PET imaging of serotonin system

5-HT

Serotonin (5-hydroxytryptamine, 5-HT) is a monoamine neurotransmitter. In gastrointestinal tract 5-HT regulates smooth muscle tone; enterochromaffin (EC) cells contain >90% of the total serotonin in the human body (Beattie and Smith, 2008). Tryptophan hydroxylase catalyses the first and rate-limiting step of synthesis of serotonin, converting L-tryptophan, one of the essential amino acids in humans, into 5-hydroxy-L-tryptophan (5-HTP). There are two isoforms of tryptophan hydroxylase, THP1 in the peripheral tissues including pineal gland, and THP2 expressed in the brain and enteric nervous system. 5-HTP is then converted to serotonin by aromatic L-amino acid decarboxylase (AADC, AAAD, 5-hydroxytryptophan decarboxylase). Serotonin synthesis rate has been studied using [11C]AMT and [11C]5-HTP. Blood platelets (thrombocytes) contain serotonin transporter and are able to store high concentrations of serotonin from the gastrointestinal tract, releasing it as vasoconstrictor from dense storage granules. Bone contains 5-HT receptors, and serotonin levels affect the bone mass.

Serotonergic neurons in the central nervous system (CNS) are also able to synthesize 5-HT. 5-HT cannot cross the BBB. Serotonergic neurons are mainly located in the dorsal raphe nucleus, from where the axons extend to other parts of the CNS, including the cerebellum and spinal cord. In the CNS serotonin regulates the mood, perception, reward, aggression, appetite, attention, etc, and is therefore involved amongst other things in anxiety and panic disorders, depression and appetite. There seems to be a link between sex hormone levels and serotonin signalling (Perfalk et al., 2017). Lysergic acid diethylamide (LSD) had a central role in discovering the serotonergic system and its involvement in the CNS disorders (L´Estrade et al., 2018). 5-HT is cleared from the synaptic cleft mainly by serotonin transporter (SERT). Serotonin reuptake inhibitors (SSRIs) are used as antidepressants. Inside the cell, 5-HT is further transported into synaptic vesicles by monoamine transporter 2 (VMAT2). 5-HT can also be degraded by MAO-A, located at mitochondrial membranes, to 5-hydroxyindoleatic acid (5-HIAA) by glial cells. 5-HIAA passes to the extracellular space and is then actively transported away from the CNS.

5-HT receptors

Serotonin receptors are categorized into seven families, 5-HT1 - 5-HT7 comprising at least 16 distinct mammalian subtypes. 5-HT3 class is ionotropic (ligand-gated cation channel), other serotonin receptors are G-protein coupled receptors.

5-HT1A receptor density is high in limbic brain regions, such as hippocampus, lateral septum, cortical areas, and raphe nuclei, but very low in the basal ganglia and cerebellum (Barnes and Sharp, 1999). 5-HT1A receptors have been successfully studied using [11C]WAY-100635, [18F]MPPF, [18F]FCWAY, and [11C]CUMI-101 (Paterson et al, 2013). [18F]MPPF has also shown promise in quantification of the endogenous serotonin concentration. Agonist tracer [18F]F13640 may provide information on the high affinity state 5-HT1ARs (Vidal et al., 2018).

For 5-HT1B [11C]AZ10419369 and [11C]P943 have been used. 5-HT1BR is found especially in the basal ganglia.

5-HT2A receptors can be studied using [18F]altanserin, [18F]deuteroaltanserin, and [11C]MDL100907. [11C]Cimbi-36 may overestimate the density of 5-HT2ARs in regions with high 5-HT2CR density (Ettrup et al., 2016). 5-HT2AR density is high in cortical areas, caudate nucleus, nucleus accumbens, and hippocampus. 5-HT2AR is also found in peripheral neurons and inflammatory cells.

5-HT4 has been studied with [11C]SB207145. 5-HT4R variants are expressed in gastrointestinal tract, urinary bladder, heart, and adrenal glands. In CNS they are predominantly located in the striatum.

5-HT6 imaging has been conducted using [11C]GSK215083. Highest 5-HT6R concentrations in the CNS are found in the striatum and nucleus accumbens, and lesser concentrations in amygdala, hypothalamus, thalamus, hippocampus, and cerebral cortex.

SERT

Serotonin transporter (SERT, 5-HTT) belongs to a family of neurotransmitter symporters. SERT and NET can take up extracellular dopamine, too, especially in the Parkinsonian striatum when dopamine transporters (DATs) are reduced. Several polymorphisms of the SERT are associated with interindividual differences in serotonergic system and predisposition to depression, anxiety disorders, and alcohol dependence.

Serotonin transporter ligands include [11C]MADAM (Lundberg et al., 2005) and [11C]DASB (Ginovart et al., 2001).

β-[123I]CIT has similar affinity for SET and DAT, and it has been used to study SERT in the midbrain where SERT is abundant as compared to DAT. [11C]McN 5652 had too slow binding kinetics in the midbrain and high nonspecific binding.

5-HT synthesis and release

5-HT synthesis rate can be quantified using [11C]AMT and [11C]HTP (Paterson et al, 2013).

Quantification of serotonin release in the brain has been difficult (Paterson et al., 2013; Tyacke and Nutt, 2015), probably because of very active autoregulation, although some success has been reported using for example [18F]altanserin.


See also:


References:

Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology 1999; 38(8): 1083-1152.

Beattie DT, Smith JA. Serotonin pharmacology in the gastrointestinal tract: a review. Naunyn Schmiedebergs Arch Pharmacol. 2008; 377(3): 181-203.

Beliveau V, Ganz M, Feng L, Ozenne B, Højgaard L, Fisher PM, Svarer C, Greve DN, Knudsen GM. A high-resolution in vivo atlas of the human brain’s serotonin system. J Neurosci. 2017; 37(1): 120-128. doi: 10.1523/JNEUROSCI.2830-16.2017.

Berger M, Gray JA, Roth BL. The expanded biology of serotonin. Annu Rev Med. 2009; 60: 355-366.

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

Hartig PR, Hoyer D, Humphrey PP, Martin GR. Alignment of receptor nomenclature with the human genome: classification of 5-HT1B and 5-HT1D receptor subtypes. Trends Pharmacol Sci. 1996; 17(3): 103-105.

Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphrey PP. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev. 1994; 46(2): 157-203.

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

Lundquist P. Imaging and Quantification of Brain Serotonergic Activity using PET. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 2006; 34, ISSN 1651-6192.

McCorvy JD, Roth BL. Structure and function of serotonin G protein-coupled receptors. Pharmacol Ther. 2015; 150: 129-142.

Olivier B. Serotonin: a never-ending story. Eur J Pharmacol. 2015; 753: 2-18.

Paterson LM, Tyacke RJ, Nutt DJ, Knudsen GM. Measuring endogenous 5-HT release by emission tomography: promises and pitfalls. J Cereb Blood Flow Metab. 2010; 30(10): 1682-1706.

Paterson LM, Kornum BR, Nutt DJ, Pike VW, Knudsen GM. 5-HT radioligands for human brain imaging with PET and SPECT. Med Res Rev. 2013; 33(1): 54-111.

Saulin A, Savli M, Lanzenberger R. Serotonin and molecular neuroimaging in humans using PET. Amino Acids 2012; 42(6): 2039-2057.

Savitz JB, Drevets WC. Neuroreceptor imaging in depression. Neurobiol Dis. 2013; 52: 49-65.

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. Normative database of the serotonergic system in healthy subjects using multi-tracer PET. Neuroimage 2012; 63(1): 447-459.

Tyacke RJ, Nutt DJ. Optimising PET approaches to measuring 5-HT release in human brain. Synapse 2015; 69: 505-511.



Literature

Blenau W, Baumann A (eds): Serotonin Receptor Technologies. Humana Press, 2015.

Chattopadhyay A (ed): Serotonin Receptors in Neurobiology. CRC Press, 2007.

Dierckx RAJO, Otte A, de Vries EFJ, van Waarde A, Luiten PGM (eds): PET and SPECT of Neurobiological Systems. Springer, 2014.

Fozard JR, Saxena PR (eds): Serotonin: Molecular Biology, Receptors and Functional Effects. BirkHäuser, 1991.

Kalueff AV, LaPorte JL (eds): Experimental Models in Serotonin Transporter Research. Cambridge University Press, 2010.

Müller CP, Jacobs BL (eds): Handbook of the Behavioral Neurobiology of Serotonin. Academic Press, 2010.

Roth BL (ed): The Serotonin Receptors - From Molecular Pharmacology to Human Therapeutics. Humana Press, 2006.



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Created at: 2016-08-23
Updated at: 2018-05-21
Written by: Vesa Oikonen