The applicability of SRTM in [18F]fallypride PET investigations: Impact of scan durations

The high-affinity radioligand [18F]fallypride (FP) is frequently used for quantification of striatal/extrastriatal D2/3 receptors and the receptor occupancies of antipsychotics (APs). Its 110 minutes half-life allows long scan durations. However, the optimum scan duration is a matter of debate. This investigation focuses on scan-duration-related effects on simplified reference tissue model (SRTM) results and the time point of transient equilibrium in a large sample of dynamic FP positron emission tomography (PET) scans. Fifty drug-free and 50 AP-treated subjects underwent FP-PET scans (180 minutes scan duration). The binding potential ( BPND) of the putamen, thalamus, and temporal cortex were calculated using the SRTM and the transient equilibrium model. Furthermore, receptor occupancies were calculated for AP-treated patients. Transient equilibrium in the unblocked putamen occurred after 121 ± 29.6 minutes. The transient equilibrium occurred much earlier in the extrastriatal regions or under AP treatment. Stepwise scan shortening caused BPND under-estimations of 0.58% for the first 10-minute reduction (putamen, SRTM), finally reaching 5.76% after 1 hour scan-time reduction. We observed preferential extrastriatal AP binding irrespective of the analytical method. [18F]fallypride scan durations of 180 minutes reliably reach equilibrium even in D2/3-receptor-rich regions. Moderate reductions in FP scan durations only caused small changes to SRTM results even in receptor-rich regions. Apparently, the D2/3 receptor occupancy results of APs, especially preferential extrastriatal binding observations, are not relevantly biased by inappropriate scan durations.

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Dual time-point imaging for post-dose binding potential estimation applied to a [11C]raclopride PET dose occupancy study

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16644463 ◽

2016 ◽

Vol 37 (3) ◽

pp. 866-876

Author(s):

Isadora L Alves ◽

Antoon TM Willemsen ◽

Rudi A Dierckx ◽

Ana Maria M da Silva ◽

Michel Koole

Keyword(s):

Receptor Occupancy ◽

Standard Uptake Value ◽

Binding Potential ◽

Post Dose ◽

Reference Tissue ◽

Tissue Model ◽

Reference Tissue Model ◽

Dual Time Point ◽

Simplified Reference Tissue Model ◽

Time Point

Receptor occupancy studies performed with PET often require time-consuming dynamic imaging for baseline and post-dose scans. Shorter protocol approximations based on standard uptake value ratios have been proposed. However, such methods depend on the time-point chosen for the quantification and often lead to overestimation and bias. The aim of this study was to develop a shorter protocol for the quantification of post-dose scans using a dual time-point approximation, which employs kinetic parameters from the baseline scan. Dual time-point was evaluated for a [11C]raclopride PET dose occupancy study with the D2 antagonist JNJ-37822681, obtaining estimates for binding potential and receptor occupancy. Results were compared to standard simplified reference tissue model and standard uptake value ratios-based estimates. Linear regression and Bland–Altman analysis demonstrated excellent correlation and agreement between dual time-point and the standard simplified reference tissue model approach. Moreover, the stability of dual time-point-based estimates is shown to be independent of the time-point chosen for quantification. Therefore, a dual time-point imaging protocol can be applied to post-dose [11C]raclopride PET scans, resulting in a significant reduction in total acquisition time while maintaining accuracy in the quantification of both the binding potential and the receptor occupancy.

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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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Validity and reliability of extrastriatal [11C]raclopride binding quantification in the living human brain

10.1101/600080 ◽

2019 ◽

Author(s):

Jonas E Svensson ◽

Martin Schain ◽

Pontus Plavén-Sigray ◽

Simon Cervenka ◽

Mikael Tiger ◽

...

Keyword(s):

Temporal Cortex ◽

Binding Potential ◽

Validity And Reliability ◽

Reference Tissue ◽

Pet Tracer ◽

Binding Data ◽

Healthy Control ◽

The Mean ◽

Cortical Regions ◽

Simplified Reference Tissue Model

Abstract[11C]raclopride is a well established PET tracer for the quantification of dopamine 2/3 receptors (D2/3R) in the striatum. Outside of the striatum the receptor density is up to two orders of magnitude lower. In contrast to striatal binding, the characteristics of extrastriatal [11C]raclopride binding quantification has not been thoroughly described. Still, binding data for e.g., neocortex is frequently reported in the scientific literature. Here we evaluate the validity and reliability of extrastriatal [11C]raclopride binding quantification. Two sets of healthy control subjects were examined with HRRT and [11C]raclopride: i) To assess the validity of extrastriatal [11C]raclopride binding estimates, eleven subjects were examined at baseline and after dosing with quetiapine, a D2/3R antagonist. ii) To assess test-retest repeatability, nine subjects were examined twice. Non displaceable binding potential (BPND) was quantified using the simplified reference tissue model. Quetiapine dosing was associated with decrease in [11C]raclopride BPND in temporal cortex (18±17% occupancy) and thalamus (20±17%), but not in frontal cortex. Extrastriatal occupancy was lower than in putamen (51±4%). The mean absolute variation was 4-7% in the striatal regions, 17% in thalamus, and 13-59% in cortical regions. Our data indicate that [11C]raclopride PET is not a suitable tool for D2/3R binding quantification in extrastriatal regions.

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Kinetics and 28-day test–retest repeatability and reproducibility of [11C]UCB-J PET brain imaging

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x20964248 ◽

2020 ◽

pp. 0271678X2096424

Author(s):

Hayel Tuncel ◽

Ronald Boellaard ◽

Emma M Coomans ◽

Erik FJ de Vries ◽

Andor WJM Glaudemans ◽

...

Keyword(s):

Grey Matter ◽

Volume Of Distribution ◽

Reference Tissue ◽

Positron Emission ◽

Tracer Kinetic ◽

Repeatability And Reproducibility ◽

Simplified Reference Tissue Model ◽

Tissue Models ◽

Pet Scans ◽

Brain Positron Emission Tomography

[11C]UCB-J is a novel radioligand that binds to synaptic vesicle glycoprotein 2A (SV2A). The main objective of this study was to determine the 28-day test–retest repeatability (TRT) of quantitative [11C]UCB-J brain positron emission tomography (PET) imaging in Alzheimer’s disease (AD) patients and healthy controls (HCs). Nine HCs and eight AD patients underwent two 60 min dynamic [11C]UCB-J PET scans with arterial sampling with an interval of 28 days. The optimal tracer kinetic model was assessed using the Akaike criteria (AIC). Micro-/macro-parameters such as tracer delivery (K1) and volume of distribution (VT) were estimated using the optimal model. Data were also analysed for simplified reference tissue model (SRTM) with centrum semi-ovale (white matter) as reference region. Based on AIC, both 1T2k_VB and 2T4k_VB described the [11C]UCB-J kinetics equally well. Analysis showed that whole-brain grey matter TRT for VT, DVR and SRTM BPND were –2.2% ± 8.5, 0.4% ± 12.0 and –8.0% ± 10.2, averaged over all subjects. [11C]UCB-J kinetics can be well described by a 1T2k_VB model, and a 60 min scan duration was sufficient to obtain reliable estimates for both plasma input and reference tissue models. TRT for VT, DVR and BPND was <15% (1SD) averaged over all subjects and indicates adequate quantitative repeatability of [11C]UCB-J PET.

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Evaluation of dopamine D3 receptor occupancy by blonanserin using [11C]-(+)-PHNO in schizophrenia patients

Psychopharmacology ◽

10.1007/s00213-020-05698-3 ◽

2020 ◽

Author(s):

Takeshi Sakayori ◽

Amane Tateno ◽

Ryosuke Arakawa ◽

Woo-chan Kim ◽

Yoshiro Okubo

Keyword(s):

Substantia Nigra ◽

Globus Pallidus ◽

Healthy Subjects ◽

Receptor Occupancy ◽

Binding Potential ◽

Positron Emission ◽

Dopamine D3 ◽

Continued Use ◽

Pet Scans ◽

Average Occupancy

Abstract Rationale Unlike other antipsychotics, our previous positron emission tomography (PET) study demonstrated that a single dose of blonanserin occupied dopamine D3 as well as dopamine D2 receptors in healthy subjects. However, there has been no study concerning the continued use of blonanserin. Objectives We examined D2 and D3 receptor occupancies in patients with schizophrenia who had been treated with blonanserin. Methods Thirteen patients with schizophrenia participated. PET examinations were performed on patients treated with clinical dosage of blonanserin or olanzapine alone. A crossover design was used in which seven patients switched drugs after the first scan, and PET examinations were conducted again. D2 and D3 receptor occupancies were evaluated by [11C]-(+)-PHNO. We used nondisplaceable binding potential (BPND) of 6 healthy subjects which we previously reported as baseline. To consider the effect of upregulation of D3 receptor by continued use of antipsychotics, D3 receptor occupancy by blonanserin in seven subjects who completed 2 PET scans were re-analyzed by using BPND of olanzapine condition as baseline. Results Average occupancy by olanzapine (10.8 ± 6.0 mg/day) was as follows: caudate 32.8 ± 18.3%, putamen 26.3 ± 18.2%, globus pallidus − 33.7 ± 34.9%, substantia nigra − 112.8 ± 90.7%. Average occupancy by blonanserin (12.8 ± 5.6 mg/day) was as follows: caudate 61.0 ± 8.3%, putamen 55.5 ± 9.5%, globus pallidus 48.9 ± 12.4%, substantia nigra 34.0 ± 20.6%. EC50 was 0.30 ng/mL for D2 receptor for caudate and putamen (df = 19, p < 0.0001) and 0.70 ng/mL for D3 receptor for globus pallidus and substantia nigra (df = 19, p < 0.0001). EC50 for D3 receptor of blonanserin changed to 0.22 ng/mL (df = 13, p = 0.0041) when we used BPND of olanzapine condition as baseline. Conclusions Our study confirmed that blonanserin occupied both D2 and D3 receptors in patients with schizophrenia.

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The importance of small polar radiometabolites in molecular neuroimaging: A PET study with [11C]Cimbi-36 labeled in two positions

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17746179 ◽

2017 ◽

Vol 38 (4) ◽

pp. 659-668 ◽

Cited By ~ 14

Author(s):

Annette Johansen ◽

Hanne D Hansen ◽

Claus Svarer ◽

Szabolcs Lehel ◽

Sebastian Leth-Petersen ◽

...

Keyword(s):

Receptor Agonist ◽

Binding Potential ◽

Reference Tissue ◽

Tissue Model ◽

Background Ratio ◽

Significant Difference ◽

Methoxy Groups ◽

Simplified Reference Tissue Model ◽

Pet Scans ◽

The Brain

[11C]Cimbi-36, a 5-HT2A receptor agonist PET radioligand, contains three methoxy groups amenable to [11C]-labeling. In pigs, [11C]Cimbi-36 yields a polar (M1) and a less polar (M2) radiometabolite fraction, while changing the labeling to [11C]Cimbi-36_5 yields only the M1 fraction. We investigate whether changing the labeling position of [11C]Cimbi-36 eliminates M2 in humans, and if this changes the signal-to-background ratio. Six healthy volunteers each underwent two dynamic PET scans; after injection of [11C]Cimbi-36, both the M1 and M2 fraction appeared in plasma, whereas only the M1 appeared after [11C]Cimbi-36_5 injection. [11C]Cimbi-36_5 generated higher uptake than [11C]Cimbi-36 in both neocortex and cerebellum. With the simplified reference tissue model mean neocortical non-displaceable binding potential for [11C]Cimbi-36 was 1.38 ± 0.07, whereas for [11C]Cimbi-36_5, it was 1.18 ± 0.14. This significant difference can be explained by higher non-displaceable binding caused by demethylation products in the M1 fraction such as [11C]formaldehyde and/or [11C]carbon dioxide/bicarbonate. Although often considered without any impact on binding measures, we show that small polar radiometabolites can substantially decrease the signal-to-background ratio of PET radioligands for neuroimaging. Further, we find that [11C]Cimbi-36 has a better signal-to-background ratio than [11C]Cimbi-36_5, and thus will be more sensitive to changes in 5-HT2A receptor levels in the brain.

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Optimization of Supervised Cluster Analysis for Extracting Reference Tissue Input Curves in (R)-[11C]PK11195 Brain PET Studies

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2012.59 ◽

2012 ◽

Vol 32 (8) ◽

pp. 1600-1608 ◽

Cited By ~ 72

Author(s):

Maqsood Yaqub ◽

Bart NM van Berckel ◽

Alie Schuitemaker ◽

Rainer Hinz ◽

Federico E Turkheimer ◽

...

Keyword(s):

Cluster Analysis ◽

Binding Potential ◽

Reference Tissue ◽

Time Activity ◽

Positron Emission ◽

Lower Blood ◽

Activity Curve ◽

Simplified Reference Tissue Model ◽

Significant Concentration ◽

Brain Positron Emission Tomography

Performance of two supervised cluster analysis (SVCA) algorithms for extracting reference tissue curves was evaluated to improve quantification of dynamic (R)-[11C]PK11195 brain positron emission tomography (PET) studies. Reference tissues were extracted from images using both a manually defined cerebellum and SVCA algorithms based on either four (SVCA4) or six (SVCA6) kinetic classes. Data from controls, mild cognitive impairment patients, and patients with Alzheimer's disease were analyzed using various kinetic models including plasma input, the simplified reference tissue model (RPM) and RPM with vascular correction (RPM V b). In all subject groups, SVCA-based reference tissue curves showed lower blood volume fractions ( V b) and volume of distributions than those based on cerebellum time-activity curve. Probably resulting from the presence of specific signal from the vessel walls that contains in normal condition a significant concentration of the 18 kDa translocation protein. Best contrast between subject groups was seen using SVCA4-based reference tissues as the result of a lower number of kinetic classes and the prior removal of extracerebral tissues. In addition, incorporation of V b in RPM improved both parametric images and binding potential contrast between groups. Incorporation of V b within RPM, together with SVCA4, appears to be the method of choice for analyzing cerebral (R)-[11C]PK11195 neurodegeneration studies.

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The Simplified Reference Tissue Model: Model Assumption Violations and Their Impact on Binding Potential

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2014.202 ◽

2014 ◽

Vol 35 (2) ◽

pp. 304-311 ◽

Cited By ~ 43

Author(s):

Cristian A Salinas ◽

Graham E Searle ◽

Roger N Gunn

Keyword(s):

Input Function ◽

Binding Potential ◽

Model Assumption ◽

Reference Tissue ◽

Tissue Model ◽

Positron Emission ◽

Assumption Violations ◽

Quantitative Accuracy ◽

Reference Tissue Model ◽

Simplified Reference Tissue Model

Reference tissue models have gained significant traction over the last two decades as the methods of choice for the quantification of brain positron emission tomography data because they balance quantitative accuracy with less invasive procedures. The principal advantage is the elimination of the need to perform arterial cannulation of the subject to measure blood and metabolite concentrations for input function generation. In particular, the simplified reference tissue model (SRTM) has been widely adopted as it uses a simplified model configuration with only three parameters that typically produces good fits to the kinetic data and a stable parameter estimation process. However, the model's simplicity and its ability to generate good fits to the data, even when the model assumptions are not met, can lead to misplaced confidence in binding potential (BPND) estimates. Computer simulation were used to study the bias introduced in BPND estimates as a consequence of violating each of the four core SRTM model assumptions. Violation of each model assumption led to bias in BPND (both over and underestimation). Careful assessment of the bias in SRTM BPND should be performed for new tracers and applications so that an appropriate decision about its applicability can be made.

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Cerebral grey matter density is associated with neuroreceptor and neurotransporter availability: A combined PET and MRI study

10.1101/2020.01.29.924530 ◽

2020 ◽

Cited By ~ 1

Author(s):

Sandra Manninen ◽

Tomi Karjalainen ◽

Lauri J. Tuominen ◽

Jarmo Hietala ◽

Valtteri Kaasinen ◽

...

Keyword(s):

Grey Matter ◽

Magnetic Resonance Images ◽

Matter Density ◽

Binding Potential ◽

Reference Tissue ◽

Grey Matter Density ◽

Positron Emission ◽

Simplified Reference Tissue Model ◽

Mri Study

AbstractPositron emission tomography (PET) can be used for in vivo measurement of specific neuroreceptors and transporters using radioligands, while voxel-based morphometric analysis of magnetic resonance images allows automated estimation of local grey matter densities. However, it is not known how regional neuroreceptor or transporter densities are reflected in grey matter densities. Here, we analyzed brain scans retrospectively from 325 subjects and compared grey matter density estimates with three different neuroreceptors and transporter availabilities. µ-opioid receptors (MORs) were measured with [11C]carfentanil (162 scans), dopamine D2 receptors with [11C]raclopride (91 scans) and serotonin transporters (SERT) with [11C]MADAM (72 scans). The PET data were modelled with simplified reference tissue model. Voxel-wise correlations between binding potential and grey matter density images were computed. Regional binding of all the used radiotracers was associated with grey matter density in region and ligand-specific manner independently of subjects’ age or sex. These data show that grey matter density and MOR and D2R neuroreceptor / SERT availability are correlated, with effect sizes (r2) ranging from 0.04 to 0.69. This suggests that future studies comparing PET outcome measure different groups (such as patients and controls) should take grey matter density differences between the groups into account.

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Interictal Brain 5-HT1A Receptors Binding in Migraine Without Aura: A 18F-MPPF-PET Study

Cephalalgia ◽

10.1111/j.1468-2982.2008.01677.x ◽

2008 ◽

Vol 28 (12) ◽

pp. 1282-1291 ◽

Cited By ~ 26

Author(s):

A Lothe ◽

I Merlet ◽

G Demarquay ◽

N Costes ◽

P Ryvlin ◽

...

Keyword(s):

Cortical Excitability ◽

Region Of Interest ◽

Binding Potential ◽

Resonance Imaging ◽

Reference Tissue ◽

Tissue Model ◽

Positron Emission ◽

Cortical Regions ◽

Simplified Reference Tissue Model ◽

The Brain

In this study we aimed to assess the brain distribution of 5-HT1A receptors in migraine patients without aura. Ten female migraine patients and 24 female healthy volunteers underwent magnetic resonance imaging and positron emission tomography using a radioligand antagonist of 5-HT1A receptors [4-(2'-methoxyphenyl)-1-[2'-( N-2-pirydynyl)-p-fluorobenzamido]-ethylpiperazine (18F-MPPF)]. A simplified reference tissue model was used to generate parametric images of 5-HT1A receptor binding potential (BP) values. Statistical Parametrical Mapping (SPM) analysis showed increased MPPF BP in posterior cortical areas and hippocampi bilaterally in patients compared with controls. Region of interest (ROI) analysis showed a non-significant trend in favour of a BP increase patients in cortical regions identified by the SPM analysis except in hippocampi, left parietal areas and raphe nuclei. During the interictal period of migraine patients without aura, the increase of MPPF BP in posterior cortical and limbic areas could reflect an increase in receptor density or a decrease of endogenous serotonin, which could explain their altered cortical excitability.

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