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 Dopaminergic Presynaptic Integrity: 6-[18F]Fluoro-L-Dopa Versus 6-[18F]Fluoro-L-m-Tyrosine

1999 ◽  
Vol 19 (3) ◽  
pp. 278-287 ◽  
Author(s):  
D. J. Doudet ◽  
G. L.-Y. Chan ◽  
S. Jivan ◽  
O. T. DeJesus ◽  
E. G. McGeer ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Metabolic Pathway ◽  
Arterial Input Function ◽  
Occipital Cortex ◽  
Input Function ◽  
Emission Tomography ◽  
Dopa Decarboxylase ◽  
Positron Emission ◽  
Pet Scans

The effectiveness of 6-[18F]fluoro-L- m-tyrosine (6FMT) to evaluate dopamine presynaptic integrity was compared to that of 6-[18F]fluoro-L-dopa (6FDOPA) in vivo by positron emission tomography (PET). Six normal and six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -lesioned monkeys received 6FDOPA and 6FMT PET scans on separate occasions with identical scanning protocols. Four measures, the rate of uptake of tracer into striatum using either the arterial input function ( Ki) or the activity in the occipital cortex as the input function ( Kc), the rate of loss of striatal radioactivity ( kloss), and an index of “effective turnover” of dopamine ( kloss/ Ki), were obtained for both tracers during extended PET studies. 6-[18F]Fluoro-L- m-tyrosine was as effective as 6FDOPA in separating normals from MPTP-lesioned subjects on the basis of the uptake rate constants Ki and Kc. However, in contrast to 6FDOPA, it was not possible to differentiate the normal from the lesioned animal using kloss or kloss/ Ki for 6FMT. Thus, FMT appears to be a reasonable, highly specific tracer for studying the activity of aromatic dopa decarboxylase enzyme as an index of presynaptic integrity. However, if one is interested in investigating further the metabolic pathway and obtaining an in vivo estimate of the effective turnover of dopamine (after pharmacologic manipulation, for example), 6FDOPA remains the tracer of choice.

scholarly journals Kinetic Modeling of the Serotonin 5-HT1B Receptor Radioligand [11C]P943 in Humans

2009 ◽  
Vol 30 (1) ◽  
pp. 196-210 ◽  
Author(s):  
Jean-Dominique Gallezot ◽  
Nabeel Nabulsi ◽  
Alexander Neumeister ◽  
Beata Planeta-Wilson ◽  
Wendol A Williams ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Arterial Input Function ◽  
Human Subjects ◽  
Emission Tomography ◽  
Binding Potential ◽  
Noninvasive Methods ◽  
Reference Tissue ◽  
Positron Emission ◽  
Tissue Models

[11C]P943 is a new radioligand recently developed to image and quantify serotonin 5-Hydroxytryptamine (5-HT1B) receptors with positron emission tomography (PET). The purpose of this study was to evaluate [11C]P943 for this application in humans, and to determine the most suitable quantification method. Positron emission tomography data and arterial input function measurements were acquired in a cohort of 32 human subjects. Using arterial input functions, compartmental modeling, the Logan graphical analysis, and the multilinear method MA1 were tested. Both the two tissue-compartment model and MA1 provided good fits of the PET data and reliable distribution volume estimates. Using the cerebellum as a reference region, BPND binding potential estimates were computed. [11C]P943 BPND estimates were significantly correlated with in vitro measurements of the density of 5-HT1B receptors, with highest values in the occipital cortex and pallidum. To evaluate noninvasive methods, two- and three-parameter graphical analyses, Simplified Reference Tissue Models (SRTM and SRTM2), and Multilinear Reference Tissue Models (MRTM and MRTM2) were tested. The MRTM2 model provided the best correlation with MA1 binding-potential estimates. Parametric images of the volume of distribution or binding potential of [11C]P943 could be computed using both MA1 and MRTM2. The results show that [11C]P943 provides quantitative measurements of 5-HT1B binding potential.

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 A Two-Compartment Description and Kinetic Procedure for Measuring Regional Cerebral [11C]Nomifensine Uptake Using Positron Emission Tomography

1990 ◽  
Vol 10 (3) ◽  
pp. 307-316 ◽  
Author(s):  
Eric Salmon ◽  
David J. Brooks ◽  
Klaus L. Leenders ◽  
David R. Turton ◽  
Sue P. Hume ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Partition Coefficient ◽  
Cell Activity ◽  
Compartment Model ◽  
Input Function ◽  
Volume Of Distribution ◽  
Red Cells ◽  
Emission Tomography ◽  
Binding Potential ◽  
Positron Emission

S-[11C]Nomifensine ( S-[11C]NMF) is a positron-emitting tracer suitable for positron emission tomography, which binds to both dopaminergic and noradrenergic reuptake sites in the striatum and the thalamus. Modelling of the cerebral distribution of this drug has been hampered by the rapid appearance of glucuronide metabolites in the plasma, which do not cross the blood–brain barrier. To date, [11C]NMF uptake has simply been expressed as regional versus nonspecific cerebellar activity ratios. We have calculated a “free” NMF input curve from red cell activity curves, using the fact that the free drug rapidly equilibrates between red cells and plasma, while glucuronides do not enter red cells. With this free [11C]NMF input function, all regional cerebral uptake curves could be fitted to a conventional two-compartment model, defining tracer distribution in terms of [11C]NMF regional volume of distribution. Assuming that the cerebellar volume of distribution of [11C]NMF represents the nonspecific volume of distribution of the tracer in striatum and thalamus, we have calculated an equilibrium partition coefficient for [11C]NMF between freely exchanging specific and nonspecific compartments in these regions, representing its “binding potential” to dopaminergic or noradrenergic uptake sites (or complexes). This partition coefficient was lower in the striatum when the racemate rather than the active S-enantiomer of [11C]NMF was administered. In the striatum of patients suffering from Parkinson's disease and multiple-system atrophy, the specific compartmentation of S-[11C]NMF was significantly decreased compared with that of age-matched volunteers.

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