scholarly journals Validation and Reproducibility of Measurement of 5-HT1A Receptor Parameters with [carbonyl-11C]WAY-100635 in Humans: Comparison of Arterial and Reference Tissue Input Functions

2000 ◽  
Vol 20 (7) ◽  
pp. 1111-1133 ◽  
Author(s):  
Ramin V. Parsey ◽  
Mark Slifstein ◽  
Dah-Ren Hwang ◽  
Anissa Abi-Dargham ◽  
Norman Simpson ◽  
...  
Keyword(s):  
Human Brain ◽  
Kinetic Analysis ◽  
Intraclass Correlation ◽  
Input Function ◽  
Graphical Analysis ◽  
Binding Potential ◽  
Reference Tissue ◽  
Time Activity ◽  
Way 100635 ◽  
Arterial Plasma

Serotonin 5-HT1A receptors are implicated in the pathophysiology of neuropsychiatric conditions. The goal of this study was to evaluate methods to derive 5-HT1A receptor parameters in the human brain with positron emission tomography (PET) and [ carbonyl-11C]WAY 100635. Five healthy volunteer subjects were studied twice. Three methods of analysis were used to derive the binding potential (BP), and the specific to nonspecific equilibrium partition coefficient (k3/k4). Two methods, kinetic analysis based on a three compartment model and graphical analysis, used the arterial plasma time-activity curves as the input function to derive BP and k3/k4. A third method, the simplified reference tissue model (SRTM), derived the input function from uptake data of a region of reference, the cerebellum, and provided only k3/k4. All methods provided estimates of regional 5-HT1A receptor parameters that were highly correlated. Results were consistent with the known distribution of 5-HT1A receptors in the human brain. Compared with kinetic BP, graphical analysis slightly underestimated BP, and this phenomenon was mostly apparent in small size-high noise regions. Compared with kinetic k3/k4, the reference tissue method underestimated k3/k4 and the underestimation was apparent primarily in regions with high receptor density. Derivation of BP by both kinetic and graphical analysis was highly reliable, with an intraclass correlation coefficient (ICC) of 0.84 ± 0.14 (mean ± SD of 15 regions) and 0.84 ± 0.19, respectively. In contrast, the reliability of k3/k4 was lower, with ICC of 0.53 ± 0.28, 0.47 ± 0.28, and 0.55 ± 0.29 for kinetic, graphical, and reference tissue methods, respectively. In conclusion, derivation of BP by kinetic analysis using the arterial plasma input function appeared as the method of choice because of its higher test—retest reproducibility, lower vulnerability to experimental noise, and absence of bias.

scholarly journals [11C]Flumazenil PET in Temporal Lobe Epilepsy: Do We Need an Arterial Input Function or Kinetic Modeling?

2007 ◽  
Vol 28 (1) ◽  
pp. 207-216 ◽  
Author(s):  
Alexander Hammers ◽  
Prasan Panagoda ◽  
Rolf A Heckemann ◽  
Wolfgang Kelsch ◽  
Federico E Turkheimer ◽  
...  
Keyword(s):  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Medial Temporal Lobe ◽  
Arterial Input Function ◽  
Diagnostic Yield ◽  
Hippocampal Sclerosis ◽  
Input Function ◽  
Binding Potential ◽  
Reference Tissue ◽  
Arterial Plasma

Reduced signal on [11C]]flumazenil (FMZ) positron emission tomography (PET) is associated with epileptogenic foci. Linear correlations within individuals between parametric and nonparametric images of FMZ binding have been shown, and various methods have been used, without comparison of diagnostic usefulness. Using hippocampal sclerosis (HS) as a test case, we formally compare the diagnostic yield of parametric images obtained either with a parent tracer arterial plasma input function and spectral analysis (yielding volume-of-distribution (VD) images), or with an image-based input function and the simplified reference tissue model (binding potential images, BP-SRTM) with the diagnostic yield of semiquantitative-integrated (ADD) images from 10 to 20 or 20 to 40 mins (ADD1020 and ADD2040). Dynamic 90-min [11C]FMZ PET datasets and arterial plasma input functions were available for 15 patients with medically refractory medial temporal lobe epilepsy (TLE) and histologically verified unilateral HS and for 13 control subjects. SPM2 was used for analysis. ADD1020 and ADD2040 images showed decreased FMZ uptake ipsilateral to the epileptogenic hippocampus in 13/15 cases; 6/13 had bilateral decreases in the ADD1020 analysis and 5/13 in the ADD2040 analysis. BP-SRTM images detected ipsilateral decreases in 12/15 cases, with bilateral decreases in three. In contrast, VD images showed ipsilateral hippocampal decreases in all 15 patients, with bilateral decreases in three patients. Bilateral decreases in the ADD images tended to be more symmetrical and in one case were more marked contralaterally. Full quantification with an image-independent input should ideally be used in the evaluation of FMZ PET; at least in TLE, intrasubject correlations do not predict equivalent clinical usefulness.

scholarly journals Measurement of Striatal and Extrastriatal Dopamine D1 Receptor Binding Potential With [11C]NNC 112 in Humans: Validation and Reproducibility

2000 ◽  
Vol 20 (2) ◽  
pp. 225-243 ◽  
Author(s):  
Anissa Abi-Dargham ◽  
Diana Martinez ◽  
Osama Mawlawi ◽  
Norman Simpson ◽  
Dah-Ren Hwang ◽  
...  
Keyword(s):  
Human Brain ◽  
Kinetic Analysis ◽  
Outcome Measures ◽  
Noise Analysis ◽  
Intraclass Correlation ◽  
Distribution Volume ◽  
D1 Receptor ◽  
Human Cognition ◽  
Binding Potential ◽  
Volume Distribution

To evaluate the postulated role of extrastriatal D1 receptors in human cognition and psychopathology requires an accurate and reliable method for quantification of these receptors in the living human brain. [11C]NNC 112 is a promising novel radiotracer for positron emission tomography imaging of the D1 receptor. The goal of this study was to develop and evaluate methods to derive D1 receptor parameters in striatal and extrastriatal regions of the human brain with [11C]NNC 112. Six healthy volunteers were studied twice. Two methods of analysis (kinetic and graphical) were applied to 12 regions (neocortical, limbic, and subcortical regions) to derive four outcome measures: total distribution volume, distribution volume ratio, binding potential (BP), and specific-to-nonspecific equilibrium partition coefficient ( k3/ k4). Both kinetic and graphic analyses provided BP and k3/ k4 values in good agreement with the known distribution of D1 receptors (striatum > limbic regions = neocortical regions > thalamus). The identifiability of outcome measures derived by kinetic analysis was excellent. Time-stability analysis indicated that 90 minutes of data collection generated stable outcome measures. Derivation of BP and k3/ k4 by kinetic analysis was highly reliable, with intraclass correlation coefficients (ICCs) of 0.90 ± 0.06 (mean ± SD of 12 regions) and 0.84 ± 0.11, respectively. The reliability of these parameters derived by graphical analysis was lower, with ICCs of 0.72 ± 0.17 and 0.58 ± 0.21, respectively. Noise analysis revealed a noise-dependent bias in the graphical but not the kinetic analysis. In conclusion, kinetic analysis of [11C]NNC 112 uptake provides an appropriate method with which to derive D1 receptor parameters in regions with both high (striatal) and low (extrastriatal) D1 receptor density.

Temporal analysis of myocardial glucose metabolism by 2-[18F]fluoro-2-deoxy-D-glucose

1990 ◽  
Vol 259 (4) ◽  
pp. H1022-H1031 ◽  
Author(s):  
V. T. Nguyen ◽  
K. A. Mossberg ◽  
T. J. Tewson ◽  
W. H. Wong ◽  
R. W. Rowe ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Work Load ◽  
Temporal Analysis ◽  
Input Function ◽  
Graphical Analysis ◽  
Time Activity ◽  
Myocardial Glucose Metabolism ◽  
Fractional Rate ◽  
Endogenous Insulin

To assess kinetic changes of myocardial glucose metabolism after physiological interventions, we perfused isolated working rat hearts with glucose and 2-[18F]fluoro-2-deoxy-D-glucose (2-FDG). Tissue uptake of 2-FDG and the input function were measured on-line by external detection. The fractional rate of 2-FDG phosphorylation was determined by graphical analysis of time-activity curves. The steady-state uptake of 2-FDG was linear with time, and the tracer was retained predominantly in its phosphorylated form. Tissue accumulation of 2-FDG decreased with a reduction in work load and with the addition of competing substrates. Insulin caused a significant increase in 2-FDG accumulation in hearts from fasted but not from fed animals. We conclude that in the isolated working rat heart there is rapid adjustment of exogenous substrate utilization and that most interventions known to alter glucose metabolism induce parallel changes in 2-FDG uptake. Qualitative differences in the in vitro response to insulin may be affected by the presence of either endogenous insulin or glycogen.

scholarly journals Synthesis and preclinical evaluation of [11C]MTP38 as a novel PET ligand for phosphodiesterase 7 in the brain

2020 ◽  
Author(s):  
Naoyuki Obokata ◽  
Chie Seki ◽  
Takeshi Hirata ◽  
Jun Maeda ◽  
Hideki Ishii ◽  
...  
Keyword(s):  
Arterial Input Function ◽  
Inflammatory Diseases ◽  
Input Function ◽  
Binding Potential ◽  
Dependent Manner ◽  
Reference Tissue ◽  
Molar Activity ◽  
The Brain

AbstractPurposePhosphodiesterase (PDE) 7 is a potential therapeutic target for neurological and inflammatory diseases, although in-vivo visualization of PDE7 has not been successful. In this study, we aimed to develop [11C]MTP38 as a novel positron emission tomography (PET) ligand for PDE7.Methods[11C]MTP38 was radiosynthesized by 11C-cyanation of a bromo precursor with [11C]HCN. PET scans of rat and rhesus monkey brains and in-vitro autoradiography of brain sections derived from these species were conducted with [11C]MTP38. In monkeys, dynamic PET data were analyzed with an arterial input function to calculate the total distribution volume (VT). The non-displaceable binding potential (BPND) in the striatum was also determined by a reference tissue model with cerebellar reference. Finally, striatal occupancy of PDE7 by an inhibitor was calculated in monkeys according to changes in BPND.Results[11C]MTP38 was synthesized with radiochemical purity ≥ 99.4% and molar activity of 38.6 ± 12.6 GBq/μmol. Autoradiography revealed high radioactivity in the striatum and its reduction by non-radiolabeled ligands, in contrast with unaltered autoradiographic signals in other regions. In-vivo PET after radioligand injection to rats and monkeys demonstrated that radioactivity was rapidly distributed to the brain and intensely accumulated in the striatum relative to the cerebellum. Correspondingly, estimated VT values in the monkey striatum and cerebellum were 3.59 and 2.69 mL/cm3, respectively. The cerebellar VT value was unchanged by pretreatment with unlabeled MTP38. Striatal BPND was reduced in a dose-dependent manner after pretreatment with MTP-X, a PDE7 inhibitor. Relationships between PDE7 occupancy by MTP-X and plasma MTP-X concentration could be described by Hill’s sigmoidal function.ConclusionWe have provided the first successful preclinical demonstration of in-vivo PDE7 imaging with a specific PET radioligand. [11C]MTP38 is a feasible radioligand for evaluating PDE7 in the brain and is currently being applied to a first-in-human PET study.

scholarly journals Kinetic Analysis of the 5-HT2A Ligand [11C]MDL 100,907

2000 ◽  
Vol 20 (6) ◽  
pp. 899-909 ◽  
Author(s):  
Hiroshi Watabe ◽  
Michael A. Channing ◽  
Margaret G. Der ◽  
H. Richard Adams ◽  
Elaine Jagoda ◽  
...  
Keyword(s):  
Kinetic Analysis ◽  
Specific Binding ◽  
Compartment Model ◽  
Input Function ◽  
Brain Regions ◽  
Time Activity ◽  
Tissue Compartment ◽  
Arterial Blood ◽  
Fixed Parameter ◽  
Mdl 100,907

The goal of this study was to develop a suitable kinetic analysis method for quantification of 5-HT2A receptor parameters with [11C]MDL 100,907. Twelve control studies and four preblocking studies (400 nmol/kg unlabeled MDL 100,907) were performed in isoflurane-anesthetized rhesus monkeys. The plasma input function was determined from arterial blood samples with metabolite measurements by extraction in ethyl acetate. The preblocking studies showed that a two-tissue compartment model was necessary to fit the time activity curves of all brain regions including the cerebellum—in other words, the need for two compartments is not proof of specific binding. Therefore, a three-tissue compartment model was used to analyze the control studies, with three parameters fixed based on the preblocking data. Reliable fits of control data could be obtained only if no more than three parameters were allowed to vary. For routine use of [11C]MDL 100,907, several simplified methods were evaluated. A two-tissue (2T‘) compartment with one fixed parameter was the most reliable compartmental approach; a one-compartment model failed to fit the data adequately. The Logan graphical approach was also tested and produced comparable results to the 2T’ model. However, a simulation study showed that Logan analysis produced a larger bias at higher noise levels. Thus, the 2T' model is the best choice for analysis of [11C]MDL 100,907 studies.

scholarly journals Long-Term Test–Retest Reliability of Striatal and Extrastriatal Dopamine D2/3 Receptor Binding: Study with [11C]Raclopride and High-Resolution PET

2015 ◽  
Vol 35 (7) ◽  
pp. 1199-1205 ◽  
Author(s):  
Kati Alakurtti ◽  
Jarkko J Johansson ◽  
Juho Joutsa ◽  
Matti Laine ◽  
Lars Bäckman ◽  
...  
Keyword(s):  
High Resolution ◽  
Intraclass Correlation ◽  
Binding Potential ◽  
Reference Tissue ◽  
Retest Reliability ◽  
Positron Emission ◽  
Simplified Reference Tissue Model ◽  
Test Retest Reliability

We measured the long-term test–retest reliability of [11C]raclopride binding in striatal subregions, the thalamus and the cortex using the bolus-plus-infusion method and a high-resolution positron emission scanner. Seven healthy male volunteers underwent two positron emission tomography (PET) [11C]raclopride assessments, with a 5-week retest interval. D2/3 receptor availability was quantified as binding potential using the simplified reference tissue model. Absolute variability (VAR) and intraclass correlation coefficient (ICC) values indicated very good reproducibility for the striatum and were 4.5%/0.82, 3.9%/0.83, and 3.9%/0.82, for the caudate nucleus, putamen, and ventral striatum, respectively. Thalamic reliability was also very good, with VAR of 3.7% and ICC of 0.92. Test-retest data for cortical areas showed good to moderate reproducibility (6.1% to 13.1%). Our results are in line with previous test–retest studies of [11C]raclopride binding in the striatum. A novel finding is the relatively low variability of [11C]raclopride binding, providing suggestive evidence that extrastriatal D2/3 binding can be studied in vivo with [11C]raclopride PET to be verified in future studies.

scholarly journals Evaluation of Methods for Generating Parametric (R)-[11C]PK11195 Binding Images

2007 ◽  
Vol 27 (9) ◽  
pp. 1603-1615 ◽  
Author(s):  
Alie Schuitemaker ◽  
Bart NM van Berckel ◽  
Marc A Kropholler ◽  
Reina W Kloet ◽  
Cees Jonker ◽  
...  
Keyword(s):  
Basis Function ◽  
Arterial Input Function ◽  
Parametric Method ◽  
Compartmental Analysis ◽  
Accurate Method ◽  
Graphical Analysis ◽  
Binding Potential ◽  
Reference Tissue ◽  
Parametric Images ◽  
Arterial Blood

Activated microglia can be visualised using ( R)-[11C]PK11195 (1-[2-chlorophenyl]- N-methyl- N-[1-methyl-propyl]-3-isoquinoline carboxamide) and positron emission tomography (PET). In previous studies, various methods have been used to quantify ( R)-[11C]PK11195 binding. The purpose of this study was to determine which parametric method would be best suited for quantifying ( R)-[11C]PK11195 binding at the voxel level. Dynamic ( R)-[11C]PK11195 scans with arterial blood sampling were performed in 20 healthy and 9 Alzheimer's disease subjects. Parametric images of both volume of distribution ( Vd) and binding potential ( BP) were obtained using Logan graphical analysis with plasma input. In addition, BP images were generated using two versions of the basis function implementation of the simplified reference tissue model, two versions of Ichise linearisations, and Logan graphical analysis with reference tissue input. Results of the parametric methods were compared with results of full compartmental analysis using nonlinear regression. Simulations were performed to assess accuracy and precision of each method. It was concluded that Logan graphical analysis with arterial input function is an accurate method for generating parametric images of Vd. Basis function methods, one of the Ichise linearisations and Logan graphical analysis with reference tissue input provided reasonably accurate and precise estimates of BP. In pathological conditions with reduced flow rates or large variations in blood volume, the basis function method is preferred because it produces less bias and is more precise.

scholarly journals Kinetic Analysis of [11C]MP4A Using a High-Radioactivity Brain Region That Represents an Integrated Input Function for Measurement of Cerebral Acetylcholinesterase Activity without Arterial Blood Sampling

2001 ◽  
Vol 21 (11) ◽  
pp. 1354-1366 ◽  
Author(s):  
Shin-Ichiro Nagatsuka ◽  
Kiyoshi Fukushi ◽  
Hitoshi Shinotoh ◽  
Hiroki Namba ◽  
Masaomi Iyo ◽  
...  
Keyword(s):  
Kinetic Analysis ◽  
Least Squares ◽  
Ache Activity ◽  
Input Function ◽  
Blood Sampling ◽  
Linear Least Squares ◽  
Reference Tissue ◽  
Arterial Blood Sampling ◽  
Arterial Blood ◽  
The Brain

N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) is an acetylcholine analog. It has been used successfully for the quantitative measurement of acetylcholinesterase (AChE) activity in the human brain with positron emission tomography (PET). [11C]MP4A is specifically hydrolyzed by AChE in the brain to a hydrophilic metabolite, which is irreversibly trapped locally in the brain. The authors propose a new method of kinetic analysis of brain AChE activity by PET without arterial blood sampling, that is, reference tissue-based linear least squares (RLS) analysis. In this method, cerebellum or striatum is used as a reference tissue. These regions, because of their high AChE activity, act as a biologic integrator of plasma input function during PET scanning, when regional metabolic rates of [11C]MP4A through AChE (k3; an AChE index) are calculated by using Blomqvist's linear least squares analysis. Computer simulation studies showed that RLS analysis yielded k3 with almost the same accuracy as the standard nonlinear least squares (NLS) analysis in brain regions with low (such as neocortex and hippocampus) and moderately high (thalamus) k3 values. The authors then applied these methods to [11C]MP4A PET data in 12 healthy subjects and 26 patients with Alzheimer disease (AD) using the cerebellum as the reference region. There was a highly significant linear correlation in regional k3 estimates between RLS and NLS analyses (456 cerebral regions, [RLS k3] = 0.98 × [NLS k3], r = 0.92, P < 0.001). Significant reductions were observed in k3 estimates of frontal, temporal, parietal, occipital, and sensorimotor cerebral neocortices ( P < 0.001, single-tailed t-test), and hippocampus ( P = 0.012) in patients with AD as compared with controls when using RLS analysis. Mean reductions (19.6%) Fin these 6 regions by RLS were almost the same as those by NLS analysis (20.5%). The sensitivity of RLS analysis for detecting cortical regions with abnormally low k3 in the 26 patients with AD (138 of 312 regions, 44%) was somewhat less than NLS analysis (52%), but was greater than shape analysis (33%), another method of [11C]MP4A kinetic analysis without blood sampling. The authors conclude that RLS analysis is practical and useful for routine analysis of clinical [11C]MP4A studies.

scholarly journals Linearized Reference Tissue Parametric Imaging Methods: Application to [11C]DASB Positron Emission Tomography Studies of the Serotonin Transporter in Human Brain

2003 ◽  
Vol 23 (9) ◽  
pp. 1096-1112 ◽  
Author(s):  
Masanori Ichise ◽  
Jeih-San Liow ◽  
Jian-Qiang Lu ◽  
Akihiro Takano ◽  
Kendra Model ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Human Brain ◽  
Positron Emission Tomography Imaging ◽  
Emission Tomography ◽  
Binding Potential ◽  
Parametric Imaging ◽  
Reference Tissue ◽  
Parametric Images ◽  
Positron Emission ◽  
Tissue Models

The authors developed and applied two new linearized reference tissue models for parametric images of binding potential ( BP) and relative delivery ( R1) for [11C]DASB positron emission tomography imaging of serotonin transporters in human brain. The original multilinear reference tissue model (MRTMO) was modified (MRTM) and used to estimate a clearance rate ( k′2) from the cerebellum (reference). Then, the number of parameters was reduced from three (MRTM) to two (MRTM2) by fixing k′2. The resulting BP and R1 estimates were compared with the corresponding nonlinear reference tissue models, SRTM and SRTM2, and one-tissue kinetic analysis (1TKA), for simulated and actual [11C]DASB data. MRTM gave k′2 estimates with little bias (<1%) and small variability (<6%). MRTM2 was effectively identical to SRTM2 and 1TKA, reducing BP bias markedly over MRTMO from 12–70% to 1–4% at the expense of somewhat increased variability. MRTM2 substantially reduced BP variability by a factor of two or three over MRTM or SRTM. MRTM2, SRTM2, and 1TKA had R1 bias <0.3% and variability at least a factor of two lower than MRTM or SRTM. MRTM2 allowed rapid generation of parametric images with the noise reductions consistent with the simulations. Rapid parametric imaging by MRTM2 should be a useful method for human [11C]DASB positron emission tomography studies.

Tremor in Parkinson’s disease and serotonergic dysfunction

Neurology ◽  
2003 ◽  
Vol 60 (4) ◽  
pp. 601-605 ◽  
Author(s):  
M. Doder ◽  
E. A. Rabiner ◽  
N. Turjanski ◽  
A. J. Lees ◽  
D. J. Brooks
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Healthy Volunteers ◽  
Rating Scale ◽  
Indirect Evidence ◽  
Binding Potential ◽  
Reference Tissue ◽  
Parkinsonian Tremor ◽  
System Integrity ◽  
Way 100635

Background: The pathophysiologic mechanisms underlying parkinsonian tremor remain unclear. The response to dopaminergic treatment is variable and nondopaminergic mechanisms may play a role in tremor generation. Midbrain raphe 5-HT1A binding provides a functional measure of serotonergic system integrity. With PET, the aim of this study was to examine regional cerebral 11C-WAY 100635 binding to 5-HT1A receptors in patients with PD and to correlate it with severity of tremor.Methods:11C-WAY 100635 PET was performed on 23 patients with PD and eight age-matched healthy volunteers. Brain 5-HT1A receptor binding was computed using compartmental modeling with a cerebellar reference tissue input function.Results: The authors found mean 27% reduction in the midbrain raphe 5-HT1A binding potential in patients with PD compared to healthy volunteers (p < 0.001). They also showed that Unified Parkinson’s Disease Rating Scale composite tremor scores, but not rigidity or bradykinesia, correlate with 5-HT1A binding in the raphe (p < 0.01).Conclusions: These findings support previous indirect evidence that serotonergic neurotransmission is decreased in PD in vivo. The authors hypothesize that the reduction in raphe 5-HT1A binding represents receptor dysfunction or loss of cell bodies due to Lewy body degeneration in PD, or both. An association between 5-HT1A receptor availability in the raphe and severity of parkinsonian tremor was also found.

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