Modeling [18F]MPPF Positron Emission Tomography Kinetics for the Determination of 5-Hydroxytryptamine(1A) Receptor Concentration with Multiinjection (original) (raw)
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Kinetic modeling of the serotonin 5HT1B receptor radioligand [11C]P943 in humans
Journal of Cerebral Blood Flow and Metabolism, 2010
11 C]P943 is a new radioligand recently developed to image and quantify serotonin 5-Hydroxytryptamine (5-HT 1B ) receptors with positron emission tomography (PET). The purpose of this study was to evaluate [ 11 C]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, BP ND binding potential estimates were computed. [ 11 C]P943 BP ND estimates were significantly correlated with in vitro measurements of the density of 5-HT 1B 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 bindingpotential estimates. Parametric images of the volume of distribution or binding potential of [ 11 C]P943 could be computed using both MA1 and MRTM2. The results show that [ 11 C]P943 provides quantitative measurements of 5-HT 1B binding potential.
The serotonin (5-hydroxytryptamine, or 5-HT) type 1A receptor (5-HT 1A R) is implicated in the pathophysiology of numerous neuropsychiatric disorders. We have published the initial evaluation and reproducibility in vivo of [O-methyl-11 C]2-(4-(4-(2methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5 (2H,4H)dione ( 11 C-CUMI-101), a novel 5-HT 1A agonist radiotracer, in Papio anubis. Here, we report the optimal modeling parameters of 11 C-CUMI-101 for human PET studies. Methods: PET scans were obtained for 7 adult human volunteers. 11 C-CUMI-101 was injected as an intravenous bolus, and emission data were collected for 120 min in 3-dimensional mode. We evaluated 10 different models using metabolite-corrected arterial input functions or reference region approaches and several outcome measures. Results: When using binding potential (BP F 5 B avail /K D [total available receptor concentration divided by the equilibrium dissociation constant]) as the outcome measure, the likelihood estimation in the graphical analysis (LEGA) model performed slightly better than the other methods evaluated at full scan duration. The average test-retest percentage difference was 9.90% 6 5.60%. When using BP ND (BP ND 5 f nd · B avail /K D ; BP ND equals the product of BP F and f nd [free fraction in the nondisplaceable compartment]), the simplified reference tissue method (SRTM) achieved the lowest percentage difference and smallest bias when compared with nondisplaceable binding potential obtained from LEGA using the metabolitecorrected plasma input function (r 2 5 0.99; slope 5 0.92). The time-stability analysis indicates that a 120-min scan is sufficient for the stable estimation of outcome measures. Voxel results were comparable to region-of-interest-based analysis, with higher spatial resolution. Conclusion: On the basis of its measurable and stable free fraction, high affinity and selectivity, good blood-brain barrier permeability, and plasma and brain kinetics, 11 C-CUMI-101 is suitable for the imaging of high-affinity 5-HT 1A binding in humans.
In vivo delineation of 5-HT1A receptors in human brain with [18F]MPPF
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2000
Serotonin-1A (5-hydroxytryptamine-1A [5-HT1A]) receptors have been reported to play an important role in the pathophysiology of a variety of psychiatric and neurodegenerative disorders. Animal experiments have shown that 4-(2'-methoxyphenyl)-1-[2'-(N-2'-pyridinyl)-p-[18F]fluorobenzamido ]ethylpiperazine ([18F]MPPF) may be suitable for 5-HT1A receptor imaging in humans. The aim of this study was to determine if [18F]MPPF can be used for the quantitative analysis of 5-HT1A receptor densities in brain regions of healthy human volunteers. [15O]H2O perfusion scanning was performed before intravenous injection of [18F]MPPF to obtain anatomic information. Cerebral radioactivity was monitored using a PET camera. Plasma metabolites of [18F]MPPF were determined by high-performance liquid chromatography. Binding potentials were calculated using the metabolite-corrected arterial input function and a linear graphic method (Logan-Patlak analysis). The highest levels of radioactivity w...
On the quantification of [18F]MPPF binding to 5-HT1A receptors in the human brain
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2001
Previous studies have shown that 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[(18)F]fluorobenzamido]ethylpiperazine ([(18)F]MPPF) binds with high selectivity to serotonin (5-HT(1A)) receptors in man. However, in these studies, the calculation of the binding potential (BP, which equals receptor density divided by equilibrium dissociation constant) used a metabolite-corrected arterial input. The aim of this study was to determine whether metabolite correction and arterial sampling are essential for the assessment of BP. Five analytic methods using full datasets obtained from 6 healthy volunteers were compared. In addition, the clinical applicability of these methods was appraised. Three methods were based on Logan analysis of the dynamic PET data using metabolite-corrected and uncorrected arterial plasma input and cerebellar input. The other 2 methods consisted of a simplified reference tissue model and standard compartmental modeling. A high correlation was found betwe...
Quantifying drug-related 5-HT1A receptor occupancy with [18F]MPPF
Psychopharmacology, 2001
Rationale: There is an increased interest in measuring the interaction of new or established drugs with their targets, in order to gain a better understanding of their mechanisms of action. PET can provide this information if an appropriate radioligand is available.
Journal of Cerebral Blood Flow & Metabolism, 2006
Positron emission tomography (PET) studies of the serotonin transporter (5-HTT) in the human brain are increasingly using the radioligand [11C] N, N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine. A variety of models have been applied to such data in several published articles; however to date, these models have not been validated with test–retest data. We recruited 11 healthy subjects and conducted two identical scans on each subject on the same day. We considered four different models (one- and two-tissue compartment kinetic models, likelihood estimation in graphical analysis (LEGA; a bias-free alternative to the graphical method), and basis pursuit) along with fast noniterative approximations to the kinetic models. We considered four different outcome measures (total volume of distribution ( VT), binding potential with (BP) and without (BP1), free-fraction adjustment, and specific-to-nonspecific equilibrium partition coefficient (BP2)). To assess the performance of each model...
Psychopharmacology, 2015
Central modulation of serotonin and dopamine underlies efficacy for a variety of psychiatric therapeutics. ITI-007 is an investigational new drug in development for treatment of schizophrenia, mood disorders, and other neuropsychiatric disorders. The purpose of this study was to determine brain occupancy of ITI-007 at serotonin 5-HT2A receptors, dopamine D2 receptors, and serotonin transporters using positron emission tomography (PET) in 16 healthy volunteers. Carbon-11-MDL100907, carbon-11-raclopride, and carbon-11-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) (carbon-11-DASB) were used as the radiotracers for imaging 5-HT2A receptors, D2 receptors, and serotonin transporters, respectively. Brain regions of interest were outlined using magnetic resonance tomography (MRT) with cerebellum as the reference region. Binding potentials were estimated by fitting a simplified reference tissue model to the measured tissue-time activity curves. Target occupancy was expressed...
NeuroImage, 2008
Brain imaging Mood PET Positron emission tomography Serotonin synthesis 5-HT 1A receptors Serotonin (5-HT) is one of the major neurotransmitters and has been implicated in a wide variety of cerebral functions. Several lines of evidence indicate that 5HT 1A receptors exert a negative feedback in the synthesis and release of serotonin. While most of what is known about serotonin comes from studies in animals, much less empirical evidence exists about the serotonergic system in the living human brain. This study aims to assess the correlation between serotonin synthesis and 5-HT 1A receptor binding using positron emission tomography (PET) in humans. Six healthy male volunteers underwent 2 PET scans in the same day: one measuring α-[ 11 C] MT K⁎ [ml/g/min] trapping constant (a measure of serotonin synthesis) and one measuring 5-HT 1A receptor binding potential BP ND with [ 18 F]MPPF. Volumes of interest (VOIs) selected a priori included: anterior cingulate cortex (ACC), anterior insula, hippocampus, amygdala, thalamus, hypothalamus and midbrain raphe nuclei. Correlation analyses were conducted voxel-by-voxel and with manually traced VOIs. A significant negative correlation between serotonin synthesis and 5-HT 1A binding potential was found bilaterally in hippocampus and anterior insula and in the left ACC. The combination of [ 18 F]MPPF and α-[ 11 C]MT PET offers a means to investigate key determinants of 5-HT neurotransmission under physiological and psychopathological conditions in the human brain in vivo.