scholarly journals Evaluation of (-)-[18 F]Flubatine-specific binding: Implications for reference region approaches

Synapse ◽  
2017 ◽  
Vol 72 (3) ◽  
pp. e22016 ◽  
Author(s):  
Shivani Bhatt ◽  
Ansel T. Hillmer ◽  
Nabeel Nabulsi ◽  
David Matuskey ◽  
Keunpoong Lim ◽  
...  
Keyword(s):  
Specific Binding ◽  
Reference Region

scholarly journals Quantification of Ligand PET Studies using a Reference Region with a Displaceable Fraction: Application to Occupancy Studies with [11C]-DASB as an Example

2011 ◽  
Vol 32 (1) ◽  
pp. 70-80 ◽  
Author(s):  
Federico E Turkheimer ◽  
Sudhakar Selvaraj ◽  
Rainer Hinz ◽  
Venkatesha Murthy ◽  
Zubin Bhagwagar ◽  
...  
Keyword(s):  
Specific Binding ◽  
Normal Subjects ◽  
Volume Of Distribution ◽  
Binding Potential ◽  
Accurate Estimation ◽  
Data Sets ◽  
Reference Region ◽  
Reference Tissue ◽  
Positron Emission ◽  
Definition Of

This paper aims to build novel methodology for the use of a reference region with specific binding for the quantification of brain studies with radioligands and positron emission tomography (PET). In particular: (1) we introduce a definition of binding potential BPD = DVR–1 where DVR is the volume of distribution relative to a reference tissue that contains ligand in specifically bound form, (2) we validate a numerical methodology, rank-shaping regularization of exponential spectral analysis (RS-ESA), for the calculation of BPD that can cope with a reference region with specific bound ligand, (3) we demonstrate the use of RS-ESA for the accurate estimation of drug occupancies with the use of correction factors to account for the specific binding in the reference. [11C]-DASB with cerebellum as a reference was chosen as an example to validate the methodology. Two data sets were used; four normal subjects scanned after infusion of citalopram or placebo and further six test—retest data sets. In the drug occupancy study, the use of RS-ESA with cerebellar input plus corrections produced estimates of occupancy very close the ones obtained with plasma input. Test-retest results demonstrated a tight linear relationship between BPD calculated either with plasma or with a reference input and high reproducibility.

scholarly journals Measuring Drug Occupancy in the Absence of a Reference Region: The Lassen Plot Re-Visited

2009 ◽  
Vol 30 (1) ◽  
pp. 46-50 ◽  
Author(s):  
Vincent J Cunningham ◽  
Eugenii A Rabiner ◽  
Mark Slifstein ◽  
Marc Laruelle ◽  
Roger N Gunn
Keyword(s):  
Graphical Method ◽  
Quantitative Estimation ◽  
Specific Binding ◽  
Volume Of Distribution ◽  
Distribution Volume ◽  
Emission Tomography ◽  
Reference Region ◽  
Site Specific ◽  
Positron Emission ◽  
Regional Estimates

Quantitative estimation of neuroreceptor occupancy by exogenous drugs using positron emission tomography is based on the reduction in the total volume of distribution ( VT) of site-specific radioligands after drug administration. An estimate of the distribution volume of free and nonspecifically bound radioligand ( VND) is also required to distinguish specific from total binding. However, a true reference region, devoid of specific binding, is often not available. We present a transformation of a graphical method, originally introduced by Lassen, using regional estimates of VT alone to determine occupancy, together with an extension that does not require baseline data.

scholarly journals Saturation Analysis in PET—Analysis of Errors Due to Imperfect Reference Regions

1994 ◽  
Vol 14 (2) ◽  
pp. 358-361 ◽  
Author(s):  
J.-E. Litton ◽  
H. Hall ◽  
S. Pauli
Keyword(s):  
Receptor Binding ◽  
Specific Binding ◽  
Scatchard Analysis ◽  
Position Emission Tomography ◽  
Reference Region ◽  
Nonspecific Binding ◽  
Binding Studies

In the determination of specific binding in receptor binding techniques in vitro as well as in vivo, determination of the nonspecific binding as well as the free component is of crucial importance. If a low proportion of specific binding is included when determining the nonspecific binding, relatively large errors may be obtained. In the present study, benzodiazepine (BZ) receptor binding in the human brain was determined in vivo using position emission tomography (PET) by applying a saturation procedure using [11C]flumazenil as an example of this problem. Analysis of the errors in Bmax and KD obtained using Scatchard analysis in PET was performed using a priori information from in vitro [3H]flumazenil binding in the pons, used normally as a reference region in BZ receptor binding studies. Even if the density of BZ receptors in the reference region pons is only 2% compared to that in the frontal cortex, this small proportion of specific binding sites will result in a 10% error in the Bmax and KD values. Simulation of a number of Scatchard plots was performed at varying ratios between the nonspecific and the specific binding.

scholarly journals Supervised clustering for TSPO PET imaging

2021 ◽  
Author(s):  
Julia Schubert ◽  
Matteo Tonietto ◽  
Federico Turkheimer ◽  
Paolo Zanotti-Fregonara ◽  
Mattia Veronese
Keyword(s):  
Clustering Algorithm ◽  
Specific Binding ◽  
Technical Note ◽  
Translocator Protein ◽  
Experimental Medicine ◽  
Reference Region ◽  
Supervised Clustering ◽  
Pet Tracer ◽  
Tspo Expression

Abstract Purpose This technical note seeks to act as a practical guide for implementing a supervised clustering algorithm (SVCA) reference region approach and to explain the main strengths and limitations of the technique in the context of 18-kilodalton translocator protein (TSPO) positron emission tomography (PET) studies in experimental medicine. Background TSPO PET is the most widely used imaging technique for studying neuroinflammation in vivo in humans. Quantifying neuroinflammation with PET can be a challenging and invasive procedure, especially in frail patients, because it often requires blood sampling from an arterial catheter. A widely used alternative to arterial sampling is SVCA, which identifies the voxels with minimal specific binding in the PET images, thus extracting a pseudo-reference region for non-invasive quantification. Unlike other reference region approaches, SVCA does not require specification of an anatomical reference region a priori, which alleviates the limitation of TSPO contamination in anatomically-defined reference regions in individuals with underlying inflammatory processes. Furthermore, SVCA can be applied to any TSPO PET tracer across different neurological and neuropsychiatric conditions, providing noninvasivequantification of TSPO expression. Methods We provide an overview of the development of SVCA as well as step-by-step instructions for implementing SVCA with suggestions for specific settings. We review the literature on SVCAapplications using first- and second- generation TSPO PET tracers and discuss potential clinically relevant limitations and applications. Conclusions The correct implementation of SVCA can provide robust and reproducible estimates of brain TSPO expression. This review encourages the standardisation of SVCA methodology in TSPO PET analysis, ultimately aiming to improve replicability and comparability across study sites.

scholarly journals Comparison of two PET radioligands, [11C]FPEB and [11C]SP203, for quantification of metabotropic glutamate receptor 5 in human brain

2016 ◽  
Vol 37 (7) ◽  
pp. 2458-2470 ◽  
Author(s):  
Talakad G Lohith ◽  
Tetsuya Tsujikawa ◽  
Fabrice G Siméon ◽  
Mattia Veronese ◽  
Sami S Zoghbi ◽  
...  
Keyword(s):  
Human Brain ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Specific Activity ◽  
Specific Binding ◽  
Distribution Volume ◽  
Whole Body ◽  
Reference Region ◽  
Metabotropic Glutamate Receptor 5 ◽  
Metabotropic Glutamate

Of the two 18F-labeled PET ligands currently available to image metabotropic glutamate receptor 5 (mGluR5), [18F]FPEB is reportedly superior because [18F]SP203 undergoes glutathionlyation, generating [18F]-fluoride ion that accumulates in brain and skull. To allow multiple PET studies on the same day with lower radiation exposure, we prepared [11C]FPEB and [11C]SP203 from [11C]hydrogen cyanide and compared their abilities to accurately quantify mGluR5 in human brain, especially as regards radiometabolite accumulation. Genomic plot was used to estimate the ratio of specific-to-nondisplaceable uptake ( BPND) without using a receptor blocking drug. Both tracers quantified mGluR5; however [11C]SP203, like [18F]SP203, had radiometabolite accumulation in brain, as evidenced by increased distribution volume ( VT) over the scan period. Absolute VT values were ∼30% lower for 11C-labeled compared with 18F-labeled radioligands, likely caused by the lower specific activities (and high receptor occupancies) of the 11C radioligands. The genomic plot indicated ∼60% specific binding in cerebellum, which makes it inappropriate as a reference region. Whole-body scans performed in healthy subjects demonstrated a low radiation burden typical for 11C-ligands. Thus, the evidence suggests that [11C]FPEB is superior to [11C]SP203. If prepared in higher specific activity, [11C]FPEB would presumably be as effective as [18F]FPEB for quantifying mGluR5 in human brain.

scholarly journals Assessment of Extrastriatal Vesicular Monoamine Transporter Binding Site Density Using Stereoisomers of [11C]Dihydrotetrabenazine

1999 ◽  
Vol 19 (12) ◽  
pp. 1376-1384 ◽  
Author(s):  
Robert A. Koeppe ◽  
Kirk A. Frey ◽  
David E. Kuhl ◽  
Michael R. Kilbourn
Keyword(s):  
Binding Site ◽  
Specific Binding ◽  
Three Dimensional ◽  
Precise Determination ◽  
Tracer Uptake ◽  
Vesicular Monoamine Transporter ◽  
Reference Region ◽  
Monoamine Transporter

Previous studies have demonstrated the utility of [nC]dihydrotetrabenazine ([11C]DTBZ) as a ligand for in vivo imaging of the vesicular monoamine transporter system. The (+)-isomer has a high affinity (approximately 1 nmol/L) for the vesicular monoamine transporter (VMAT2) binding site, whereas the (–)-isomer has an extremely low affinity (approximately 2 μmol/L). Efforts to model dynamic (+)-[11C]DTBZ data demonstrate the difficulty in separating the specific binding component from the free plus nonspecific component of the total positron emission tomography (PET) measure. The authors' previous*** PET work, as well as in vitro studies, indicate that there is little specific VMAT2 binding in neocortical regions. However, precise determination of in vivo binding levels have not been made, leaving important questions unanswered. At one extreme, is there sufficient specific binding in cortex or other extrastriate regions to be estimated reliably with PET? At the other extreme, is there sufficiently little binding in cortex so that it can be used as a reference region representing nonsaturable tracer uptake? The authors address these questions using paired studies with both active (+) and inactive (–) stereoisomers of [11C]DTBZ. Six normal control subjects were scanned twice, 2 hours apart, after injections of 16 mCi of (+)- and (–)-[11C]DTBZ (order counter-balanced). Three-dimensional PET acquisition consisted of 15 frames over 60 minutes for each scan. Arterial samples were acquired throughout, plasma counted, and corrected for radiolabeled metabolites. Analysis of specific binding was assessed by comparison of total distribution volume measures from the (+)- and (–)-[11C]DTBZ scans. The authors' findings indicate that only approximately 5% of the cortical signal in (+)-[11C]DTBZ scans results from binding to VMAT2 sites. The strongest extrastriatal signal comes from the midbrain regions where approximately 30% of the PET measure results from specific binding. The authors conclude that (1) the density of VMAT2 binding sites in cortical regions is not high enough to be quantified reliably with DTBZ PET, and (2) binding does appear to be low enough so that cortex can be used as a free plus nonspecific reference region for striatum.

scholarly journals Assessment of a white matter reference region for 11C-UCB-J PET quantification

2019 ◽  
Vol 40 (9) ◽  
pp. 1890-1901 ◽  
Author(s):  
Samantha Rossano ◽  
Takuya Toyonaga ◽  
Sjoerd J Finnema ◽  
Mika Naganawa ◽  
Yihuan Lu ◽  
...  
Keyword(s):  
Gray Matter ◽  
Specific Binding ◽  
Region Of Interest ◽  
Volume Of Distribution ◽  
Reference Region ◽  
Synaptic Density ◽  
Positron Emission ◽  
The Difference ◽  
Density Marker

11C-UCB-J is a positron emission tomography (PET) radioligand that has been used in humans for synaptic vesicle glycoprotein 2A (SV2A) imaging and as a potential synaptic density marker. The centrum semiovale (CS) is a proposed reference region for noninvasive quantification of 11C-UCB-J, due to negligible concentrations of SV2A in this region in baboon brain assessed by in vitro methods. However, in displacement scans with SV2A-specific drug levetiracetam in humans, a decrease in 11C-UCB-J concentration was observed in the CS, consistent with some degree of specific binding. The current study aims to validate the CS as a reference region by (1) optimizing CS region of interest (ROI) to minimize spill-in from gray matter with high radioactivity concentrations; (2) investigating convergence of CS ROI values using ordered subset expectation maximization (OS-EM) reconstruction, and (3) comparing baseline CS volume of distribution ( VT) to nondisplaceable uptake in gray matter, VND. Improving ROI definition and increasing OS-EM iterations during reconstruction decreased the difference between CS VT and VND. However, even with these corrections, CS VT overestimated VND by ∼35–40%. These measures showed significant correlation, suggesting that, though biased, the CS may be a useful estimate of nondisplaceable uptake, allowing for noninvasive quantification for SV2A PET.

scholarly journals Accuracy and reliability of [11C]PBR28 specific binding estimated without the use of a reference region

2018 ◽  
Author(s):  
Pontus Plaven-Sigray ◽  
Martin Schain ◽  
Francesca Zanderigo ◽  
Ilan Rabiner ◽  
Roger Gunn ◽  
...  
Keyword(s):  
Outcome Measure ◽  
Specific Binding ◽  
Distribution Volume ◽  
Translocator Protein ◽  
Simultaneous Estimation ◽  
Reference Region ◽  
Simulation Experiments ◽  
Time Activity ◽  
Healthy Humans ◽  
Specific Distribution

[11C]PBR28 is a positron emission tomography radioligand used to estimate the expression of 18kDa translocator protein (TSPO). TSPO is expressed on glial cells and can function as a marker for immune activation. Since TSPO is expressed throughout the brain, no true reference region exists. For this reason, an arterial input function is required for accurate quantification of [11C]PBR28 binding and the most common outcome measure is the total distribution volume (VT). Notably, VT reflects both specific binding and non-displaceable binding (VND). Therefore, estimates of specific binding, such as binding potentials (e.g., BPND) and specific distribution volume (VS) should theoretically be more sensitive to underlying differences in TSPO expression. It is unknown, however, if unbiased and accurate estimates of these measures are obtainable for [11C]PBR28.The Simultaneous Estimation (SIME) method uses time-activity-curves from multiple brain regions with the aim to obtain a brain-wide estimate of VND, which can subsequently be used to improve the estimation of BPND and VS. In this study we evaluated the accuracy of SIME-derived VND, and the reliability of resulting estimates of specific binding for [11C]PBR28, using a combination of simulation experiments and in vivo studies in healthy humans.The simulation experiments showed that VND values estimated using SIME were both precise and accurate. Data from a pharmacological competition challenge showed that SIME provided VND values that were on average 19% lower than those obtained using the Lassen plot, but similar to values obtained using the Likelihood-Estimation of Occupancy technique. Test-retest data showed that SIME-derived VS values exhibited good reliability and precision, while larger variability was observed in SIME-derived BPND values.The results support the use of SIME for quantifying specific binding of [11C]PB28, and suggest that VS can be used in preference to, or as a complement to the conventional outcome measure VT. Additional studies in patient cohorts are warranted.

scholarly journals Accuracy and reliability of [11C]PBR28 specific binding estimated without the use of a reference region

NeuroImage ◽  
2019 ◽  
Vol 188 ◽  
pp. 102-110 ◽  
Author(s):  
Pontus Plavén-Sigray ◽  
Martin Schain ◽  
Francesca Zanderigo ◽  
Eugenii A. Rabiner ◽  
Roger N. Gunn ◽  
...  
Keyword(s):  
Specific Binding ◽  
Reference Region
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