price JC, Lopresti BJ, Meltzer CC, Smith GS, Mason NS, Huang Y et al (2001) Analyses of [18F]altanserin bolus injection PET data. II: consideration of radiolabeled metabolites in humans. Synapse 41(1):11–21PubMedCrossRefGoogle Scholar
  121. 121.
    Eastwood SL, Burnet PWJ, Gittins R, Baker K, Harrison PJ (2001) Expression of serotonin 5-HT2A receptors in the human cerebellum and alterations in schizophrenia. Synapse 42(2):104–114PubMedCrossRefGoogle Scholar
  122. 122.
    Biver F, Goldman S, Luxen A, Monclus M, Forestini M, Mendlewicz J et al (1994) Multicompartmental study of [18F]Altanserin binding to brain 5-HT2 receptors in humans using positron emission tomography. Eur J Nucl Med 21(9):937–946PubMedCrossRefGoogle Scholar
  123. 123.
    Riss PJ, Hong YT, Williamson D, Caprioli D, Sitnikov S, Ferrari V et al (2011) Validation and quantification of [18F]altanserin binding in the rat brain using blood input and reference tissue modeling. J Cereb Blood Flow Metabol 31(12):2334–2342CrossRefGoogle Scholar
  124. 124.
    Kroll T, Elmenhorst D, Matusch A, Wedekind F, Weisshaupt A, Beer S et al (2013) Suitability of [18F]altanserin and PET to determine 5-HT2A receptor availability in the rat brain: in vivo and in vitro validation of invasive and non-invasive kinetic models. Mol Imaging Biol 15(4):456–467PubMedCrossRefGoogle Scholar
  125. 125.
    Kroll T, Elmenhorst D, Matusch A, Celik AA, Wedekind F, Weisshaupt A et al (2014) [18F]Altanserin and small animal PET: impact of multidrug efflux transporters on ligand brain uptake and subsequent quantification of 5-HT2A receptor densities in the rat brain. Nucl Med Biol 41(1):1–9PubMedCrossRefGoogle Scholar
  126. 126.
    Riss PJ, Hong YT, Williamson D, Caprioli D, Sitnikov S, Ferrari V et al (2011) Validation and quantification of [F-18]altanserin binding in the rat brain using blood input and reference tissue modeling. J Cerebr Blood Flow Metab 31(12):2334–2342CrossRefGoogle Scholar
  127. 127.
    Shrestha SS, Liow J, Lu S, Jenko K, Gladding RL, Svenningsson P, Morse CL, Zoghbi SS, Pike VW, Innis RB (2014) [11C]CUMI-101, a PET Radioligand, behaves as a serotonin 1A recepor antagonist and also binds to alpha-1 adrenoceptors in brain. J Nucl Med 55:141–146PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Sadzot B, Lemaire C, Maquet P, Salmon E, Plenevaux A, Degueldre C et al (1995) Serotonin 5-HT2A receptor imaging in the human brain using positron emission tomography and a new radioligand, [18F]Altanserin—results in young normal controls. J Cereb Blood Flow Metab 15(5):787–797PubMedCrossRefGoogle Scholar
  129. 129.
    Syvanen S, Lindhe O, Palner M, Kornum BR, Rahman O, Langstrom B et al (2009) Species differences in blood-brain barrier Transport of three positron emission tomography radioligands with emphasis on P-Glycoprotein transport. Drug Metab Dispos 37(3):635–643PubMedCrossRefGoogle Scholar
  130. 130.
    Froklage FE, Syvänen S, Hendrikse NH, Huisman MC, Molthoff CMF, Tagawa Y, Reijneveld JC, Heimans JJ, Lammertsma AA, Eriksson J, de Lange ECM, Voskuyl RA (2012) [11C]Flumazenil brain uptake is influenced by the blood-brain barrier efflux transporter P-glycoprotein. EJNMMI Res 2:12PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Martin A, Szczupak B, Gomez-Vallejo V, Plaza S, Padro D, Cano A et al (2013) PET imaging of serotoninergic neurotransmission with [11C]DASB and [18F]altanserin after focal cerebral ischemia in rats. J Cereb Blood Flow Metab 33(12):1967–1975PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Moses EL, Drevets WC, Smith G, Mathis CA, Kalro BN, Butters MA et al (2000) Effects of estradiol and progesterone administration on human serotonin 2A receptor binding: a PET study. Biol Psychiatry 48(8):854–860PubMedCrossRefGoogle Scholar
  133. 133.
    Mintun MA, Sheline YI, Moerlein SM, Vlassenko AG, Huang YY, Snyder AZ (2004) Decreased hippocampal 5-HT2A receptor binding in major depressive disorder: in vivo measurement with [18F]Altanserin positron emission tomography. Biol Psychiatry 55(3):217–224PubMedCrossRefGoogle Scholar
  134. 134.
    Haugbol S, Pinborg LH, Arfan HM, Frokjaer VM, Madsen J, Dyrby TB et al (2007) Reproducibility of 5-HT2A receptor measurements and sample size estimations with [18F]altanserin PET using a bolus/infusion approach. Eur J Nucl Med Mol Imaging 34(6):910–915PubMedCrossRefGoogle Scholar
  135. 135.
    Soares JC, van Dyck CH, Tan PZ, Zoghbi SS, Garg P, Soufer R et al (2001) Reproducibility of in vivo brain measures of 5-HT2A receptors with PET and [18F]deuteroaltanserin. Psychiatry Res Neuroim 106(2):81–93CrossRefGoogle Scholar
  136. 136.
    Staley JK, Van Dyck CH, Tan PZ, Al Tikriti M, Ramsby Q, Klump H et al (2001) Comparison of [18F]altanserin and [18F]deuteroaltanserin for PET imaging of serotonin(2A) receptors in baboon brain: pharmacological studies. Nucl Med Biol 28(3):271–279PubMedCrossRefGoogle Scholar
  137. 137.
    Kugaya A, Epperson CN, Zoghbi S, van Dyck CH, Hou Y, Fujita M et al (2003) Increase in prefrontal cortex serotonin(2A) receptors following estrogen treatment in postmenopausal women. Am J Psychiat 160(8):1522–1524PubMedCrossRefGoogle Scholar
  138. 138.
    Santhosh L, Estok KM, Vogel RS, Tamagnan GD, Baldwin RM, Mitsis EM et al (2009) Regional distribution and behavioral correlates of 5-HT2A receptors in Alzheimer’s disease with [18F]deuteroaltanserin and PET. Psychiatry Res 173(3):212–217PubMedCrossRefGoogle Scholar
  139. 139.
    Dezi C, Brea J, Alvarado M, Ravina E, Masaguer CF, Loza MI et al (2007) Multistructure 3D-QSAR studies on a series of conformationally constrained butyrophenones docked into a new homology model of the 5-HT2A receptor. J Med Chem 50(14):3242–3255PubMedCrossRefGoogle Scholar
  140. 140.
    Scott DO, Heath TG (1998) Investigation of the CNS penetration of a potent 5-HT2A receptor antagonist (MDL 100907) and an active metabolite (MDL 105725) using in vivo microdialysis sampling in the rat. J Pharm Biomed Anal 17(1):17–25PubMedCrossRefGoogle Scholar
  141. 141.
    Ito H, Nyberg S, Halldin C, Lundkvist C, Farde L (1997) 5-HT2A receptor imaging in the human brain using [11C]MDL 100,907 and PET. J Nucl Med 38(5):297Google Scholar
  142. 142.
    Hirani E, Sharp T, Sprakes M, Grasby P, Hume S (2003) Fenfluramine evokes 5-HT2A receptor-mediated responses but does not displace [11C]MDL 100907: small animal PET and gene expression studies. Synapse 50(3):251–260PubMedCrossRefGoogle Scholar
  143. 143.
    Hinz R, Bhagwagar Z, Cowen PJ, Cunningham VJ, Grasby PM (2007) Validation of a tracer kinetic model for the quantification of 5-HT2A receptors in human brain with [11C]MDL 100907. J Cereb Blood Flow Metab 27(1):161–172PubMedCrossRefGoogle Scholar
  144. 144.
    Bhagwagar Z, Hinz R, Cunningham VJ, Cowen PJ, Grasby PM (2003) Conference: Summer Meeting of the British-Association-for-Psychopharmacology. J Psychopharmacology 17Google Scholar
  145. 145.
    Bhagwayar Z, Hinz R, Taylor M, Fancy S, Cowen PJ, Grasby PM (2006) Increased 5-HT2A receptor binding in euthymic, medciation free recovered depressed patients: a positron emission study with [11C]MDL 100907. Am J Psychiatry 163(9):1580–1587CrossRefGoogle Scholar
  146. 146.
    Talbot PS, Slifstein M, Hwang DR, Huang YY, Scher E, Abi-Dargham A et al (2012) Extended characterisation of the serotonin 2A (5-HT2A) receptor-selective PET radiotracer [11C]MDL 100907 in humans: Quantitative analysis, test-retest reproducibility, and vulnerability to endogenous 5-HT tone. NeuroImage 59(1):271–285PubMedCrossRefGoogle Scholar
  147. 147.
    Urban NBL, Girgis RR, Talbot PS, Kegeles LS, Xu X, Frankle WG et al (2012) Sustained recreational use of ecstasy is associated with altered pre and postsynaptic markers of serotonin transmission in neocortical areas: a PET study with [11C]DASB and [11C]MDL 100907. Neuropsychopharmacology 37(6):1465–1473PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Bhagwagar Z, Hinz R, Taylor M, Fancy S, Cowen PJ, Grasby PM (2005) Increased 5-HT2A receptor binding in euthymic, medication free recovered depressed patients: a positron emission study with [11C]MDL 100,907. J Psychopharmacol 19(5):A52–A5AGoogle Scholar
  149. 149.
    Bhagwagar Z, Hinz R, Taylor M, Fancy S, Cowen P, Grasby P (2006) Increased 5-HT2A receptor binding in euthymic, medication-free patients recovered from depression: a positron emission study with [11C]MDL 100907. Am J Psychiatry 163(9):1580–1587PubMedCrossRefGoogle Scholar
  150. 150.
    Muhlhausen U, Ermert J, Herth MM, Coenen HH (2009) Synthesis, radiofluorination and first evaluation of (+/−)-[18F]MDL 100907 as serotonin 5-HT2A receptor antagonist for PET. J Labelled Comp Radiat 52(1–2):6–12CrossRefGoogle Scholar
  151. 151.
    Ren H, Wey HY, Strebl M, Neelamegam R, Ritter T, Hooker JM (2014) Synthesis and imaging validation of [18F]MDL 100907 enabled by Ni-mediated fluorination. ACS Chem Neurosci 5(7):611–615PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Ren H, Strebl M, Neelamegam R, Hooker J, Ritter T (2014) Advancing PET imaging of central 5-HT2A receptors with [18F]MDL100907: passing the stumbling blocks in late-stage Ni-mediated 18F-fluorination. J Nucl Med 55:554Google Scholar
  153. 153.
    Schmitt U, Leed DE, Herth MM, Piel M, Buchholz HG, Roesch F et al (2011) P-Glycoprotein influence on the brain uptake of a 5-HT2A ligand: [18F]MH.MZ. Neuropsychobiology 63(3):183–190PubMedCrossRefGoogle Scholar
  154. 154.
    Kramer VHM, Hernandez E, Juri C, Pruzzo R, Rösch F, Amaral H (2015) Quantification of 5-HT2A-receptors in the human brainwith [18F]MH.MZ. EANM. Dent Abstr 427:545Google Scholar
  155. 155.
    Hansen H, Herth MM, Ettrup A, Dyssegaard A, Knudsen GM (2013) Comparison of the 5-HT2A PET tracers, [18F]MH.MZ and [18F]altanserin. J Labelled Comp Radiat 56:S338CrossRefGoogle Scholar
  156. 156.
    Dalley JW, Fryer TD, Brichard L, Robinson ESJ, Theobald DEH, Laane K et al (2007) Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. Science 315(5816):1267–1270PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Visser AK, De Vries EF, Ramakrishnan NK, Willemsen AT, Bosker FJ, den Boer JA, Dierckx RA, van Waarde A (2013) Analysis of 5-HT2A receptor binding with [11C]MDL 100907 in rats: optimization of kinetic modeling. Mol Imaging Biol 15(s):730–738PubMedCrossRefGoogle Scholar
  158. 158.
    Fitzgerald LW, Conklin DS, Krause CM, Marshall AP, Patterson JP, Tran DP et al (1999) 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 72(5):2127–2134PubMedCrossRefGoogle Scholar
  159. 159.
    Paterson LM, Tyacke RJ, Nutt DJ, Knudsen GM (2010) Measuring endogenous 5-HT release by emission tomography: promises and pitfalls. J Cereb Blood Flow Metab 30(10):1682–1706PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Verdurand M, Berod A, Le Bars D, Zimmer L (2011) Effects of amyloid-beta peptides on the serotoninergic 5-HT1A receptors in the rat hippocampus. Neurobiol Aging 32(1):103–114PubMedCrossRefGoogle Scholar
  161. 161.
    Lopez-Gimenez JF, Villazon M, Brea J, Loza MI, Palacios JM, Mengod G et al (2001) Multiple conformations of native and recombinant human 5-hydroxytryptamine(2A) receptors are labeled by agonists and discriminated by antagonists. Mol Pharmacol 60(4):690–699PubMedGoogle Scholar
  162. 162.
    Branchek T, Adham N, Macchi M, Kao HT, Hartig PR (1990) [3H]DOB (4-Bromo-2,5-dimethoxyphenylisopropylamine) and [3H]Ketanserin label 2 affinity states of the cloned human 5-hydroxytryptamine2 receptor. Mol Pharmacol 38(5):604–609PubMedGoogle Scholar
  163. 163.
    Narendran R, Hwang DR, Slifstein M, Hwang YC, Huang Y, Ekelund J et al (2004) Measurement of in vivo affinity of [11C]NPA and the proportion of D2 receptors configured in agonist high affinity state (%Rhigh) in baboons using PET. NeuroImage 22:T19–T20Google Scholar
  164. 164.
    Narendran R, Mason NS, Laymon CM, Lopresti BJ, Velasquez ND, May MA et al (2010) A comparative evaluation of the dopamine D2/3 agonist radiotracer [11C](−)-N-propyl-norapomorphine and antagonist [11C]raclopride to measure amphetamine-induced dopamine release in the human striatum. J Pharmacol Exp Ther 333(2):533–539PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Cumming P, Wong DF, Gillings N, Hilton J, Scheffel U, Gjedde A (2002) Specific binding of [11C]raclopride and N-[3H]propyl-norapomorphine to dopamine receptors in living mouse striatum: occupancy by endogenous dopamine and guanosine triphosphate-free G protein. J Cereb Blood Flow Metab 22(5):596–604PubMedCrossRefGoogle Scholar
  166. 166.
    Paterson LM, Nutt DJ, Knudsen GM (2010) A critical review of studies measuring endogenous 5-HT release by emission tomography. NeuroImage 52:107CrossRefGoogle Scholar
  167. 167.
    Diaz SL, Doly S, Narboux-Neme N, Fernandez S, Mazot P, Banas SM et al (2012) 5-HT2B receptors are required for serotonin-selective antidepressant actions. Mol Psychiatry 17(2):154–163PubMedCrossRefGoogle Scholar
  168. 168.
    Bonhaus DW, Bach C, Desouza A, Salazar FHR, Matsuoka BD, Zuppan P et al (1995) The pharmacology and distribution of human 5-hydroxytryptamine(2b) (5-HT2B) receptor gene-products—comparison with 5-HT2A and 5-HT2C receptors. Br J Pharmacol 115(4):622–628PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Choi DS, Maroteaux L (1996) Immunohistochemical localisation of the serotonin 5-HT2B receptor in mouse gut, cardiovascular system, and brain. FEBS Lett 391(1–2):45–51PubMedCrossRefGoogle Scholar
  170. 170.
    Duxon MS, Flanigan TP, Reavley AC, Baxter GS, Blackburn TP, Fone KCF (1997) Evidence for expression of the 5-hydroxytryptamine-2B receptor protein in the rat central nervous system. Neuroscience 76(2):323–329PubMedCrossRefGoogle Scholar
  171. 171.
    Leth-Petersen S, Gabel-Jensen C, Gillings N, Lehel S, Hansen HD, Knudsen GM et al (2016) Metabolic Fate of Hallucinogenic NBOMes. Chem Res Toxicol 29(1):96–100PubMedCrossRefGoogle Scholar
  172. 172.
    Ettrup A, Palner M, Gillings N, Santini MA, Hansen M, Kornum BR et al (2010) Radiosynthesis and evaluation of [11C]Cimbi-5 as a 5-HT2A receptor agonist radioligand for PET. J Nucl Med 51(11):1763–1770PubMedCrossRefGoogle Scholar
  173. 173.
    Ettrup AHS, Hansen M, Wasim M, Santini MA, Palner M, Madsen J, Svarer C, Kristensen JL, Knudsen GM (2013) Preclinical safety assessment of the 5-HT2A receptor agonist PET radioligand [11C]Cimbi-36. Mol Imaging Biol 15(4):376–383PubMedCrossRefGoogle Scholar
  174. 174.
    Finnema SJ, Stepanov V, Ettrup A, Nakao R, Amini N, Svedberg M et al (2014) Characterization of [11C]Cimbi-36 as an agonist PET radioligand for the 5-HT2A and 5-HT2C receptors in the nonhuman primate brain. NeuroImage 84:342–353PubMedCrossRefGoogle Scholar
  175. 175.
    Ettrup A, da Cunha-Bang S, McMahon B, Lehel S, Dyssegaard A, Skibsted AW et al (2014) Serotonin 2A receptor agonist binding in the human brain with [11C]Cimbi-36. J Cereb Blood Flow Metab 34(7):1188–1196PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Ettrup A, Hansen M, Gillings N, Dyssegaard A, Lehel S, Hansen HD et al (2012) Development of an 18F-labeled 5-HT2A receptor agonist PET radioligand. J Cereb Blood Flow Metab 32:109Google Scholar
  177. 177.
    Herth MM, Petersen IN, Hansen HD, Hansen M, Ettrup A, Jensen AA, Lehel S, Dyssegaard A, Gillings N, Knudsen GM, Kristensena JL (2016) Synthesis and evaluation of 18F-labeled 5-HT2A receptor agonists as PET ligands. Nucl Med Biol 43(8):455–462PubMedCrossRefGoogle Scholar
  178. 178.
    Prabhakaran J, Underwood MD, Kumar JSD, Simpson NR, Kassir SA, Bakalian MJ et al (2015) Synthesis and in vitro evaluation of [18F]FECIMBI-36: a potential agonist PET ligand for 5-HT2A/2C receptors. Bioorg Med Chem Lett 25(18):3933–3936PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Olesen J, Leonardi M (2003) The burden of brain diseases in Europe. Eur J Neurol 10(5):471–477PubMedCrossRefGoogle Scholar
  180. 180.
    Turecki G, Briere R, Dewar K, Antonetti T, Lesage A, Seguin M et al (1999) 5-HTR2A genetic variation and level of 5-HT2A receptor binding in completed suicide cases. Biol Psychiatry 45(8):123Google Scholar
  181. 181.
    Arango V, Ernsberger P, Marzuk PM, Chen JS, Tierney H, Stanley M et al (1990) Autoradiographic demonstration of increased serotonin 5-HT2 and beta-adrenergic-receptor binding-sites in the brain of suicide victims. Arch Gen Psychiatry 47(11):1038–1047PubMedCrossRefGoogle Scholar
  182. 182.
    Hrdina PD, Demeter E, Vu TB, Sotonyi P, Palkovits M (1993) 5-HT uptake sites and 5-HT2 receptors in brain of antidepressant-free suicide victims depressives—increase in 5-HT2 sites in cortex and amygdala. Brain Res 614(1–2):37–44PubMedCrossRefGoogle Scholar
  183. 183.
    Stockmeier CA (2003) Involvement of serotonin in depression: evidence from postmortem and imaging studies of serotonin receptors and the serotonin transporter. J Psychiatr Res 37(5):357–373PubMedCrossRefGoogle Scholar
  184. 184.
    Biver F, Wikler D, Lotstra F, Damhaut P, Goldman S, Mendlewicz J (1997) Serotonin 5-HT2 receptor imaging in major depression: focal changes in orbito-insular cortex. Br J Psychiatry 171:444–448PubMedCrossRefGoogle Scholar
  185. 185.
    Sheline YI, Mintun MA, Barch DM, Wilkins C, Snyder AZ, Moerlein SM (2004) Decreased hippocampal 5-HT2A receptor binding in older depressed patients using [18F]altanserin positron emission tomography. Neuropsychopharmacology 29(12):2235–2241PubMedCrossRefGoogle Scholar
  186. 186.
    Meyer JH, McMain S, Kennedy SH, Korman L, Brown GM, DaSilva JN et al (2003) Dysfunctional attitudes and 5-HT2 receptors during depression and self-harm. Am J Psychiatry 160(1):90–99PubMedCrossRefGoogle Scholar
  187. 187.
    Kurita M, Holloway T, Garcia-Bea A, Kozlenkov A, Friedman AK, Moreno JL et al (2012) HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity. Nat Neurosci 15(9):1245–1254PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Miyamoto S, Duncan GE, Marx CE, Lieberman JA (2005) Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 10(1):79–104PubMedCrossRefGoogle Scholar
  189. 189.
    Fribourg M, Moreno JL, Holloway T, Provasi D, Baki L, Mahajan R et al (2011) Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs. Cell 147(5):1011–1023PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Young BG (1974) A phenomenological comparison of LSD and schizophrenic states. Br J Psychiatry 124(578):64–74PubMedCrossRefGoogle Scholar
  191. 191.
    Hermle L, Funfgeld M, Oepen G, Botsch H, Borchardt D, Gouzoulis E et al (1992) Mescaline-induced psychopathological, neuropsychological, and neurometabolic effects in normal subjects: experimental psychosis as a tool for psychiatric research. Biol Psychiatry 32(11):976–991PubMedCrossRefGoogle Scholar
  192. 192.
    Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A, Vogel H, Hell D (1998) Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport 9(17):3897–3902PubMedCrossRefGoogle Scholar
  193. 193.
    Gouzoulis-Mayfrank E, Arnold S, Heekeren K (2006) Deficient inhibition of return in schizophrenia-further evidence from an independent sample. Prog Neuro-Psychopharmacol Biol Psychiatry 30(1):42–49CrossRefGoogle Scholar
  194. 194.
    Quednow BB, Ettinger U, Mossner R, Rujescu D, Giegling I, Collier DA et al (2011) The schizophrenia risk allele C of the TCF4 rs9960767 polymorphism disrupts sensorimotor gating in schizophrenia spectrum and healthy volunteers. J Neurosci 31(18):6684–6691PubMedCrossRefGoogle Scholar
  195. 195.
    Gonzalez-Maeso J, Sealfon SC (2009) Agonist-trafficking and hallucinogens. Curr Med Chem 16(8):1017–1027PubMedCrossRefGoogle Scholar
  196. 196.
    Muguruza C, Moreno JL, Umali A, Callado LF, Meana JJ, Gonzalez-Maeso J (2013) Dysregulated 5-HT2A receptor binding in postmortem frontal cortex of schizophrenic subjects. Eur Neuropsychopharmacol 23(8):852–864PubMedCrossRefGoogle Scholar
  197. 197.
    Bennett JP Jr, Enna SJ, Bylund DB, Gillin JC, Wyatt RJ, Snyder SH (1979) Neurotransmitter receptors in frontal cortex of schizophrenics. Arch Gen Psychiatry 36(9):927–934PubMedCrossRefGoogle Scholar
  198. 198.
    Gurevich EV, Joyce JN (1997) Alterations in the cortical serotonergic system in schizophrenia: a postmortem study. Biol Psychiatry 42(7):529–545PubMedCrossRefGoogle Scholar
  199. 199.
    Dean B, Crossland N, Boer S, Scarr E (2008) Evidence for altered post-receptor modulation of the serotonin 2a receptor in schizophrenia. Schizophr Res 104(1–3):185–197PubMedCrossRefGoogle Scholar
  200. 200.
    Kang K, Huang XF, Wang Q, Deng C (2009) Decreased density of serotonin 2A receptors in the superior temporal gyrus in schizophrenia—a postmortem study. Prog Neuro-Psychopharmacol Biol Psychiatry 33(5):867–871CrossRefGoogle Scholar
  201. 201.
    Gonzalez-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, Lopez-Gimenez JF et al (2008) Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 452(7183):93–97PubMedPubMedCentralCrossRefGoogle Scholar
  202. 202.
    Dean B (2003) The cortical serotonin2A receptor and the pathology of schizophrenia: a likely accomplice. J Neurochem 85(1):1–13PubMedCrossRefGoogle Scholar
  203. 203.
    Lewis R, Kapur S, Jones C, DaSilva J, Brown GM, Wilson AA et al (1999) Serotonin 5-HT2 receptors in schizophrenia: a PET study using [18F]setoperone in neuroleptic-naive patients and normal subjects. Am J Psychiatry 156(1):72–78PubMedCrossRefGoogle Scholar
  204. 204.
    Okubo Y, Suhara T, Suzuki K, Kobayashi K, Inoue O, Terasaki O et al (2000) Serotonin 5-HT2 receptors in schizophrenic patients studied by positron emission tomography. Life Sci 66(25):2455–2464PubMedCrossRefGoogle Scholar
  205. 205.
    Trichard C, Paillere-Martinot ML, Attar-Levy D, Blin J, Feline A, Martinot JL (1998) No serotonin 5-HT2A receptor density abnormality in the cortex of schizophrenic patients studied with PET. Schizophr Res 31(1):13–17PubMedCrossRefGoogle Scholar
  206. 206.
    Ngan ET, Yatham LN, Ruth TJ, Liddle PF (2000) Decreased serotonin 2A receptor densities in neuroleptic-naive patients with schizophrenia: a PET study using [18F]setoperone. Am J Psychiatry 157(6):1016–1018PubMedCrossRefGoogle Scholar
  207. 207.
    Hurlemann R, Boy C, Meyer PT, Scherk H, Wagner M, Herzog H et al (2005) Decreased prefrontal 5-HT2A receptor binding in subjects at enhanced risk for schizophrenia. Anat Embryol 210(5–6):519–523PubMedCrossRefGoogle Scholar
  208. 208.
    Rasmussen H, Erritzoe D, Andersen R, Ebdrup BH, Aggernaes B, Oranje B et al (2010) Decreased frontal serotonin(2A) receptor binding in antipsychotic-naive patients with first-episode schizophrenia. Arch Gen Psychiatry 67(1):9–16PubMedCrossRefGoogle Scholar
  209. 209.
    Roerig JL, Steffen KJ, Mitchell JE (2011) Atypical antipsychotic-induced weight gain: insights into mechanisms of action. CNS Drugs 25(12):1035–1059PubMedCrossRefGoogle Scholar
  210. 210.
    Huang XF, Han M, Storlien LH (2004) Differential expression of 5-HT2A and 5-HT2C receptor mRNAs in mice prone, or resistant, to chronic high-fat diet-induced obesity. Brain Res Mol Brain Res 127(1–2):39–47PubMedCrossRefGoogle Scholar
  211. 211.
    Huang XF, Huang X, Han M, Chen F, Storlien L, Lawrence AJ (2004) 5-HT2A/2C receptor and 5-HT transporter densities in mice prone or resistant to chronic high-fat diet-induced obesity: a quantitative autoradiography study. Brain Res 1018(2):227–235PubMedCrossRefGoogle Scholar
  212. 212.
    Pinborg LH, Adams KH, Svarer C, Holm S, Hasselbalch SG, Haugbol S et al (2003) Quantification of 5-HT2A receptors in the human brain using [18F]altanserin-PET and the bolus/infusion approach. J Cereb Blood Flow Metab 23(8):985–996PubMedCrossRefGoogle Scholar
  213. 213.
    Erritzoe D, Frokjaer VG, Haugbol S, Marner L, Svarer C, Holst K et al (2009) Brain serotonin 2A receptor binding: relations to body mass index, tobacco and alcohol use. NeuroImage 46(1):23–30PubMedCrossRefGoogle Scholar
  214. 214.
    Haahr ME, Hansen DL, Fisher PM, Svarer C, Stenbaek DS, Madsen K et al (2015) Central 5-HT neurotransmission modulates weight loss following gastric bypass surgery in obese individuals. J Neurosci 35(14):5884–5889PubMedCrossRefGoogle Scholar
  215. 215.
    Newcomer JW, Ratner RE, Eriksson JW, Emsley R, Meulien D, Miller F et al (2009) A 24-week, multicenter, open-label, randomized study to compare changes in glucose metabolism in patients with schizophrenia receiving treatment with olanzapine, quetiapine, or risperidone. J Clin Psychiatry 70(4):487–499PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Rasmussen H, Ebdrup BH, Oranje B, Pinborg LH, Knudsen GM, Glenthoj B (2014) Neocortical serotonin2A receptor binding predicts quetiapine associated weight gain in antipsychotic-naive first-episode schizophrenia patients. Int J Neuropsychopharmacol 17(11):1729–1736PubMedCrossRefGoogle Scholar
  217. 217.
  218. 218.
    Lai MK, Tsang SW, Alder JT, Keene J, Hope T, Esiri MM et al (2005) Loss of serotonin 5-HT2A receptors in the postmortem temporal cortex correlates with rate of cognitive decline in Alzheimer’s disease. Psychopharmacology 179(3):673–677PubMedCrossRefGoogle Scholar
  219. 219.
    Blin J, Baron JC, Dubois B, Crouzel C, Fiorelli M, Attarlevy D et al (1993) Loss of brain 5-HT2 receptors in Alzheimers-disease—in-vivo assessment with positron emission tomography and [18F]setoperone. Brain 116:497–510PubMedCrossRefGoogle Scholar
  220. 220.
    Meltzer CC, Price JC, Mathis CA, Greer PJ, Cantwell MN, Houck PR et al (1999) PET imaging of serotonin type 2A receptors in late-life neuropsychiatric disorders. Am J Psychiatry 156(12):1871–1878PubMedGoogle Scholar
  221. 221.
    Versijpt J, Van Laere KJ, Dumont F, Decoo D, Vandecapelle M, Santens P et al (2003) Imaging of the 5-HT2A system: age-, gender-, and Alzheimer’s disease-related findings. Neurobiol Aging 24(4):553–561PubMedCrossRefGoogle Scholar
  222. 222.
    Marner L, Knudsen GM, Madsen K, Holm S, Baare W, Hasselbalch SG (2011) The reduction of baseline serotonin 2A receptors in mild cognitive impairment is stable at two-year follow-up. J Alzheimers Dis 23(3):453–459PubMedGoogle Scholar
  223. 223.
    Dierckx RAJO, Otte A, de Vries EFJ, van Waarde A, Luiten PGM (2014) S.G. PET and SPECT of neurobiological systems. Springer, New York. Chapter 23 (ISBN 978-3-642-42014-6)CrossRefGoogle Scholar
  224. 224.
    Marner L, Frokjaer VG, Kalbitzer J, Lehel S, Madsen K, Baare WFC et al (2012) Loss of serotonin 2A receptors exceeds loss of serotonergic projections in early Alzheimer’s disease: a combined [11C]DASB and [18F]altanserin-PET study. Neurobiol Aging 33(3):479–487PubMedCrossRefGoogle Scholar
  225. 225.
    Braak H, Braak E (1991) Demonstration of amyloid deposits and neurofibrillary changes in whole brain sections. Brain Pathol 1(3):213–216PubMedCrossRefGoogle Scholar
  226. 226.
    Jack CR, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW et al (2010) Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 9(1):119–128PubMedPubMedCentralCrossRefGoogle Scholar
  227. 227.
    Holm P, Ettrup A, Klein AB, Santini MA, El-Sayed M, Elvang AB et al (2010) Plaque deposition dependent decrease in 5-HT2A serotonin receptor in a beta PPswe/PS1dE9 amyloid overexpressing mice. J Alzheimers Dis 20(4):1201–1213PubMedCrossRefGoogle Scholar
  228. 228.
    Christensen R, Marcussen AB, Wortwein G, Knudsen GM, Aznar S (2008) A beta((1-42)) injection causes memory impairment, lowered cortical and serum BDNF levels, and decreased hippocampal 5-HT2A levels. Exp Neurol 210(1):164–171PubMedCrossRefGoogle Scholar
  229. 229.
    Meltzer CC, Smith G, DeKosky ST, Pollock BG, Mathis CA, Moore RY et al (1998) Serotonin in aging, late-life depression, and Alzheimer’s disease: the emerging role of functional imaging. Neuropsychopharmacology 18(6):407–430PubMedCrossRefGoogle Scholar
  230. 230.
    Friedman JH (2013) Pimavanserin for the treatment of Parkinson’s disease psychosis. Expert Opin Pharmacol 14(14):1969–1975CrossRefGoogle Scholar
  231. 231.
    Vanover KE, Weiner DM, Makhay M, Veinbergs I, Gardell LR, Lameh J et al (2006) Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N '-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R, 3R)-dihydroxybutanedioate (2, 1) (ACP-103), a novel 5-hydroxytryptamine(2A) receptor inverse agonist. J Pharmacol Exp Ther 317(2):910–918PubMedCrossRefGoogle Scholar
  232. 232.
    Nordstrom AL, Mansson M, Jovanovic H, Karlsson P, Halldin C, Farde L et al (2008) PET analysis of the 5-HT2A receptor inverse agonist ACP-103 in human brain. Int J Neuropsychopharmacol 11(2):163–171PubMedCrossRefGoogle Scholar
  233. 233.
    Andersen VL, Hansen HD, Herth MM, Dyssegaard A, Knudsen GM, Kristensen JL (2015) 11C-labeling and preliminary evaluation of pimavanserin as a 5-HT2A receptor PET-radioligand. Bioorg Med Chem Lett 25(5):1053–1056PubMedCrossRefGoogle Scholar
  234. 234.
    Rasmussen H, Ebdrup BH, Erritzoe D, Aggernaes B, Oranje B, Kalbitzer J et al (2011) Serotonin 2A receptor blockade and clinical effect in first-episode schizophrenia patients treated with quetiapine. Psychopharmacology 213(2–3):583–592PubMedCrossRefGoogle Scholar
  235. 235.
    Laruelle M, Abi-Dargham A, van Dyck C, Gil R, D'Souza DC, Krystal J et al (2000) Dopamine and serotonin transporters in patients with schizophrenia: an imaging study with [123I]beta-CIT. Biol Psychiatry 47(5):371–379PubMedCrossRefGoogle Scholar
  236. 236.
    Egerton A, Demjaha A, Grasby PM, McGuire PK, Murray RM, Howes OD (2009) Longitudinal assessment of presynaptic dopamine function in the striatum: a [18F]DOPA PET test-retest study. Eur Neuropsychopharmacol 19:S313–S3S4Google Scholar
  237. 237.
    Egerton A, McGuire PK, Howes OD, Egerton A, Howes OD (2009) Functionally defined regions may aid interpretation of striatal dopamine elevation in schizophrenia. Schizophr Res 109(1–3):200PubMedCrossRefGoogle Scholar
  238. 238.
    Abi-Dargham A (2004) Antipsychotics across the spectrum: an overview of their mechanisms of action. Int J Neuropsychopharmacol 7:100CrossRefGoogle Scholar
  239. 239.
    Brooks DJ, Piccini P (2006) Imaging in Parkinson’s disease: the role of monoamines in behavior. Biol Psychiatry 59(10):908–918PubMedCrossRefGoogle Scholar
  240. 240.
    Tyacke RJ, Nutt DJ (2015) Optimising PET approaches to measuring 5-HT release in human brain. Synapse 69(10):505–511PubMedCrossRefGoogle Scholar
  241. 241.
    Larisch R, Klimke A, Hamacher K, Henning U, Estaji S, Hohlfeld T et al (2003) Influence of synaptic serotonin level on [18F]altanserin binding to 5-HT2A receptors in man. Behav Brain Res 139(1–2):21–29PubMedCrossRefGoogle Scholar
  242. 242.
    Toll LB-GI, Polgar WE, Brandt SR, Adapa ID, Rodriguez L, Schwartz RW, Haggart D, O'Brien A, White A, Kennedy JM, Craymer K, Farrington L, Auh JS (1998) Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications. NIDA Res Monogr 178:440–466PubMedGoogle Scholar
  243. 243.
    Millan MJGA, Lejeune F, Newman-Tancredi A, Rivet JM, Auclair A, Peglion JL (2001) S33005, a novel ligand at both serotonin and norepinephrine transporters: I. Receptor binding, electrophysiological, and neurochemical profile in comparison with venlafaxine, reboxetine, citalopram, and clomipramine. J Pharmacol Exp Ther 298(2):565–580PubMedGoogle Scholar
  244. 244.
    Palvimaki EP, Roth BL, Majasuo H, Laakso A, Kuoppamaki M, Syvalahti E et al (1996) Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2C receptor. Psychopharmacology 126(3):234–240PubMedCrossRefGoogle Scholar
  245. 245.
    Pinborg LH, Adams KH, Yndgaard T, Hasselbalch SG, Holm S, Kristiansen H et al (2004) [18F]altanserin binding to human 5-HT2A receptors is unaltered after citalopram and pindolol challenge. J Cereb Blood Flow Metab 24(9):1037–1045PubMedCrossRefGoogle Scholar
  246. 246.
    Mork A, Kreilgaard M, Sanchez C (2003) The R-enantiomer of citalopram increase in extracellular 5-HT counteracts escitalopram-induced in the frontal cortex of freely moving rats. Neuropharmacology 45(2):167–173PubMedCrossRefGoogle Scholar
  247. 247.
    Quednow BB, Treyer V, Hasler F, Dorig N, Wyss MT, Burger C et al (2012) Assessment of serotonin release capacity in the human brain using dexfenfluramine challenge and [18F]altanserin positron emission tomography. NeuroImage 59(4):3922–3932PubMedCrossRefGoogle Scholar
  248. 248.
    Matusch A, Hurlemann R, Kops ER, Winz OH, Elmenhorst D, Herzog H et al (2007) Acute S-ketamine application does not alter cerebral [18F]altanserin binding: a pilot PET study in humans. J Neural Transm 114(11):1433–1442PubMedCrossRefGoogle Scholar
  249. 249.
    Rothman RB, Jayanthi S, Wang XY, Dersch CM, Cadet JL, Prisinzano T et al (2003) High-dose fenfluramine administration decreases serotonin transporter binding, but not serotonin transporter protein levels, in rat forebrain. Synapse 50(3):233–239PubMedCrossRefGoogle Scholar
  250. 250.
    Rothman RB, Baumann MH (2003) Monoamine transporters and psychostimulant drugs. Eur J Pharmacol 479(1–3):23–40PubMedCrossRefGoogle Scholar
  251. 251.
    Rothman RB, Clark RD, Partilla JS, Baumann MH (2003) (+)-Fenfluramine and its major metabolite, (+)-norfenfluramine, are potent substrates for norepinephrine transporters. J Pharmacol Exp Ther 305(3):1191–1199PubMedCrossRefGoogle Scholar
  252. 252.
    Jorgensen LM, Weikop P, Villadsen J, Visnapuu T, Ettrup A, Hansen HD et al (2016) Cerebral 5-HT release correlates with [11C]Cimbi36 PET measures of 5-HT2A receptor occupancy in the pig brain. J Cereb Blood Flow Metab 37(2):425–434PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Center for Integrated Molecular Brain ImagingCopenhagen University Hospital, RigshospitaletCopenhagenDenmark
  2. 2.Department of Drug Design and Pharmacology, Faculty of Health and MedicineUniversity of CopenhagenCopenhagenDenmark
  3. 3.Department of Clinical Physiology, Nuclear Medicine and PETCopenhagen University HospitalCopenhagenDenmark

Personalised recommendations