Serotonin system and PET
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). In the pineal gland, serotonin is precursor for melatonin. 5-HT synthesis rate can be quantified using [11C]AMT and [11C]HTP (Paterson et al, 2013).
Blood platelets contain serotonin transporter and are able to store high concentrations of serotonin from the gastrointestinal tract, releasing it as vasoconstrictor from dense-core 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. 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).
There seems to be a link between sex hormone levels and serotonin signalling (Perfalk et al., 2017).
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.
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.
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.
N,N-dimethyltryptamine (DMT), which is the active compound in ayahuasca, is endogenously synthesized in the brain (Borjigin et al., 2019); DMT activates at least 5-HT2A, 5-HT2C, and 5-HT1A 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). In major depressive disorder (MDD) [11C]WAY-100635 binding is initially high, reduced after SSRI treatment, and reverses to original level within 2 weeks of medication discontinuation (Metts et al., 2019). [18F]MPPF has also shown promise in quantification of the endogenous serotonin concentration.
5-HT1BR is found especially in the basal ganglia. For 5-HT1BR PET, [11C]AZ10419369 and [11C]P943 have been used. [11C]AZ10419369 is sensitive to changes in cerebral synaptic serotonin level (Finnema et al., 2010; Jørgensen et al., 2018).
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. Brain 5-HT2AR density is shown to be different in patients with AD, schizophrenia, and OCD.
5-HT2AR agonism is a necessary property of hallucinogens (Cumming et al., 2022). The psychedelic effects of LSD and psilocybin are attributable to 5-HT2A receptors (Preller et al., 2018; Madsen et al., 2019), but they also promote brain plasticity by binding to BDNF receptor TrkB (Moliner et al., 2023).
5-HT2AR agonist [11C]Cimbi-36 is sensitive to increases in extracellular 5-HT induced by an acute d-amphetamine challenge (Erritzoe et al., 2020), and this has been used to show that brain serotonin release is reduced in patients with depression (Erritzoe et al., 2022). Psilocybin's active metabolite psilocin binds and activates 5-HT2ARs, and the receptor occupancy has been studied with [11C]Cimbi-36 PET (Madsen et al., 2019). [11C]Cimbi-36 may overestimate the density of 5-HT2ARs in regions with high 5-HT2CR density (Ettrup et al., 2016).
Decreased cerebral uptake of [11C]SB207145 has been seen in major depressive disorder, and that correlated with verbal memory performance (Köhler-Forsberg et al., 2023).
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. 5-HT6 imaging has been conducted using [11C]GSK215083, which has high affinity for 5-HT6Rs and ∼5-fold lower affinity for 5-HT2ARs. Striatal [11C]GSK215083 binding is primarily reflective of 5-HT6R availability but binding in the cortex is reflective of 5-HT2AR availability (Parker et al., 2012, 2015; Radhakrishnan et al., 2020). Significant age-related decline in 5-HT6R availability in caudate and putamen has been observed with [11C]GSK215083 (Radhakrishnan et al., 2018).
Serotonin transporter (SERT, 5-HTT) belongs to a family of neurotransmitter symporters. SERT and NAT can take up extracellular dopamine, too, especially in the Parkinsonian striatum when dopamine transporters (DATs) are reduced. Organic cation transporters (OCTs) and other monoamine transporters may participate in serotonin reuptake (Daws, 2009; Gebauer et al., 2021).
Several polymorphisms of the SERT are associated with interindividual differences in serotonergic system and predisposition to depression, anxiety disorders, and alcohol dependence. Risk-taking behaviour when faced with gains correlates with increased SERT radioligand binding (Skandali et al., 2022).
Serotonin transporter radioligands for PET include [11C]MADAM (Lundberg et al., 2005), [11C]DASB (Ginovart et al., 2001), [18F](+)-FMe-McN5652 (Brust et al., 2003), and 4-[18F]-ADAM (Huang et al., 2013).
β-[123I]CIT has similar affinity for SERT 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.
SERT is expressed on human platelets and pulmonary vascular endothelium (Ramamoorthy et al., 1993, which leads to high lung uptake of serotonin radiopharmaceuticals, which can be blocked by pharmacological doses of SSRIs (Suhara et al., 1998). In PET studies SSRIs could lead to markedly higher input function than in non-medicated state.
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Updated at: 2023-10-30
Created at: 2016-08-23
Written by: Vesa Oikonen