PET imaging of dopaminergic system
Dopamine (DA, 3,4-dihydroxyphenethylamine, 3-hydroxytyramine) is a catecholamine neurotransmitter that also is a precursor to the synthesis of other neurotransmitters, including norepinephrine (NE) and epinephrine. Dopaminergic system is involved reward, locomotion, motivation, and numerous other processes, and abnormalities of the dopaminergic system in the CNS can lead to diseases such as Parkinson's disease, Huntington's disease, and schizophrenia.
Dopaminergic pathways in the CNS
The nigrostriatal pathway consists of neurons in the substantia nigra in the midbrain, projecting to the GABAergic neurons in the dorsal striatum (caudate nucleus and putamen). This pathway is particularly involved in the production of movement, and loss of DA neurons in the substantia nigra leads to Parkinson's disease.
The mesolimbic pathway projects from the ventral tegmental area (VTA) in the midbrain to the nucleus accumbens in ventral striatum. This pathway is involved in reward and aversion related cognition.
The mesocortical pathway projects from the ventral tegmental area (VTA) in the midbrain to the frontal lobes of the cerebrum, particularly the prefrontal cortex. It is involved in the cognitive control of behaviour.
The tuberoinfundibular pathway connects the arcuate nucleus of the hypothalamus to the anterior pituitary gland (median eminence), controlling (inhibiting) the secretion of prolactin and some other hormones.
DA synthesis and degradation
Dopamine is mainly synthesized in neurons and in the medulla of the adrenal glands, but also in other tissues, including immune cells. Mesenteric organs produce almost half of the dopamine formed in the body (Eisenhofer et al., 1997; Eisenhofer & Goldstein, 2004). In the kidneys, proximal tubules produce dopamine, which increases renal blood flow and inhibits renin secretion. The direct precursor of dopamine, L-DOPA, is converted to dopamine by aromatic L-amino acid decarboxylase (AAAD, AADC, DOPA decarboxylase). Dopamine itself cannot cross the blood-brain barrier, but L-DOPA can, and it is therefore used in the treatment of Parkinson's disease. 18F-labelled L-DOPA (6-[18F]-L-DOPA, FDOPA) has been used to study the activity of AAAD in the brain. Main application has been to assess presynaptic dopaminergic function in degenerative brain diseases. Dopamine synthesis rate during cognitive processing may also be studied using FDOPA PET (Hahn et al., 2021).
L-DOPA is produced from L-tyrosine, a non-essential amino acid, by tyrosine hydroxylase (TH), which is usually the rate-limiting step. L-tyrosine can be synthesized from L-phenylalanine, an essential amino acid, by phenylalanine hydroxylase. Dopamine is packaged into synaptic vesicles by vesicular monoamine transporter 2 (VMAT2).
Dopamine can be converted into norepinephrine by dopamine β-hydroxylase and further into epinephrine by phenylethanolamine N-methyltransferase. Dopamine β-hydroxylase is released into the blood by the adrenal medulla.
Degradation of dopamine into inactive metabolites is catalyzed by monoamine oxidases (MAO-A and MAO-B) and catechol-O-methyl transferase (COMT). MAO-A and -B are located at the mitochondrial outer membranes, in CNS and peripheral tissues and also in platelets. Catecholamines are actively transported into red blood cells, which contain COMT (Danon & Sapira, 1972). Inhibitors of these enzymes, such as clorgyline and deprenyl, are given with L-DOPA medication. Dopamine can also be autoxidated in the presence of O2 and ferric iron. MAO-A activity in the brain can be quantified using [11C]clorgyline-D2 or [11C]harmine (Zanderigo et al., 2018), and MAO-B activity using [11C]L-deprenyl-D2 (Fowler et al., 2015) and [11C]SL25.1188 (Rusjan et al., 2014). VAP-1 (AOC3) can also deaminate short-chain primary amines.
The main end product of DA metabolism is homovanillic acid (HVA), which is excreted to urine by the kidneys. Some dopamine is found in the circulation, most of it as dopamine sulphate, which also is excreted to urine.
Five dopamine receptors (D1R - D5R) have been identified in mammals. All DA receptors are metabotropic G protein-coupled receptors. D1R is the most abundant of DA receptors in the CNS, D2R is also common, but D3, D4, and D5 receptor densities are much lower. However, D5R has 10-fold higher affinity to dopamine than D1R, and D3R has 20-fold higher affinity to dopamine than D2R. Coding regions of D2, D3, and D4 receptor genes are interrupted by several introns, leading to receptor subtypes such as the variants D2SR and D2SL (short and long, respectively).
In addition to these cell membrane receptors, an intracellular receptor TAAR1 in the presynaptic dopamine neurons, is involved in regulation of DA signalling.
DA receptors are found not only in the CNS, but also in the arterial walls, modulating blood flow. DA performs also local exocrine and paracrine functions, especially in the kidneys and the pancreas. Lymphocytes contain DA receptors, and DA affects the immune system in the spleen and bone marrow.
D1R availability can be studied using [11C]SCH23390, [11C]NNC112, and [11C]NNC756 (Laihinen et al., 1994; Cervenka, 2019). [11C]SCH23390 and [11C]NNC112 are not selective against D1R but bind also to 4-HT2AR. As antagonists, these radioligands do not discriminate between the high- and low-affinity states of D1 receptor. Lately, specific agonist radioligands, that bind preferentially the high-affinity state, have been developed, including [18F]MNI-968 (Barret et al., 2021).
D2 and D3 receptors in the striatum (where D2R density is high) have been studied using [11C]raclopride and [18F]fallypride. Drawback of [18F]fallypride is defluorination and subsequent spillover from skull into cerebral cortex. [11C]Raclopride and [11C]NPA have equal affinities for D2 and D3 receptors. These radiopharmaceuticals do not offer sufficient signal-to-noise ratio in extrastriatal regions, where [11C]FLB 457 can be used instead. C957T (rs6277) polymorphism is related to the D2R availability (Hirvonen et al., 2009; Smith et al., 2017). D2Rs are found in two isoforms, "long" and "short", caused by alternative splicing; D2LRs are mainly postsynaptic and D2SRs mainly presynaptic, but the expression isoforms depends on the genotype (CC, CA, AA). CC and CA carriers have higher D2/3R availability in ventral striatum (Valli et al., 2019). D2R polymorphism genotypes have a role in personality traits and affect medication responsiveness.
D2 and D3 receptors can be in high or low affinity state for agonists, depending on whether the receptors are coupled or uncoupled with the G protein; the proportion of receptors in these configurations will thus affect the apparent agonist ligand affinity. [11C]raclopride and [18F]fallypride are D2/3 antagonists, binding equally to both high and low configurations, while [11C]NPA is an agonist and can be used to study the density of high-affinity D2/3Rs (Narendran et al., 2010). D2R antagonists are used as antipsychotics. Antipsychotics induce regional increases in perfusion and glucose metabolism, depending on the receptor distribution (Selvaggi et al., 2019).
Presynaptic D2Rs modulate glutamate release, and postsynaptic D2Rs inhibite GABA. D2 receptors are coupled through G protein mechanism to Ca2+-dependent cytosolic phospholipase A2 (cPLA2), which releases arachidonic acid (AA) from membrane phospholipids. AA is then rapidly taken up again by the neurons to replenish the synaptic membranes. The incorporation rate of AA can be measured using [1-11C]AA, and used as an index of D2R signal transduction (Thambisetty et al., 2012).
[11C]-(+)-PHNO is considered to prefer D3 receptors over D2Rs, and can be used to assess D3R availability in D3R rich areas (substantia nigra), D2R availability in D2R rich areas (dorsal striatum), and a weighted sum of D2/3R availability in mixed D2/3R regions (ventral striatum) (Worhunsky et al., 2017; Doot et al., 2019).
(N-methyl)benperidol (NMB) is specific to D2Rs, but cannot be displaced by dopamine (Moerlein et al., 1997). Cerebellum can be used as reference region (Anteror-Dorsey et al., 2008). NMB can be labelled with 18F or 11C without affecting the molecular structure (Moerlein & Perlmutter, 1992; Moerlein et al., 2004). [18F]NMB and [11C]NMB can be used to assess also extrastriatal D2Rs (Eisenstein et al., 2012 and 2013).
Metoclopramide is a D2R antagonist, used to prevent nausea and to help with emptying of the stomach. [11C]metoclopramide has been used to study the biodistribution and transport of the drug (Pottier et al., 2016; Hernández-Lozano et al., 2021). Metoclopramide is also a mixed 5-HT3R antagonist and 5-HT4R agonist.
Dopamine in synaptic cleft is mainly cleared by presynaptic dopamine transporter (DAT). In the neurons, DA is then repackaged into synaptic vesicles by vesicular monoamine transporter (VMAT2). This recycling is the main source of dopamine for vesicular release in the neurons. DAT is a member of the Na+/Cl--dependent neurotransmitter transporter family. The density of DAT in the presynaptic cell membrane is strictly regulated via trafficking of DAT between the cell membrane and intracellular compartments. Also the activity of DAT is regulated.
The availability of DAT can be measured using several radioligands, including [11C]CIT, [18F]FP-CIT, [11C]CFT, [18F]β-CFT (Rinne et al., 1999); Nurmi et al., 2000), [11C]PE2I, and [18F]FE-PE2I. [11C]Cocaine was the first radiopharmaceutical for DAT PET imaging (Fowler et al., 1989; Volkow et al., 1992), and can be used to study the pharmacokinetics of cocaine, but is not well suited for DAT quantification because of its fast metabolism.
In clinical diagnostic imaging [123I]FP-CIT SPECT is commonly used. Both age and sex should be accounted for in diagnostics (Honkanen et al., 2021).
Vesicular monoamine transporter 2 (VMAT2), which transports dopamine into presynaptic vesicles of the brain, can be studied using [11C]DTBZ (Asser et al., 2016) and [18F]FP-(+)-DTBZ (Lin et al., 2014). VMAT2 is found in all monoaminergic nerve terminals, but in the striatum predominantly in dopaminergic terminals. VMAT2 radiopharmaceuticals have also been used to quantify β-cell mass in the pancreas (Naganawa et al., 2016; Cline et al., 2018).
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Updated at: 2021-12-06
Created at: 2016-08-23
Written by: Vesa Oikonen