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

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.

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2009.190 ◽

2009 ◽

Vol 30 (1) ◽

pp. 46-50 ◽

Cited By ~ 138

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.

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Analysis of Four Dopaminergic Tracers Kinetics Using Two Different Tissue Input Function Methods

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200004000-00002 ◽

2000 ◽

Vol 20 (4) ◽

pp. 653-660 ◽

Cited By ~ 15

Author(s):

V. Sossi ◽

J. E. Holden ◽

G. Chan ◽

M. Krzywinski ◽

A. J. Stoessl ◽

...

Keyword(s):

Dopaminergic System ◽

Specific Binding ◽

Input Function ◽

D1 Receptors ◽

Binding Potential ◽

Intrasubject Variability ◽

Reference Tissue ◽

Good Reliability ◽

Positron Emission ◽

And Performance

The integrity of the dopaminergic system can be studied using positron emission tomography. The presynaptic tracers [11C]-methylphenidate and [11C]dihydrotetrabenazine (DTBZ) are used to investigate the dopamine transporter availability, the dopamine vesicular transporter integrity; the post-synaptic tracers [11C]-raclopride and [11C]-Schering 23990 (SCH) are used to probe the D2 and D1 receptors. These are reversible tracers, where the binding potential (BP) = Bmax/Kd often is used to quantify the amount of their specific binding to the sites of interest. The simplified tissue input methods to calculate BP are attractive, since they do not require a blood input function. The suitability and performance of two such methods were evaluated: the Logan graphical tissue method, and the Lammertsma reference tissue method (RTM). The BP estimates obtained with the two methods were nearly identical in most cases, with similar reliability and reproducibility indicating that all four tracers satisfy the assumptions required by each method. The correlations among the fitted parameters obtained from the RTM were estimated and were found not to introduce noticeable bias in the RTM BP and R1 estimates. R1 showed low intersubject and intrasubject variability. The k2 estimate showed good reliability for SCH with cerebellar input function and DTBZ with occipital input function.

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x19879230 ◽

2019 ◽

Vol 40 (9) ◽

pp. 1890-1901 ◽

Cited By ~ 12

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.

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Reference Region Automatic Extraction in Dynamic [11C]PIB

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2013.133 ◽

2013 ◽

Vol 33 (11) ◽

pp. 1725-1731 ◽

Cited By ~ 15

Author(s):

Yoko Ikoma ◽

Paul Edison ◽

Anil Ramlackhansingh ◽

David J Brooks ◽

Federico E Turkheimer

Keyword(s):

Gray Matter ◽

Specific Binding ◽

Amyloid Plaque ◽

Blood Pool ◽

Binding Potential ◽

Automatic Extraction ◽

Reference Region ◽

Supervised Clustering ◽

Plaque Deposition ◽

Positron Emission

The positron emission tomography (PET) radiotracer [11C]Pittsburgh Compound B (PIB) is a marker of amyloid plaque deposition in brain, and binding potential is usually quantified using the cerebellum as a reference where the specific binding is negligible. The use of the cerebellum as a reference, however, has been questioned by the reported cerebellar [11C]PIB retention in familial Alzheimer's disease (AD) subjects. In this work, we developed a supervised clustering procedure for the automatic extraction of a reference region in [11C]PIB studies. Supervised clustering models each gray matter voxel as the linear combination of three predefined kinetic classes, normal and lesion gray matter, and blood pool, and extract reference voxels in which the contribution of the normal gray matter class is high. In the validation with idiopathic AD subjects, supervised clustering extracted reference voxels mostly in the cerebellum that indicated little specific [11C]PIB binding, and total distribution volumes of the extracted region were lower than those of the cerebellum. Next, the methodology was applied to the familial AD cohort where the cerebellar amyloid load had been demonstrated previously, resulting in higher binding potential compared with that obtained with the cerebellar reference. The supervised clustering method is a useful tool for the accurate quantification of [11C]PIB studies.

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A Graphical Method to Compare the in vivo Binding Potential of PET Radioligands in the Absence of a Reference Region: Application to [11C]PBR28 and [18F]PBR111 for TSPO Imaging

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2014.65 ◽

2014 ◽

Vol 34 (7) ◽

pp. 1162-1168 ◽

Cited By ~ 13

Author(s):

Qi Guo ◽

David R Owen ◽

Eugenii A Rabiner ◽

Federico E Turkheimer ◽

Roger N Gunn

Keyword(s):

Outcome Measure ◽

Graphical Method ◽

Volume Of Distribution ◽

Translocator Protein ◽

Binding Potential ◽

Reference Region ◽

Positron Emission ◽

Tspo Imaging

Positron emission tomography (PET) radioligands for a reversible central nervous system (CNS) demand a high specific to nonspecific signal characterized by the binding potential ( BPND). The quantification of BPND requires the determination of the nondisplaceable binding usually derived from a reference region devoid of the target of interest. However, for many CNS targets, there is no valid reference region available. In such cases, the total volume of distribution ( VT) is often used as the outcome measure, which includes both the specific and nonspecific binding signals. Here we present a graphical method that allows for direct comparison of the binding potential of ligands using the regional VT data alone via linear regression. The method was first validated using literature data for five serotonin transporter ligands, for which a reference region exists, and then applied to two second generation 18 kDa translocator protein radioligands, namely [ 11 C]PBR28 and [ 18 F]PBR111. The analysis determined that [ 11 C]PBR28 had a higher BPND than [ 18 F]PBR111.

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Non-invasive Standardised Uptake Value for Verification of the Use of Previously Validated Reference Region for [18F]Flortaucipir and [18F]Florbetapir Brain PET Studies

Molecular Imaging and Biology ◽

10.1007/s11307-020-01572-y ◽

2021 ◽

Author(s):

Bart M. de Vries ◽

Tessa Timmers ◽

Emma E. Wolters ◽

Rik Ossenkoppele ◽

Sander C. J. Verfaillie ◽

...

Keyword(s):

Grey Matter ◽

Specific Binding ◽

Volume Of Distribution ◽

Elderly Subjects ◽

Reference Region ◽

Reference Tissue ◽

Non Invasive ◽

Standardised Uptake Value ◽

Arterial Sampling ◽

Dynamic Scanning

Abstract Purpose The simplified reference tissue model (SRTM) is commonly applied for the quantification of brain positron emission tomography (PET) studies, particularly because it avoids arterial cannulation. SRTM requires a validated reference region which is obtained by baseline-blocking or displacement studies. Once a reference region is validated, the use should be verified for each new subject. This verification normally requires volume of distribution (VT) of a reference region. However, performing dynamic scanning and arterial sampling is not always possible, specifically in elderly subjects and in advanced disease stages. The aim of this study was to investigate the use of non-invasive standardised uptake value (SUV) approaches, in comparison to VT, as a verification of the previously validated grey matter cerebellum reference region for [18F]flortaucipir and [18F]florbetapir PET imaging in Alzheimer’s disease (AD) patients and controls. Procedures Dynamic 130-min [18F]flortaucipir PET scans obtained from nineteen subjects (10 AD patients) and 90-min [18F]florbetapir dynamic scans obtained from fourteen subjects (8 AD patients) were included. Regional VT’s were estimated for both tracers and were considered the standard verification of the previously validated reference region. Non-invasive SUVs corrected for body weight (SUVBW), lean body mass (SUL), and body surface area (SUVBSA) were obtained by using later time intervals of the dynamic scans. Simulations were also performed to assess the effect of flow and specific binding (BPND) on the SUVs. Results A low SUV corresponded well with a low VT for both [18F]flortaucipir and [18F]florbetapir. Simulation confirmed that SUVs were only slightly affected by flow changes and that increases in SUV were predominantly determined by the presence of specific binding. Conclusions In situations where dynamic scanning and arterial sampling is not possible, a low SUV(80–100 min) for [18F]flortaucipir and a low SUV(50–70 min) for [18F]florbetapir may be used as indication for absence of specific binding in the grey matter cerebellum reference region.

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The pharmacokinetics of [18F]UCB-H revisited in the healthy non-human primate brain

EJNMMI Research ◽

10.1186/s13550-021-00777-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sébastien Goutal ◽

Martine Guillermier ◽

Guillaume Becker ◽

Mylène Gaudin ◽

Yann Bramoullé ◽

...

Keyword(s):

Slow Component ◽

Specific Binding ◽

Compartment Model ◽

Brain Regions ◽

Volume Of Distribution ◽

Pharmacokinetic Data ◽

Limited Information ◽

Positron Emission ◽

Human Primate

Abstract Background Positron Emission Tomography (PET) imaging of the Synaptic Vesicle glycoprotein (SV) 2A is a new tool to quantify synaptic density. [18F]UCB-H was one of the first promising SV2A-ligands to be labelled and used in vivo in rodent and human, while limited information on its pharmacokinetic properties is available in the non-human primate. Here, we evaluate the reliability of the three most commonly used modelling approaches for [18F]UCB-H in the non-human cynomolgus primate, adding the coupled fit of the non-displaceable distribution volume (VND) as an alternative approach to improve unstable fit. The results are discussed in the light of the current state of SV2A PET ligands. Results [18F]UCB-H pharmacokinetic data was optimally fitted with a two-compartment model (2TCM), although the model did not always converge (large total volume of distribution (VT) or large uncertainty of the estimate). 2TCM with coupled fit K1/k2 across brain regions stabilized the quantification, and confirmed a lower specific signal of [18F]UCB-H compared to the newest SV2A-ligands. However, the measures of VND and the influx parameter (K1) are similar to what has been reported for other SV2A ligands. These data were reinforced by displacement studies using [19F]UCB-H, demonstrating only 50% displacement of the total [18F]UCB-H signal at maximal occupancy of SV2A. As previously demonstrated in clinical studies, the graphical method of Logan provided a more robust estimate of VT with only a small bias compared to 2TCM. Conclusions Modeling issues with a 2TCM due to a slow component have previously been reported for other SV2A ligands with low specific binding, or after blocking of specific binding. As all SV2A ligands share chemical structural similarities, we hypothesize that this slow binding component is common for all SV2A ligands, but only hampers quantification when specific binding is low.

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.53 ◽

2015 ◽

Vol 35 (7) ◽

pp. 1199-1205 ◽

Cited By ~ 30

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.

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No Evidence for Additional Blood–Brain Barrier P-Glycoprotein Dysfunction in Alzheimer's Disease Patients with Microbleeds

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2012.64 ◽

2012 ◽

Vol 32 (8) ◽

pp. 1468-1471 ◽

Cited By ~ 12

Author(s):

Daniëlle ME van Assema ◽

Jeroen DC Goos ◽

Wiesje M van der Flier ◽

Mark Lubberink ◽

Ronald Boellaard ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Blood Brain Barrier ◽

Volume Of Distribution ◽

Brain Barrier ◽

Binding Potential ◽

Amyloid Angiopathy ◽

P Glycoprotein ◽

Blood Brain ◽

Positron Emission

Decreased blood–brain barrier P-glycoprotein (Pgp) function has been shown in Alzheimer's disease (AD) patients using positron emission tomography (PET) with the radiotracer ( R)-[11C]verapamil. Decreased Pgp function has also been hypothesized to promote cerebral amyloid angiopathy (CAA) development. Here, we used PET and ( R)-[11C]verapamil to assess Pgp function in eighteen AD patients, of which six had microbleeds (MBs), presumably reflecting underlying CAA. No differences were found in binding potential and nonspecific volume of distribution of ( R)-[11C]verapamil between patient groups. These results provide no evidence for additional Pgp dysfunction in AD patients with MBs.

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Kinetic Analysis of Drug–Target Interactions with PET for Characterization of Pharmacological Hysteresis

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2012.208 ◽

2013 ◽

Vol 33 (5) ◽

pp. 700-707 ◽

Cited By ~ 12

Author(s):

Cristian Salinas ◽

David Weinzimmer ◽

Graham Searle ◽

David Labaree ◽

Jim Ropchan ◽

...

Keyword(s):

Simulated Data ◽

Receptor Occupancy ◽

Volume Of Distribution ◽

Data Sets ◽

Suitable Model ◽

Dose Selection ◽

Care Needs ◽

Positron Emission

In vivo characterization of the brain pharmacokinetics of novel compounds provides important information for drug development decisions involving dose selection and the determination of administration regimes. In this context, the compound-target affinity is the key parameter to be estimated. However, if compounds exhibit a dynamic lag between plasma and target bound concentrations leading to pharmacological hysteresis, care needs to be taken to ensure the appropriate modeling approach is used so that the system is characterized correctly and that the resultant estimates of affinity are correct. This work focuses on characterizing different pharmacokinetic models that relate the plasma concentration to positron emission tomography outcomes measurements (e.g., volume of distribution and target occupancy) and their performance in estimating the true in vivo affinity. Measured (histamine H3 receptor antagonist—GSK189254) and simulated data sets enabled the investigation of different modeling approaches. An indirect pharmacokinetic-receptor occupancy model was identified as a suitable model for the calculation of affinity when a compound exhibits pharmacological hysteresis.

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