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Imaging of the Serotonin System: Radiotracers and Applications in Memory Disorders

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PET and SPECT of Neurobiological Systems

Abstract

The serotonergic system plays a key modulatory role in the brain and is the target for many drug treatments for brain disorders either through reuptake blockade or via interactions at the 14 subtypes of serotonin (5-HT) receptors. This chapter provides the current status of radioligands used for positron emission tomography (PET) and single-photon emission computerised tomography (SPECT) imaging of the human brain 5-HT receptors and the 5-HT transporter (SERT) with particular emphasis on the applications in Alzheimer’s disease (AD).

Currently available radioligands for in vivo brain imaging of the 5-HT system in humans include radiolabelled compounds for the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT4 and to some extent 5-HT6 receptors and for SERT. Imaging of serotonergic targets in humans has given invaluable insight into the normal brain function and into brain disorders where the serotonergic system is perturbed.

Imaging studies show that the 5-HT1A receptor binding is increased, and 5-HT2A receptor binding is decreased in mild cognitive impairment (MCI). In early AD, 5-HT4 receptor binding is increased, whereas in early and more advanced AD, SERT and the 5-HT1A and 5-HT2A receptor binding are reduced in a region-specific manner. Future studies should focus on the association between serotonergic dysfunction and symptomatology in order to increase our understanding of the neurobiological background for neuropsychiatric symptoms in neurodegenerative and neuropsychiatric disorders.

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References

  • Adams KH, Pinborg LH, Svarer C, Hasselbalch SG, Holm S, Haugbol S, Madsen K, Frokjaer V, Martiny L, Paulson OB, Knudsen GM (2004) A database of [(18)F]-altanserin binding to 5-HT(2A) receptors in normal volunteers: normative data and relationship to physiological and demographic variables. NeuroImage 21:1105–1113

    Google Scholar 

  • Aletrino MA, Vogels OJ, Van Domburg PH, Ten Donkelaar HJ (1992) Cell loss in the nucleus raphes dorsalis in Alzheimer’s disease. Neurobiol Aging 13:461–468

    Article  CAS  PubMed  Google Scholar 

  • Atri A, Frölich L, Ballard C, Tariot PN, Molinuevo JL, Boneva N, Windfeld K, Raket LL, Cummings JL (2018) Effect of idalopirdine as adjunct to cholinesterase inhibitors on change in cognition in patients with Alzheimer disease: three randomized clinical trials. JAMA 319((2):130–142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ballard C, Bannister C, Solis M, Oyebode F, Wilcock G (1996) The prevalence, associations and symptoms of depression amongst dementia sufferers. J Affect Disord 36:135–144

    Article  CAS  PubMed  Google Scholar 

  • Becker G, Streichenberger N, Billard T, Newman-Tancredi A, Zimmer L (2014) A postmortem study to compare agonist and antagonist 5-HT1A receptor-binding sites in Alzheimer’s disease. CNS Neurosci Ther 20(10):930–949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beliveau V, Ganz M, Feng L, Ozenne B, Højgaard L, Fisher PM, Svarer C, Greve DN, Knudsen GM (2017) A high-resolution in vivo atlas of the human Brain’s serotonin system. J Neurosci. 37(1):120–128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blin J, Baron JC, Dubois B, Crouzel C, Fiorelli M, Ttar-Levy D, Pillon B, Fournier D, Vidailhet M, Agid Y (1993) Loss of brain 5-HT2 receptors in Alzheimer’s disease. In vivo assessment with positron emission tomography and [18F]setoperone. Brain 116(Pt 3):497–510

    Article  PubMed  Google Scholar 

  • Bockaert J, Claeysen S, Compan V, Dumuis A (2004) 5-HT4 receptors. Curr Drug Targets CNS Neurol Disord 3:39–51

    Article  CAS  PubMed  Google Scholar 

  • Bowen DM, Najlerahim A, Procter AW, Francis PT, Murphy E (1989) Circumscribed changes of the cerebral cortex in neuropsychiatric disorders of later life. Proc Natl Acad Sci U S A 86:9504–9508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Braak H, Braak E (1991) Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 82:239–259

    Article  CAS  PubMed  Google Scholar 

  • de Bruin NM, Prickaerts J, van Loevezijn A, Venhorst J, de Groote L, Houba P, Reneerkens O, Akkerman S, Kruse CG (2011) Two novel 5-HT6 receptor antagonists ameliorate scopolamine-induced memory deficits in the object recognition and object location tasks in Wistar rats. Neurobiol Learn Mem 96:392–402

    Article  PubMed  CAS  Google Scholar 

  • Cachard-Chastel M, Lezoualc’h F, Dewachter I, Delomenie C, Croes S, Devijver H, Langlois M, Van LF, Sicsic S, Gardier AM (2007) 5-HT4 receptor agonists increase sAPPalpha levels in the cortex and hippocampus of male C57BL/6j mice. Br J Pharmacol 150:883–892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen CP, Alder JT, Bowen DM, Esiri MM, McDonald B, Hope T, Jobst KA, Francis PT (1996) Presynaptic serotonergic markers in community-acquired cases of Alzheimer’s disease: correlations with depression and neuroleptic medication. J Neurochem 66:1592–1598

    Article  CAS  PubMed  Google Scholar 

  • Cheng AV, Ferrier IN, Morris CM, Jabeen S, Sahgal A, McKeith IG, Edwardson JA, Perry RH, Perry EK (1991) Cortical serotonin-S2 receptor binding in Lewy body dementia, Alzheimer’s and Parkinson’s diseases. J Neurol Sci 106:50–55

    Article  CAS  PubMed  Google Scholar 

  • Christensen R, Marcussen AB, Wortwein G, Knudsen GM, Aznar S (2008) Abeta(1-42) injection causes memory impairment, lowered cortical and serum BDNF levels, and decreased hippocampal 5-HT(2A) levels. Exp Neurol 210:164–171

    Article  CAS  PubMed  Google Scholar 

  • da Cunha-Bang S, Ettrup A, Mc Mahon B, Skibsted AP, Schain M, Lehel S, Dyssegaard A, Jørgensen LM, Møller K, Gillings N, Svarer C, Knudsen GM (2019) Measuring endogenous changes in serotonergic neurotransmission with [11C]Cimbi-36 positron emission tomography in humans. Transl Psychiatry 9(1):134

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Da Silva C-AV, Quiedeville A, Boulouard M, Dauphin F (2012) 5-HT6 receptor blockade differentially affects scopolamine-induced deficits of working memory, recognition memory and aversive learning in mice. Psychopharmacology 222:99–115

    Article  CAS  Google Scholar 

  • Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, Delacourte A, Frisoni G, Fox NC, Galasko D, Gauthier S, Hampel H, Jicha GA, Meguro K, O’Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Sarazin M, de Souza LC, Stern Y, Visser PJ, Scheltens P (2010) Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol 9:1118–1127

    Article  PubMed  Google Scholar 

  • Erritzoe D, Frokjaer VG, Haugbol S, Marner L, Svarer C, Holst K, Baare WF, Rasmussen PM, Madsen J, Paulson OB, Knudsen GM (2009) Brain serotonin 2A receptor binding: relations to body mass index, tobacco and alcohol use. NeuroImage 46:23–30

    Article  CAS  PubMed  Google Scholar 

  • Erritzoe D, Holst K, Frokjaer VG, Licht CL, Kalbitzer J, Nielsen FA, Svarer C, Madsen J, Knudsen G (2010) A nonlinear relationship between cerebral serotonin transporter and 5-HT2A receptor binding: an in vivo molecular imaging study in humans. J Neurosci 30:3391–3397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ettrup A, da Cunha-Bang S, McMahon B, Lehel S, Dyssegaard A, Skibsted AW, Jørgensen LM, Hansen M, Baandrup AO, Bache S, Svarer C, Kristensen JL, Gillings N, Madsen J, Knudsen GM (2014a) Serotonin 2A receptor agonist binding in the human brain with [11C]Cimbi-36. J Cereb Blood Flow Metab 34(7):1188–1196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ettrup A, da Cunha-Bang S, McMahon B, Lehel S, Dyssegaard A, Skibsted AW, Jørgensen LM, Hansen M, Baandrup AO, Bache S, Svarer C, Kristensen JL, Gillings N, Madsen J, Knudsen GM (2014b Jul) Serotonin 2A receptor agonist binding in the human brain with [11C]Cimbi-36. J Cereb Blood Flow Metab 34(7):1188–1196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ettrup A, Svarer C, McMahon B, da Cunha-Bang S, Lehel S, Møller K, Dyssegaard A, Ganz M, Beliveau V, Jørgensen LM, Gillings N, Knudsen GM (2016) Serotonin 2A receptor agonist binding in the human brain with [(11)C]Cimbi-36: test-retest reproducibility and head-to-head comparison with the antagonist [(18)F]altanserin. Neuroimage 130:167–174

    Article  CAS  PubMed  Google Scholar 

  • Finnema SJ, Varrone A, Hwang TJ, Gulyas B, Pierson ME, Halldin C, Farde L (2010) Fenfluramine-induced serotonin release decreases [11C]AZ10419369 binding to 5-HT1B-receptors in the primate brain. Synapse 64:573–577

    Article  CAS  PubMed  Google Scholar 

  • Fisher PM, Holst KK, Adamsen D, Klein AB, Frokjaer VG, Jensen PS, Svarer C, Gillings N, Baare WF, Mikkelsen JD, Knudsen GM (2015a) BDNF Val66met and 5-HTTLPR polymorphisms predict a human in vivo marker for brain serotonin levels. Hum Brain Mapp 36(1):313–323

    Article  PubMed  Google Scholar 

  • Fisher PM, Holst KK, Adamsen D, Klein AB, Frokjaer VG, Jensen PS, Svarer C, Gillings N, Baare WFC, Mikkelsen JD, Knudsen GM (2015b Jan) BDNF val66met and 5-HTTLPR polymorphisms predict a human in vivo marker for brain serotonin levels. Hum Brain Mapp 36(1):313–323

    Article  PubMed  Google Scholar 

  • Frankle WG, Huang Y, Hwang DR, Talbot PS, Slifstein M, Van HR, bi-Dargham A, Laruelle M (2004) Comparative evaluation of serotonin transporter radioligands 11C-DASB and 11C-McN 5652 in healthy humans. J Nucl Med 45:682–694

    CAS  PubMed  Google Scholar 

  • Frokjaer VG, Pinborg LH, Madsen J, de Nijs R, Svarer C, Wagner A, Knudsen GM (2008) Evaluation of the serotonin transporter ligand 123I-ADAM for SPECT studies on humans. J Nucl Med 49:247–254

    Article  PubMed  Google Scholar 

  • Frokjaer VG, Erritzoe D, Madsen J, Paulson OB, Knudsen GM (2009) Gender and the use of hormonal contraception in women are not associated with cerebral cortical 5-HT 2A receptor binding. Neuroscience 163:640–645

    Article  CAS  PubMed  Google Scholar 

  • Gallezot JD, Nabulsi N, Neumeister A, Planeta-Wilson B, Williams WA, Singhal T, Kim S, Maguire RP, McCarthy T, Frost JJ, Huang Y, Ding YS, Carson RE (2010) Kinetic modeling of the serotonin 5-HT(1B) receptor radioligand [(11)C]P943 in humans. J Cereb Blood Flow Metab 30:196–210

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Alloza M, Hirst WD, Chen CP, Lasheras B, Francis PT, Ramirez MJ (2004) Differential involvement of 5-HT(1B/1D) and 5-HT6 receptors in cognitive and non-cognitive symptoms in Alzheimer’s disease. Neuropsychopharmacology 29:410–416

    Article  CAS  PubMed  Google Scholar 

  • Gee AD, Martarello L, Passchier J, Wishart M, Parker C, Matthews J, Comley R, Hopper R, Gunn R (2008) Synthesis and evaluation of [11C]SB207145 as the first in vivo serotonin 5-HT4 receptor radioligand for PET imaging in man. Curr Radiopharm 1:110–114

    Article  CAS  Google Scholar 

  • Ginovart N, Wilson AA, Meyer JH, Hussey D, Houle S (2001) Positron emission tomography quantification of [(11)C]-DASB binding to the human serotonin transporter: modeling strategies. J Cereb Blood Flow Metab 21:1342–1353

    Article  CAS  PubMed  Google Scholar 

  • Haahr ME, Fisher P, Holst K, Madsen K, Jensen CG, Marner L, Lehel S, Baare W, Knudsen G, Hasselbalch S (2013) The 5-HT(4) receptor levels in hippocampus correlates inversely with memory test performance in humans. Hum Brain Mapp 34:3066–3074

    Article  PubMed  Google Scholar 

  • Haahr ME, Fisher PM, Jensen CG, Frokjaer VG, Mahon BM, Madsen K, BaarĂ© WF, Lehel S, Norremolle A, Rabiner EA, Knudsen GM (2014) Central 5-HT4 receptor binding as biomarker of serotonergic tonus in humans: a [11C]SB207145 PET study. Mol Psychiatry 19(4):427–432

    Article  CAS  PubMed  Google Scholar 

  • Halford JC, Harrold JA, Boyland EJ, Lawton CL, Blundell JE (2007) Serotonergic drugs: effects on appetite expression and use for the treatment of obesity. Drugs 67:27–55

    Article  CAS  PubMed  Google Scholar 

  • Halliday GM, McCann HL, Pamphlett R, Brooks WS, Creasey H, McCusker E, Cotton RG, Broe GA, Harper CG (1992) Brain stem serotonin-synthesizing neurons in Alzheimer’s disease: a clinicopathological correlation. Acta Neuropathol 84:638–650

    Article  CAS  PubMed  Google Scholar 

  • Hansen HD, Herth MM, Ettrup A, Andersen VL, Lehel S, Dyssegaard A, Kristensen JL, Knudsen GM (2014) Radiosynthesis and in vivo evaluation of novel radioligands for PET imaging of cerebral 5-HT7 receptors. J Nucl Med 55(4):640–646

    Article  CAS  PubMed  Google Scholar 

  • Hasselbalch SG, Madsen K, Svarer C, Pinborg LH, Holm S, Paulson OB, Waldemar G, Knudsen GM (2008) Reduced 5-HT2A receptor binding in patients with mild cognitive impairment. Neurobiol Aging 29:1830–1838

    Article  CAS  PubMed  Google Scholar 

  • Haugbol S, Pinborg LH, Arfan HM, Frokjaer VM, Madsen J, Dyrby TB, Svarer C, Knudsen GM (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 34:910–915

    Article  PubMed  CAS  Google Scholar 

  • Hendricksen M, Thomas AJ, Ferrier IN, Ince P, O’Brien JT (2004) Neuropathological study of the dorsal raphe nuclei in late-life depression and Alzheimer’s disease with and without depression. Am J Psychiatry 161:1096–1102

    Article  PubMed  Google Scholar 

  • Henningsson S, Borg J, Lundberg J, Bah J, Lindstrom M, Ryding E, Jovanovic H, Saijo T, Inoue M, Rosen I, Traskman-Bendz L, Farde L, Eriksson E (2009) Genetic variation in brain-derived neurotrophic factor is associated with serotonin transporter but not serotonin-1A receptor availability in men. Biol Psychiatry 66:477–485

    Article  CAS  PubMed  Google Scholar 

  • Holm P, Ettrup A, Klein AB, Santini MA, El-Sayed M, Elvang AB, Stensbol TB, Mikkelsen JD, Knudsen GM, Aznar S (2010) Plaque deposition dependent decrease in 5-HT2A serotonin receptor in AbetaPPswe/PS1dE9 amyloid overexpressing mice. J Alzheimers Dis 20:1201–1213

    Article  CAS  PubMed  Google Scholar 

  • Hoyer D, Hannon JP, Martin GR (2002) Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71:533–554

    Article  CAS  PubMed  Google Scholar 

  • Huang Y, Zheng MQ, Gerdes JM (2010) Development of effective PET and SPECT imaging agents for the serotonin transporter: has a twenty-year journey reached its destination? Curr Top Med Chem 10:1499–1526

    Article  CAS  PubMed  Google Scholar 

  • Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ (2010) Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 9:119–128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust W, Jessen F, Karlawish J, Liu E, Molinuevo JL, Montine T, Phelps C, Rankin KP, Rowe CC, Scheltens P, Siemers E, Snyder HM, Sperling R (2018) NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement 14(4):535–562

    Article  PubMed  PubMed Central  Google Scholar 

  • Jones T, Rabiner EA (2012) The development, past achievements, and future directions of brain PET. J Cereb Blood Flow Metab 32:1426–1454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jørgensen LM, Weikop P, Svarer C, Feng L, Keller SH, Knudsen GM (2018a) Cerebral serotonin release correlates with [(11)C]AZ10419369 PET measures of 5-HT(1B) receptor binding in the pig brain. J Cereb Blood Flow Metab 38(7):1243–1252

    Article  PubMed  Google Scholar 

  • Jørgensen LM, Weikop P, Svarer C, Feng L, Keller SH, Knudsen GM (2018b Jul) Cerebral serotonin release correlates with [11C]AZ10419369 PET measures of 5-HT1B receptor binding in the pig brain. J Cereb Blood Flow Metab 38(7):1243–1252

    Article  PubMed  Google Scholar 

  • Jovanovic H, Lundberg J, Karlsson P, Cerin A, Saijo T, Varrone A, Halldin C, Nordstrom AL (2008) Sex differences in the serotonin 1A receptor and serotonin transporter binding in the human brain measured by PET. NeuroImage 39:1408–1419

    Article  PubMed  Google Scholar 

  • Kepe V, Barrio JR, Huang SC, Ercoli L, Siddarth P, Shoghi-Jadid K, Cole GM, Satyamurthy N, Cummings JL, Small GW, Phelps ME (2006) Serotonin 1A receptors in the living brain of Alzheimer’s disease patients. Proc Natl Acad Sci U S A 103:702–707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim JS, Ichise M, Sangare J, Innis RB (2006) PET imaging of serotonin transporters with [11C]DASB: test-retest reproducibility using a multilinear reference tissue parametric imaging method. J Nucl Med 47:208–214

    CAS  PubMed  Google Scholar 

  • King MV, Marsden CA, Fone KC (2008) A role for the 5-HT(1A), 5-HT4 and 5-HT6 receptors in learning and memory. Trends Pharmacol Sci 29:482–492

    Article  CAS  PubMed  Google Scholar 

  • 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 58:249–257

    Article  CAS  PubMed  Google Scholar 

  • Kumar JS, Mann JJ (2014) PET tracers for serotonin receptors and their applications. Cent Nerv Syst Agents Med Chem 14(2):96–112

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lai MK, Tsang SW, Francis PT, Esiri MM, Hope T, Lai OF, Spence I, Chen CP (2003a) [H-3]GR113808 binding to serotonin 5-HT4 receptors in the postmortem neocortex of Alzheimer disease: a clinicopathological study. J Neural Transm 110:779–788

    Article  CAS  PubMed  Google Scholar 

  • Lai MK, Tsang SW, Francis PT, Esiri MM, Keene J, Hope T, Chen CP (2003b) Reduced serotonin 5-HT1A receptor binding in the temporal cortex correlates with aggressive behavior in Alzheimer disease. Brain Res 974:82–87

    Article  CAS  PubMed  Google Scholar 

  • Lai MK, Tsang SW, Alder JT, Keene J, Hope T, Esiri MM, Francis PT, Chen CP (2005) Loss of serotonin 5-HT2A receptors in the postmortem temporal cortex correlates with rate of cognitive decline in Alzheimer’s disease. Psychopharmacology 179:673–677

    Article  CAS  PubMed  Google Scholar 

  • Lamirault L, Simon H (2001) Enhancement of place and object recognition memory in young adult and old rats by RS 67333, a partial agonist of 5-HT4 receptors. Neuropharmacology 41:844–853

    Article  CAS  PubMed  Google Scholar 

  • Lee HM, Roth BL (2012) Hallucinogen actions on human brain revealed. Proc Natl Acad Sci U S A 109:1820–1821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lelong V, Dauphin F, Boulouard M (2001) RS 67333 and D-cycloserine accelerate learning acquisition in the rat. Neuropharmacology 41:517–522

    Article  CAS  PubMed  Google Scholar 

  • L’Estrade ET, Erlandsson M, Edgar FG, Ohlsson T, Knudsen GM, Herth MM (2020) Towards selective CNS PET imaging of the 5-HT7 receptor system: past, present and future. Neuropharmacology. [Epub ahead of print] 172:107830

    Article  PubMed  CAS  Google Scholar 

  • Leysen JE (2004) 5-HT2 receptors. Curr Drug Targets CNS Neurol Disord 3:11–26

    Article  CAS  PubMed  Google Scholar 

  • Lorke DE, Lu G, Cho E, Yew DT (2006) Serotonin 5-HT2A and 5-HT6 receptors in the prefrontal cortex of Alzheimer and normal aging patients. BMC Neurosci 7:36

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lundberg J, Odano I, Olsson H, Halldin C, Farde L (2005) Quantification of 11C-MADAM binding to the serotonin transporter in the human brain. J Nucl Med 46:1505–1515

    CAS  PubMed  Google Scholar 

  • Lundberg J, Halldin C, Farde L (2006) Measurement of serotonin transporter binding with PET and [11C]MADAM: a test-retest reproducibility study. Synapse 60:256–263

    Article  CAS  PubMed  Google Scholar 

  • Lundberg J, Christophersen JS, Petersen KB, Loft H, Halldin C, Farde L (2007) PET measurement of serotonin transporter occupancy: a comparison of escitalopram and citalopram. Int J Neuropsychopharmacol 10:777–785

    Article  CAS  PubMed  Google Scholar 

  • Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky S (2002) Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288:1475–1483

    Article  PubMed  Google Scholar 

  • Lyon RA, Titeler M, Frost JJ, Whitehouse PJ, Wong DF, Wagner HN Jr, Dannals RF, Links JM, Kuhar MJ (1986) 3H-3-N-methylspiperone labels D2 dopamine receptors in basal ganglia and S2 serotonin receptors in cerebral cortex. J Neurosci 6:2941–2949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Madsen K, Erritzoe D, Mortensen EL, Gade A, Madsen J, Baare W, Knudsen GM, Hasselbalch SG (2011a) Cognitive function is related to fronto-striatal serotonin transporter levels – a brain PET study in young healthy subjects. Psychopharmacology 213:573–581

    Article  CAS  PubMed  Google Scholar 

  • Madsen K, Haahr MT, Marner L, Keller SH, Baare WF, Svarer C, Hasselbalch SG, Knudsen GM (2011b) Age and sex effects on 5-HT(4) receptors in the human brain: a [(11)C]SB207145 PET study. J Cereb Blood Flow Metab 31:1475–1481

    Article  PubMed  PubMed Central  Google Scholar 

  • Madsen K, Marner L, Haahr M, Gillings N, Knudsen GM (2011c) Mass dose effects and in vivo affinity in brain PET receptor studies – a study of cerebral 5-HT(4) receptor binding with [(11)C]SB207145. Nucl Med Biol 38:1085–1091

    Article  CAS  PubMed  Google Scholar 

  • Madsen K, Neumann WJ, Holst K, Marner L, Haahr MT, Lehel S, Knudsen GM, Hasselbalch SG (2011d) Cerebral serotonin 4 receptors and amyloid-beta in early Alzheimer’s disease. J Alzheimers Dis 26:457–466

    Article  CAS  PubMed  Google Scholar 

  • Maher-Edwards G, Zvartau-Hind M, Hunter AJ, Gold M, Hopton G, Jacobs G, Davy M, Williams P (2010) Double-blind, controlled phase II study of a 5-HT6 receptor antagonist, SB-742457, in Alzheimer’s disease. Curr Alzheimer Res 7:374–385

    Google Scholar 

  • Marchetti E, Dumuis A, Bockaert J, Soumireu-Mourat B, Roman FS (2000) Differential modulation of the 5-HT(4) receptor agonists and antagonist on rat learning and memory. Neuropharmacology 39:2017–2027

    Article  CAS  PubMed  Google Scholar 

  • Marchetti-Gauthier E, Roman FS, Dumuis A, Bockaert J, Soumireu-Mourat B (1997) BIMU1 increases associative memory in rats by activating 5-HT4 receptors. Neuropharmacology 36:697–706

    Article  CAS  PubMed  Google Scholar 

  • Marner L, Gillings N, Comley RA, Baare WF, Rabiner EA, Wilson AA, Houle S, Hasselbalch SG, Svarer C, Gunn RN, Laruelle M, Knudsen GM (2009) Kinetic modeling of 11C-SB207145 binding to 5-HT4 receptors in the human brain in vivo. J Nucl Med 50:900–908

    Article  CAS  PubMed  Google Scholar 

  • Marner L, Gillings N, Madsen K, Erritzoe D, Baare WF, Svarer C, Hasselbalch SG, Knudsen GM (2010) Brain imaging of serotonin 4 receptors in humans with [11C]SB207145-PET. NeuroImage 50:855–861

    Article  CAS  PubMed  Google Scholar 

  • 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 23:453–459

    Article  PubMed  Google Scholar 

  • Marner L, Frokjaer VG, Kalbitzer J, Lehel S, Madsen K, Baare WF, Knudsen GM, Hasselbalch SG (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 33:479–487

    Article  CAS  PubMed  Google Scholar 

  • Matuskey D, Pittman B, Planeta-Wilson B, Walderhaug E, Henry S, Gallezot JD, Nabulsi N, Ding YS, Bhagwagar Z, Malison R, Carson RE, Neumeister A (2012) Age effects on serotonin receptor 1B as assessed by PET. J Nucl Med 53:1411–1414

    Article  CAS  PubMed  Google Scholar 

  • Meltzer CC, Price JC, Mathis CA, Greer PJ, Cantwell MN, Houck PR, Mulsant BH, Ben-Eliezer D, Lopresti B, Dekosky ST, Reynolds CF III (1999) PET imaging of serotonin type 2A receptors in late-life neuropsychiatric disorders. Am J Psychiatry 156:1871–1878

    Article  CAS  PubMed  Google Scholar 

  • Meyer JH, Wilson AA, Sagrati S, Hussey D, Carella A, Potter WZ, Ginovart N, Spencer EP, Cheok A, Houle S (2004) Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study. Am J Psychiatry 161:826–835

    Article  PubMed  Google Scholar 

  • Milak MS, Severance AJ, Ogden RT, Prabhakaran J, Kumar JS, Majo VJ, Mann JJ, Parsey RV (2008) Modeling considerations for 11C-CUMI-101, an agonist radiotracer for imaging serotonin 1A receptor in vivo with PET. J Nucl Med 49:587–596

    Article  CAS  PubMed  Google Scholar 

  • Nelson DL (2004) 5-HT5 receptors. Curr Drug Targets CNS Neurol Disord 3:53–58

    Article  CAS  PubMed  Google Scholar 

  • Newberg AB, Plossl K, Mozley PD, Stubbs JB, Wintering N, Udeshi M, Alavi A, Kauppinen T, Kung HF (2004) Biodistribution and imaging with (123)I-ADAM: a serotonin transporter imaging agent. J Nucl Med 45:834–841

    CAS  PubMed  Google Scholar 

  • Ouchi Y, Yoshikawa E, Futatsubashi M, Yagi S, Ueki T, Nakamura K (2009) Altered brain serotonin transporter and associated glucose metabolism in Alzheimer disease. J Nucl Med 50:1260–1266

    Article  PubMed  Google Scholar 

  • Parker RM, Barnes JM, Ge J, Barber PC, Barnes NM (1996) Autoradiographic distribution of [3H]-(S)-zacopride-labelled 5-HT3 receptors in human brain. J Neurol Sci 144:119–127

    Article  CAS  PubMed  Google Scholar 

  • Parker CA, Gunn RN, Rabiner EA, Slifstein M, Comley R, Salinas C, Johnson CN, Jakobsen S, Houle S, Laruelle M, Cunningham VJ, Martarello L (2012) Radiosynthesis and characterization of 11C-GSK215083 as a PET radioligand for the 5-HT6 receptor. J Nucl Med 53:295–303

    Article  CAS  PubMed  Google Scholar 

  • 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 33:54–111

    Article  CAS  PubMed  Google Scholar 

  • Pike VW, McCarron JA, Lammerstma AA, Hume SP, Poole K, Grasby PM, Malizia A, Cliffe IA, Fletcher A, Bench CJ (1995) First delineation of 5-HT1A receptors in human brain with PET and [11C]WAY-100635. Eur J Pharmacol 283:R1–R3

    Article  CAS  PubMed  Google Scholar 

  • Pinborg LH, Adams KH, Svarer C, Holm S, Hasselbalch SG, Haugbol S, Madsen J, Knudsen GM (2003) Quantification of 5-HT2A receptors in the human brain using [18F]altanserin-PET and the bolus/infusion approach. J Cereb Blood Flow Metab 23:985–996

    Article  CAS  PubMed  Google Scholar 

  • Pinborg LH, Arfan H, Haugbol S, Kyvik KO, Hjelmborg JV, Svarer C, Frokjaer VG, Paulson OB, Holm S, Knudsen GM (2008) The 5-HT2A receptor binding pattern in the human brain is strongly genetically determined. NeuroImage 40:1175–1180

    Article  PubMed  Google Scholar 

  • Pinborg LH, Feng L, Haahr ME, Gillings N, Dyssegaard A, Madsen J, Svarer C, Yndgaard S, Kjaer TW, Parsey RV, Hansen HD, Ettrup A, Paulson OB, Knudsen GM (2012) No change in [(1)(1)C]CUMI-101 binding to 5-HT(1A) receptors after intravenous citalopram in human. Synapse 66:880–884

    Article  CAS  PubMed  Google Scholar 

  • Radhakrishnan R, Nabulsi N, Gaiser E, Gallezot JD, Henry S, Planeta B, Lin SF, Ropchan J, Williams W, Morris E, D’Souza DC, Huang Y, Carson RE, Matuskey D (2018) Age-related change in 5-HT(6) receptor availability in healthy male volunteers measured with (11)C-GSK215083 PET. J Nucl Med 59(9):1445–1450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rebholz H, Friedman E, Castello J (2018) Alterations of expression of the serotonin 5-HT4 receptor in brain disorders. Int J Mol Sci 13:19(11)

    Google Scholar 

  • Ridler K, Plisson C, Rabiner EA, Gunn RN, Easwaramoorthy B, bi-Dargham A, Laruelle M, Slifstein M (2011) Characterization of in vivo pharmacological properties and sensitivity to endogenous serotonin of [11C] P943: a positron emission tomography study in Papio anubis. Synapse 65:1119–1127

    Article  CAS  PubMed  Google Scholar 

  • Ryu YH, Liow JS, Zoghbi S, Fujita M, Collins J, Tipre D, Sangare J, Hong J, Pike VW, Innis RB (2007) Disulfiram inhibits defluorination of (18)F-FCWAY, reduces bone radioactivity, and enhances visualization of radioligand binding to serotonin 5-HT1A receptors in human brain. J Nucl Med 48:1154–1161

    Article  CAS  PubMed  Google Scholar 

  • Savli M, Bauer A, Mitterhauser M, Ding YS, Hahn A, Kroll T, Neumeister A, Haeusler D, Ungersboeck J, Henry S, Isfahani SA, Rattay F, Wadsak W, Kasper S, Lanzenberger R (2012) Normative database of the serotonergic system in healthy subjects using multi-tracer PET. NeuroImage 63:447–459

    Article  CAS  PubMed  Google Scholar 

  • Schmitt JA, Wingen M, Ramaekers JG, Evers EA, Riedel WJ (2006) Serotonin and human cognitive performance. Curr Pharm Des 12:2473–2486

    Article  CAS  PubMed  Google Scholar 

  • Shrestha SS, Liow JS, Lu S, Jenko K, Gladding RL, Svenningsson P, Morse CL, Zoghbi SS, Pike VW, Innis RB (2014) (11)C-CUMI-101, a PET radioligand, behaves as a serotonin 1A receptor antagonist and also binds to α(1) adrenoceptors in brain. J Nucl Med 55(1):141–146

    Article  CAS  PubMed  Google Scholar 

  • Shrestha SS, Liow JS, Jenko K, Ikawa M, Zoghbi SS, Innis RB (2016) The 5-HT1A receptor PET radioligand 11C-CUMI-101 has significant binding to α1-adrenoceptors in human cerebellum, limiting its use as a reference region. J Nucl Med 57(12):1945–1948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith GS, Barrett FS, Joo JH, Nassery N, Savonenko A, Sodums DJ, Marano CM, Munro CA, Brandt J, Kraut MA, Zhou Y, Wong DF, Workman CI (2017) Molecular imaging of serotonin degeneration in mild cognitive impairment. Neurobiol Dis 105:33–41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spies M, Knudsen GM, Lanzenberger R, Kasper S (2015) The serotonin transporter in psychiatric disorders: insights from PET imaging. Lancet Psychiatry 2(8):743–755

    Article  PubMed  Google Scholar 

  • Szabo Z, Kao PF, Scheffel U, Suehiro M, Mathews WB, Ravert HT, Musachio JL, Marenco S, Kim SE, Ricaurte GA (1995) Positron emission tomography imaging of serotonin transporters in the human brain using [11C](+)McN5652. Synapse 20:37–43

    Article  CAS  PubMed  Google Scholar 

  • Talbot PS, Slifstein M, Hwang DR, Huang Y, Scher E, bi-Dargham A, Laruelle M (2012) Extended characterisation of the serotonin 2A (5-HT2A) receptor-selective PET radiotracer 11C-MDL100907 in humans: quantitative analysis, test-retest reproducibility, and vulnerability to endogenous 5-HT tone. NeuroImage 59:271–285.

    Google Scholar 

  • Tejani-Butt SM, Yang J, Pawlyk AC (1995) Altered serotonin transporter sites in Alzheimer’s disease raphe and hippocampus. Neuroreport 6:1207–1210

    Article  CAS  PubMed  Google Scholar 

  • Terry AV Jr, Buccafusco JJ, Jackson WJ, Prendergast MA, Fontana DJ, Wong EH, Bonhaus DW, Weller P, Eglen RM (1998) Enhanced delayed matching performance in younger and older macaques administered the 5-HT4 receptor agonist, RS 17017. Psychopharmacology 135:407–415

    Article  CAS  PubMed  Google Scholar 

  • Tfelt-Hansen P (2012) Clinical pharmacology of current and future drugs for the acute treatment of migraine: a review and an update. Curr Clin Pharmacol 7:66–72

    Article  CAS  PubMed  Google Scholar 

  • Thomas AJ, Hendriksen M, Piggott M, Ferrier IN, Perry E, Ince P, O’Brien JT (2006) A study of the serotonin transporter in the prefrontal cortex in late-life depression and Alzheimer’s disease with and without depression. Neuropathol Appl Neurobiol 32:296–303

    Article  CAS  PubMed  Google Scholar 

  • Truchot L, Costes SN, Zimmer L, Laurent B, Le BD, Thomas-Anterion C, Croisile B, Mercier B, Hermier M, Vighetto A, Krolak-Salmon P (2007) Up-regulation of hippocampal serotonin metabolism in mild cognitive impairment. Neurology 69:1012–1017

    Article  CAS  PubMed  Google Scholar 

  • Tsang SW, Lai MK, Francis PT, Wong PT, Spence I, Esiri MM, Keene J, Hope T, Chen CP (2003) Serotonin transporters are preserved in the neocortex of anxious Alzheimer’s disease patients. Neuroreport 14:1297–1300

    CAS  PubMed  Google Scholar 

  • Varnas K, Nyberg S, Halldin C, Varrone A, Takano A, Karlsson P, Andersson J, McCarthy D, Smith M, Pierson ME, Soderstrom J, Farde L (2011) Quantitative analysis of [11C]AZ10419369 binding to 5-HT1B receptors in human brain. J Cereb Blood Flow Metab 31:113–123

    Article  PubMed  CAS  Google Scholar 

  • Versijpt J, Van Laere KJ, Dumont F, Decoo D, Vandecapelle M, Santens P, Goethals I, Audenaert K, Slegers G, Dierckx RA, Korf J (2003) Imaging of the 5-HT2A system: age-, gender-, and Alzheimer’s disease-related findings. Neurobiol Aging 24:553–561

    Article  CAS  PubMed  Google Scholar 

  • Vidal B, Sebti J, Verdurand M, Fieux S, Billard T, Streichenberger N, Troakes C, Newman-Tancredi A, Zimmer L (2016) Agonist and antagonist bind differently to 5-HT1A receptors during Alzheimer’s disease: a post-mortem study with PET radiopharmaceuticals. Neuropharmacology 109:88–95

    Article  CAS  PubMed  Google Scholar 

  • Volk B, Nagy BJ, Vas S, Kostyalik D, Simig G, Bagdy G (2010) Medicinal chemistry of 5-HT5A receptor ligands: a receptor subtype with unique therapeutical potential. Curr Top Med Chem 10:554–578

    Article  CAS  PubMed  Google Scholar 

  • Wilson AA, Houle S (1999) Radiosynthesis of carbon-11 labelled N-methyl-2-(arylthio)benzylamines; potential radiotracers for the serotonin reuptake receptor. J Label Compd Radiopharm 42:1277–1288

    Article  CAS  Google Scholar 

  • Wong DF, Wagner HN Jr, Dannals RF, Links JM, Frost JJ, Ravert HT, Wilson AA, Rosenbaum AE, Gjedde A, Douglass KH (1984) Effects of age on dopamine and serotonin receptors measured by positron tomography in the living human brain. Science 226:1393–1396

    Google Scholar 

  • Woolley ML, Marsden CA, Fone KC (2004) 5-ht6 receptors. Curr Drug Targets CNS Neurol Disord 3:59–79

    Article  CAS  PubMed  Google Scholar 

  • Xu Y, Yan J, Zhou P, Li J, Gao H, Xia Y, Wang Q (2012) Neurotransmitter receptors and cognitive dysfunction in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol 97:1–13

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yang KC, Stepanov V, Martinsson S, Ettrup A, Takano A, Knudsen GM, Halldin C, Farde L, Finnema SJ (2017) Fenfluramine reduces [11C]Cimbi-36 binding to the 5-HT2A receptor in the nonhuman primate brain. Int J Neuropsychopharmacol 20(9):683–691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the Lundbeck Foundation Center grant to Center for Integrated Molecular Brain Imaging (Cimbi).

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Knudsen, G.M., Hasselbalch, S.G. (2021). Imaging of the Serotonin System: Radiotracers and Applications in Memory Disorders. In: Dierckx, R.A., Otte, A., de Vries, E.F., van Waarde, A., Lammertsma, A.A. (eds) PET and SPECT of Neurobiological Systems. Springer, Cham. https://doi.org/10.1007/978-3-030-53176-8_25

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