scholarly journals Measuring Endogenous 5-HT Release by Emission Tomography: Promises and Pitfalls

2010 ◽  
Vol 30 (10) ◽  
pp. 1682-1706 ◽  
Author(s):  
Louise M Paterson ◽  
Robin J Tyacke ◽  
David J Nutt ◽  
Gitte M Knudsen
Keyword(s):  
Emission Tomography ◽  
Basic Knowledge ◽  
Binding Potential ◽  
Endogenous Dopamine ◽  
Positron Emission ◽  
Serotonin Reuptake Transporter ◽  
Endogenous Dopamine Release ◽  
Receptor Targets ◽  
Neuroimaging Techniques

Molecular in vivo neuroimaging techniques can be used to measure regional changes in endogenous neurotransmitters, evoked by challenges that alter synaptic neurotransmitter concentration. This technique has most successfully been applied to the study of endogenous dopamine release using positron emission tomography, but has not yet been adequately extended to other neurotransmitter systems. This review focuses on how the technique has been applied to the study of the 5-hydroxytryptamine (5-HT) system. The principles behind visualising fluctuations in neurotransmitters are introduced, with reference to the dopaminergic system. Studies that aim to image acute, endogenous 5-HT release or depletion at 5-HT receptor targets are summarised, with particular attention to studies in humans. Radiotracers targeting the 5-HT1A, 5-HT2A, and 5-HT4 receptors and the serotonin reuptake transporter have been explored for their sensitivity to 5-HT fluctuations, but with mixed outcomes; tracers for these targets cannot reliably image endogenous 5-HT in humans. Shortcomings in our basic knowledge of the mechanisms underlying changes in binding potential are addressed, and suggestions are made as to how the selection of targets, radiotracers, challenge paradigms, and experimental design might be optimised to improve our chances of successfully imaging endogenous neurotransmitters in the future.

scholarly journals Apomorphine-Induced Changes in Synaptic Dopamine Levels: Positron Emission Tomography Evidence for Presynaptic Inhibition

2001 ◽  
Vol 21 (10) ◽  
pp. 1151-1159 ◽  
Author(s):  
Raúl de la Fuente-Fernández ◽  
Andrew S. Lim ◽  
Vesna Sossi ◽  
James E. Holden ◽  
Donald B. Calne ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Parkinson Disease ◽  
Dopamine Agonists ◽  
Emission Tomography ◽  
Binding Potential ◽  
Endogenous Dopamine ◽  
Positron Emission ◽  
Tomography Method ◽  
Induced Changes

The authors developed a novel positron emission tomography method to estimate changes in the synaptic level of dopamine ([DA]) induced by direct dopamine agonists (for example, apomorphine) in patients with Parkinson disease. The method is based on the typical asymmetry of the nigrostriatal lesion that often occurs in Parkinson disease. Using the between-side difference (ipsilateral (I) and contralateral (C) putamen to the more affected body side) of the inverse of the putamen [11C]raclopride binding potential (BP), the authors obtained [Formula: see text] at baseline (that is, before apomorphine administration) and [Formula: see text] after apomorphine administration (assuming the concentration of apomorphine is equal in both putamina). The between-side difference in the estimated synaptic concentration of dopamine (diff[DA]) should remain constant unless apomorphine affects dopamine release differently between the two sides. The authors found that apomorphine given subcutaneously at doses of 0.03 and 0.06 mg/kg induced significant changes in their estimate of diff[DA] (P < 0.05). Such changes were more pronounced when only patients with a stable response to levodopa were considered ( P < 0.01). These findings provide in vivo evidence that direct dopamine agonists can inhibit the release of endogenous dopamine. The authors propose that this effect is mainly mediated by the activation of presynaptic D2 /D3 dopamine receptors.

In Vivo PET Measurements with [11C]PE2I to Evaluate Fetal Mesencephalic Transplantations to Unilateral 6-OHDA-Lesioned Rats

2005 ◽  
Vol 14 (9) ◽  
pp. 655-663 ◽  
Author(s):  
Motoki Inaji ◽  
Takahito Yoshizaki ◽  
Takashi Okauchi ◽  
Jun Maeda ◽  
Yuji Nagai ◽  
...  
Keyword(s):  
Dopamine Transporter ◽  
High Performance ◽  
Emission Tomography ◽  
Binding Potential ◽  
In Vitro Autoradiography ◽  
Positron Emission ◽  
Pet Scans ◽  
Mesencephalic Cells

Positron emission tomography (PET) is a useful tool to assess and visualize neurotransmissions in vivo. In this study, we performed repeated PET scans with [11C]PE2I, a tracer of the dopamine transporter, to evaluate the alteration of the expression of dopamine (DA) transmission component after a fetal mesencephalic transplantation. The fetal mesencephalic cells were transplanted into the striatum of unilateral 6-OHDA-lesioned rats. PET scans with [11C]PE2I were performed to evaluate the DA transporter before and 2 and 4 weeks after the transplantation. Rotation behavior tests, in vitro autoradiography, measurements of DA contents in the striatum by high-performance liquid chromatography (HPLC), and tyrosine hydroxylase (TH) immuno-histological examinations were performed at the same time points and examined for their relationship to changes in the dopamine transporter. The number of ipsilateral rotations induced by methamphetamine injections decreased. DA contents in the striatum measured with HPLC significantly increased. In the PET study, the binding potential of [11C]PE2I increased at 4 weeks. The results of the in vitro autoradiography study corresponded with those of the PET study. The degrees of the change in the binding potentials correlated with those of the numbers of rotations in the behavioral study and the DA contents in the striatum. In the histological examination, TH-positive cells with axons were observed at 2 and 4 weeks after the transplantation. As the dopamine transporter exists only in the axon terminal of DA neurons, these results suggested that PET measurements of [11C]PE2I binding indicated not only survival, but maturity and functioning of the transplanted cells. Repeated PET measurements of DA transporters are a useful tool in assessing the effectiveness of neural transplantations.

scholarly journals Temperament, character and serotonin activity in the human brain: a positron emission tomography study based on a general population cohort

2012 ◽  
Vol 43 (4) ◽  
pp. 881-894 ◽  
Author(s):  
L. Tuominen ◽  
J. Salo ◽  
J. Hirvonen ◽  
K. Någren ◽  
P. Laine ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Serotonin Transporter ◽  
Population Based ◽  
Emission Tomography ◽  
Brain Serotonin ◽  
Binding Potential ◽  
Positron Emission ◽  
General Population Cohort ◽  
Temperament Dimension

BackgroundThe psychobiological model of personality by Cloninger and colleagues originally hypothesized that interindividual variability in the temperament dimension ‘harm avoidance’ (HA) is explained by differences in the activity of the brain serotonin system. We assessed brain serotonin transporter (5-HTT) density in vivo with positron emission tomography (PET) in healthy individuals with high or low HA scores using an ‘oversampling’ study design.MethodSubjects consistently in either upper or lower quartiles for the HA trait were selected from a population-based cohort in Finland (n = 2075) with pre-existing Temperament and Character Inventory (TCI) scores. A total of 22 subjects free of psychiatric and somatic disorders were included in the matched high- and low-HA groups. The main outcome measure was regional 5-HTT binding potential (BPND) in high- and low-HA groups estimated with PET and [11C]N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine ([11C]MADAM). In secondary analyses, 5-HTT BPND was correlated with other TCI dimensions.Results5-HTT BPND did not differ between high- and low-HA groups in the midbrain or any other brain region. This result remained the same even after adjusting for other relevant TCI dimensions. Higher 5-HTT BPND in the raphe nucleus predicted higher scores in ‘self-directedness’.ConclusionsThis study does not support an association between the temperament dimension HA and serotonin transporter density in healthy subjects. However, we found a link between high serotonin transporter density and high ‘self-directedness’ (ability to adapt and control one's behaviour to fit situations in accord with chosen goals and values). We suggest that biological factors are more important in explaining variability in character than previously thought.

scholarly journals Serotonin 5HT2 Receptor Imaging in the Human Brain Using Positron Emission Tomography and a New Radioligand, [18F]Altanserin: Results in Young Normal Controls

1995 ◽  
Vol 15 (5) ◽  
pp. 787-797 ◽  
Author(s):  
B. Sadzot ◽  
C. Lemaire ◽  
P. Maquet ◽  
E. Salmon ◽  
A. Plenevaux ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
High Specific Activity ◽  
Emission Tomography ◽  
Binding Potential ◽  
Receptor Imaging ◽  
Time Activity ◽  
Arterial Blood ◽  
Positron Emission

Changes in serotonin-2 receptors have been demonstrated in brain autopsy material from patients with various neurodegenerative and affective disorders. It would be desirable to locate a ligand for the study of these receptors in vivo with positron emission tomography (PET). Altanserin is a 4-benzoylpiperidine derivative with a high affinity and selectivity for S2 receptors in vitro. Dynamic PET studies were carried out in nine normal volunteers with high-specific activity (376–1,680 mCi/μmol) [18F]altanserin. Arterial blood samples were obtained and the plasma time–activity curves were corrected for the presence of labeled metabolites. Thirty minutes after injection, selective retention of the radioligand was observed in cortical areas, while the cerebellum, caudate, and thalamus had low radioactivity levels. Specific binding reached a plateau between 30 and 65 min postinjection at 1.8% of the injected dose/L of brain and then decreased, indicating the reversibility of the binding. The total/nonspecific binding ratio reached 2.6 for times between 50 and 70 min postinjection. The graphical analysis proposed by Logan et al. allowed us to estimate the binding potential ( Bmax/ KD). Pretreatment with ketanserin was given to three volunteers and brain activity remained uniformly low. An additional study in one volunteer showed that [18F]altanserin can be displaced from the receptors by large doses of ketanserin. At the end of the study, unchanged altanserin was 57% of the total plasma activity. These results suggest that [18F]altanserin is selective for S2 receptors in vivo as it is in vitro. They indicate that [18F]altanserin is suitable for imaging and quantifying S2 receptors with PET in humans.

scholarly journals Kinetic Modeling of [11C]Raclopride: Combined PET-Microdialysis Studies

1997 ◽  
Vol 17 (9) ◽  
pp. 932-942 ◽  
Author(s):  
Christopher J. Endres ◽  
Bhaskar S. Kolachana ◽  
Richard C. Saunders ◽  
Tom Su ◽  
Daniel Weinberger ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Specific Binding ◽  
Compartment Model ◽  
Emission Tomography ◽  
Extended Model ◽  
Simulation Studies ◽  
Time Activity ◽  
Endogenous Dopamine ◽  
Positron Emission

The in vivo binding of D2 receptor ligands can be affected by agents that alter the concentration of endogenous dopamine. To define a more explicit relation between dopamine and D2 receptor binding, the conventional compartment model for reversible ligands has been extended to account for a time-varying dopamine pulse. This model was tested with [11C]raclopride positron emission tomography and dopamine microdialysis data that were acquired simultaneously in rhesus monkeys. The microdialysis data were incorporated into the model assuming a proportional relation to synaptic dopamine. Positron emission tomography studies used a bolus-plus-infusion tracer delivery with amphetamine given at 40 minutes to induce dopamine release. The extended model described the entire striatal time–activity curve, including the decrease in radioactivity concentration after an amphetamine-induced dopamine pulse. Based on these results, simulation studies were performed using the extended model. The simulation studies showed that the percent decrease in specific binding after amphetamine measured with the bolus-plus-infusion protocol correlates well with the integral of the postamphetamine dopamine pulse. This suggests that changes in specific binding observed in studies in humans can be interpreted as being linearly proportional to the integral of the amphetamine-induced dopamine pulse.

scholarly journals In vivo Serotonin-Sensitive Binding of [11C]CUMI-101: A Serotonin 1A Receptor Agonist Positron Emission Tomography Radiotracer

2010 ◽  
Vol 31 (1) ◽  
pp. 243-249 ◽  
Author(s):  
Matthew S Milak ◽  
Alin J Severance ◽  
Jaya Prabhakaran ◽  
JS Dileep Kumar ◽  
Vattoly J Majo ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Arterial Input Function ◽  
Input Function ◽  
Emission Tomography ◽  
Binding Potential ◽  
Papio Anubis ◽  
Positron Emission ◽  
Future Work ◽  
G Protein Coupled

Positron emission tomography studies of 5-hydroxytryptamine (5-HT)1A receptors have hitherto been limited to antagonist radiotracers. Antagonists do not distinguish high/low-affinity conformations of G protein-coupled receptors and are less likely to be sensitive to intrasynaptic serotonin levels. We developed a novel 5-HT1A agonist radiotracer [11C]CUMI-101. This study evaluates the sensitivity of [11C]CUMI-101 binding to increases in intrasynaptic serotonin induced by intravenous citalopram and fenfluramine. Two Papio anubis were scanned, using [11C]CUMI-101 intravenous bolus of 4.5±1.5 mCi. Binding potential (BPF= Bavail/ KD) was measured before ( n=10) and 20 minutes after elevation of intrasynaptic serotonin by intravenous citalopram (2 mg/kg, n=3; 4 mg/kg, n=3) and fenfluramine (2.5 mg/kg, n=3) using a metabolite-corrected arterial input function. Occupancy was also estimated by the Lassen graphical approach. Both citalopram and fenfluramine effects were significant for BPF ( P=0.031, P=0.049, respectively). The Lassen approach estimated 15.0, 30.4, and 23.7% average occupancy after citalopram 2 mg/kg, 4 mg/kg, and fenfluramine 2.5 mg/kg, respectively. [11C]CUMI-101 binding is sensitive to a large increase in intrasynaptic serotonin in response to robust pharmacological challenges. These modest changes in BPF may make it unlikely that this ligand will detect changes in intrasynaptic 5-HT under physiologic conditions; future work will focus on evaluating its utility in measuring the responsiveness of the 5-HT system to pharmacological challenges.

scholarly journals Evaluation of Four Pyridine Analogs to Characterize 6-OHDA-Induced Modulation of mGluR5 Function in Rat Brain Using microPET Studies

2007 ◽  
Vol 27 (9) ◽  
pp. 1623-1631 ◽  
Author(s):  
Aijun Zhu ◽  
Xukui Wang ◽  
Meixiang Yu ◽  
Ji-Quan Wang ◽  
Anna-Liisa Brownell
Keyword(s):  
Positron Emission Tomography ◽  
Pet Imaging ◽  
Emission Tomography ◽  
Binding Potential ◽  
Sprague Dawley ◽  
Imaging Studies ◽  
Reference Tissue ◽  
Positron Emission ◽  
The Right

Micro-positron emission tomography imaging studies were conducted to characterize modulation of metabotropic glutamate subtype-5 receptor (mGluR5) function in a 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease using four analogical PET ligands: 2-[11C]methyl-6-(2-phenylethynyl) pyridine ([11C]MPEP), 2-(2-(3-[11C]methoxyphenyl)ethynyl)pyridine ([11C]M-MPEP), 2-(2-(5-[11C]methoxypyridin-3-yl)ethynyl)pyridine ([11C]M-PEPy), and 3-[(2-[18F]methyl-1,3-thiazol-4-yl)ethynyl]pyridine ([18F]M-TEP). A total of 45 positron emission tomography (PET) imaging studies were conducted on nine male Sprague-Dawley rats within 4 to 6 weeks after unilateral 6-OHDA lesioning into the right medial forebrain bundle. The severity of the lesion was determined with [11C]CFT ([11C]2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane), a specific and sensitive ligand for imaging dopamine transporter function. The binding potential (BP) images were processed on pixel-by-pixel basis by using a method of the distribution volume ratio with cerebellum as a reference tissue. The values for BP were determined on striatum, hippocampus, and cortex. [11C]CFT binding was decreased on the lesioned (right) striatum by 35.4% ± 13.4% compared with the intact left striatum, indicating corresponding loss of presynaptic dopamine terminals. On the same areas of the lesioned striatum, three of the four tested mGluR5 ligands showed enhanced binding characteristics. The average differences between the right and left striatum were 4.4% ± 6.5% ( P < 0.05) with [11C]MPEP, 0.1% ± 1.7% ( P > 0.05) with [11C]M-MPEP, 3.9% ± 4.6% ( P < 0.05) with [11C]M-PEPy, and 6.6% ± 2.7% ( P > 0.05) with [18F]M-TEP. The enhanced binding was also observed in the right hippocampus and cortex. These studies showed that glutamatergic neurotransmission might have a complementary role in dopaminergic degeneration, which can be evaluated by in vivo PET imaging.

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