Positron Emission Tomography Quantification of [11C]-DASB Binding to the Human Serotonin Transporter: Modeling Strategies

[11C]-DASB, namely [11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile, is a new highly selective radioligand for the in vivo visualization of the serotonin transporter (SERT) using positron emission tomography (PET). The current study evaluates different kinetic modeling strategies for quantification of [11C]-DASB binding in five healthy humans. Kinetic analyses of tissue data were performed with a one-tissue (1CM) and a two-tissue (2CM) compartment model. Time-activity curves were well described by a 1CM for all regions. A 2CM model with four parameters failed to converge reliably. Reliable fits of the data were obtained only if no more than three parameters were allowed to vary. However, even then, the rate constants k3 and k4 were estimated with poor precision. Only the ratio k3/k4 was stable. Goodness of fit was not improved by using a 2CM as compared with a 1CM. The minimal study duration required to obtain stable k3/k4 estimates was 80 minutes. For routine use of [11C]-DASB, several simplified methods using the cerebellum as a reference region to estimate nonspecific binding were also evaluated. The transient equilibrium, the linear graphical analysis, the ratio of target to reference region, and the simplified reference tissue methods all gave binding potential values consistent with those obtained with the 2CM. The suitability of [11C]-DASB for research on the SERT using PET is thus supported by the observations that tissue data can be described using a kinetic analysis and that simplified quantitative methods, using the cerebellum as reference, provide reliable estimates of SERT binding parameters.

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Tracer Kinetic Modeling of [11C]AFM, a New PET Imaging Agent for the Serotonin Transporter

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2013.134 ◽

2013 ◽

Vol 33 (12) ◽

pp. 1886-1896 ◽

Cited By ~ 8

Author(s):

Mika Naganawa ◽

Nabeel Nabulsi ◽

Beata Planeta ◽

Jean-Dominique Gallezot ◽

Shu-Fei Lin ◽

...

Keyword(s):

Positron Emission Tomography ◽

Serotonin Transporter ◽

Emission Tomography ◽

Binding Potential ◽

Reference Tissue ◽

Time Activity ◽

Tissue Model ◽

Positron Emission ◽

Arterial Input Functions ◽

Tissue Models

[11C]AFM, or [11C]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine, is a new positron emission tomography (PET) radioligand with high affinity and selectivity for the serotonin transporter (SERT). The purpose of this study was to determine the most appropriate kinetic model to quantify [11C]AFM binding in the healthy human brain. Positron emission tomography data and arterial input functions were acquired from 10 subjects. Compartmental modeling and the multilinear analysis-1(MA1) method were tested using the arterial input functions. The one-tissue model showed a lack of fit in low-binding regions, and the two-tissue model failed to estimate parameters reliably. Regional time–activity curves were well described by MA1. The rank order of [11C]AFM binding potential ( BPND) matched well with the known regional SERT densities. For routine use of [11C]AFM, several noninvasive methods for quantification of regional binding were evaluated, including simplified reference tissue models (SRTM and SRTM2), and multilinear reference tissue models (MRTM and MRTM2). The best methods for region of interest (ROI) analysis were MA1, MRTM2, and SRTM2, with fixed population kinetic values ( k′2 or b′) for the reference methods. The MA1 and MRTM2 methods were best for parametric imaging. These results showed that [11C]AFM is a suitable PET radioligand to image and quantify SERT in humans.

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

Psychological Medicine ◽

10.1017/s003329171200164x ◽

2012 ◽

Vol 43 (4) ◽

pp. 881-894 ◽

Cited By ~ 19

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.

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1995.99 ◽

1995 ◽

Vol 15 (5) ◽

pp. 787-797 ◽

Cited By ~ 66

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.

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Brain Serotonin Transporter Binding Potential Measured With Carbon11–Labeled DASB Positron Emission Tomography

Archives of General Psychiatry ◽

10.1001/archpsyc.61.12.1271 ◽

2004 ◽

Vol 61 (12) ◽

pp. 1271 ◽

Cited By ~ 178

Author(s):

Jeffrey H. Meyer ◽

Sylvain Houle ◽

Sandra Sagrati ◽

Anna Carella ◽

Doug F. Hussey ◽

...

Keyword(s):

Positron Emission Tomography ◽

Serotonin Transporter ◽

Emission Tomography ◽

Brain Serotonin ◽

Binding Potential ◽

Positron Emission

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Lack of Age-Dependent Decrease in Dopamine D3 Receptor Availability: A [11C]-(+)-PHNO and [11C]-Raclopride Positron Emission Tomography Study

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.129 ◽

2015 ◽

Vol 35 (11) ◽

pp. 1812-1818 ◽

Cited By ~ 17

Author(s):

Shinichiro Nakajima ◽

Fernando Caravaggio ◽

Isabelle Boileau ◽

Jun K Chung ◽

Eric Plitman ◽

...

Keyword(s):

Positron Emission Tomography ◽

Ventral Striatum ◽

Emission Tomography ◽

Ventral Pallidum ◽

Binding Potential ◽

Healthy Humans ◽

Positron Emission ◽

Age Dependent ◽

Dopamine D3 ◽

The Relationship

Positron emission tomography with antagonist radiotracers has showed that striatal dopamine D2/3 receptor (D2/3R) availability decreases with age. However, no study has specifically assessed whether D2/3R availability decreases with age in healthy persons as measured with agonist radiotracers. Moreover, it is unknown whether D3R availability changes with age in healthy humans. Thus, we explored the relationship between age and D2/3R availability in healthy humans using the D3 receptor (D3R)-preferential agonist radiotracer [11C]-(+)-PHNO ( n = 72, mean ± s.d. age = 40 ± 15, range = 18 to 73) and the antagonist [11C]-Raclopride ( n = 70, mean ± s.d. age = 40 ± 14, range = 18 to 73) (both, n = 33). The contribution of D3R to the [11C]-(+)-PHNO signal varies across regions of interest; the substantia nigra and hypothalamus represent D3R-specific regions, the ventral pallidum, globus pallidus, and ventral striatum represent D2/3R-mixed regions, and the caudate and putamen represent D2 receptor (D2R)-specific regions. With [11C]-(+)-PHNO, a negative correlation was observed between age and nondisplaceable binding potential (BPND) in the caudate ( r(70) = −0.32, P = 0.005). No correlations were observed in the other regions. With [11C]-Raclopride, negative correlations were observed between age and BPND in the caudate ( r(68) = −0.50, P < 0.001), putamen ( r(68) = −0.41, P < 0.001), and ventral striatum ( r(68) = −0.43, P < 0.001). In conclusion, in contrast with the age-dependent decrease in D2R availability, these findings suggest that D3R availability does not change with age.

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