Validation of reference tissue modelling for [11C]flumazenil positron emission tomography following head injury

Geeraerts, Thomas; Coles, Jonathan P.; Aigbirhio, Franklin I.; Pickard, John D.; Menon, David; Fryer, Tim D.; Hong, Young T.

doi:10.1007/s12149-011-0480-4

Cited by 20 publications

(10 citation statements)

References 36 publications

(60 reference statements)

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“…The pons, a part of the brainstem, is known as a region where mGluR1 concentration is negligible, 8 and it is often used as a reference region in noninvasive quantitative PET analysis of neuroreceptors. 29,30 To estimate BP ND for mGluR1 noninvasively with [ 11 C]ITDM-PET, we validated the reference tissue method using the tTAC of the pons. In PET studies with SD rats, accumulation of receptor-bound radioactivity was not observed in the pons (Figures 1 and 2), and there was no significant difference in V T value of the pons between PET studies on animals pretreated with and without FITM for the saturation of mGluR1 binding sites (data not shown), suggesting that the pons is a reasonable reference region.…”

Section: Discussionmentioning

confidence: 99%

Noninvasive Quantification of Metabotropic Glutamate Receptor Type 1 with [¹¹C]ITDM: a Small-Animal PET Study

Yamasaki¹,

Fujinaga²,

Yui³

et al. 2014

J Cereb Blood Flow Metab

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Because of its role in multiple central nervous system (CNS) pathways, metabotropic glutamate receptor type 1 (mGluR1) is a crucial target in the development of pharmaceuticals for CNS disorders. N-[4-[6-(isopropylamino)-pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methyl-4-[(11)C]-methylbenzamide ([(11)C]ITDM) was recently developed as a positron emission tomography (PET) ligand for mGluR1. To devise a method for measurement of the binding potential (BPND) of [(11)C]ITDM to mGluR1, reference tissue methods aimed at replacing measurement of the arterial input function are desirable. In this study, we evaluated a noninvasive quantification method of mGluR1 with [(11)C]ITDM, demonstrating its accuracy using Huntington disease model R6/2 mice. The BPND measurements based on the Logan reference (Logan Ref) method have closely approximated that based on the arterial input method. We performed PET analysis with Logan Ref to assess its accuracy in quantifying the decline of mGluR1 expression in R6/2 mice. Significant decreases in BPND values in R6/2 mice were detected in cerebellum, thalamus, striatum, and cingulate cortex. We compared autoradiographs of R6/2 mouse brain sections with immunohistochemical images, and found a close correlation between changes in radioactive signal intensity and degree of mGluR1 expression. In conclusion, [(11)C]ITDM-PET is a promising tool for in vivo quantification of mGluR1 expression.

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Section: Discussionmentioning

confidence: 99%

Noninvasive Quantification of Metabotropic Glutamate Receptor Type 1 with [¹¹C]ITDM: a Small-Animal PET Study

Yamasaki¹,

Fujinaga²,

Yui³

et al. 2014

J Cereb Blood Flow Metab

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“…More specifically, flumazenil displays comparable levels of binding to the GABA A receptors containing α1, α2, α3, or α5 subunits, which is why this compound is considered to be not subtype-selective [ 4 ]. For these reasons, [ 11 C]flumazenil can be considered a versatile PET tracer and it has been used in the study and assessment of several conditions, such as neuronal damage in head injury [ 5 ], epilepsy [ 6 ], stroke-induced penumbral areas of infarction [ 7 ], and Alzheimer’s disease [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic modeling of [11C]flumazenil kinetics in the rat brain

et al. 2017

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BackgroundPreferred models for the pharmacokinetic analysis of [11C]flumazenil human studies have been previously established. However, direct translation of these models and settings to animal studies might be sub-optimal. Therefore, this study evaluates pharmacokinetic models for the quantification of [11C]flumazenil binding in the rat brain.Dynamic (60 min) [11C]flumazenil brain PET scans were performed in two groups of male Wistar rats (tracer dose (TD), n = 10 and pre-saturated (PS), n = 2). Time-activity curves from five regions were analyzed, including the pons (pseudo-reference region). Distribution volume (VT) was calculated using one- and two-tissue compartment models (1TCM and 2TCM) and spectral analysis (SA). Binding potential (BPND) was determined from full and simplified reference tissue models with one or two compartments for the reference tissue (FRTM, SRTM, and SRTM-2C). Model preference was determined by Akaike information criterion (AIC), while parameter agreement was assessed by linear regression, repeated measurements ANOVA and Bland-Altman plots.Results1TCM and 2TCM fits of regions with high specific binding showed similar AIC, a preference for the 1TCM, and good VT agreement (0.1% difference). In contrast, the 2TCM was markedly preferred and necessary for fitting low specific-binding regions, where a worse VT agreement (17.6% difference) and significant VT differences between the models (p < 0.005) were seen. The PS group displayed results similar to those of low specific-binding regions. All reference models (FRTM, SRTM, and SRTM-2C) resulted in at least 13% underestimation of BPND.ConclusionsAlthough the 1TCM was sufficient for the quantification of high specific-binding regions, the 2TCM was found to be the most adequate for the quantification of [11C]flumazenil in the rat brain based on (1) higher fit quality, (2) lower AIC values, and (3) ability to provide reliable fits for all regions. Reference models resulted in negatively biased BPND and were affected by specific binding in the pons of the rat.

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“…In that context, the quantification of [ 11 C]flumazenil binding has been previously performed by different pharmacokinetic models. In human studies, the one-tissue compartment model (1TCM) and the simplified reference tissue model (SRTM) [ 10 ] using the pons as a reference tissue have been validated [ 11 ] and applied [ 12 – 14 ]. Although useful, these models have been mostly applied for regional quantification of [ 11 C]flumazenil binding, analyzing the average kinetic profile of a specific volume of interest (VOI).…”

Section: Introductionmentioning

confidence: 99%

Parametric Imaging of [11C]Flumazenil Binding in the Rat Brain

et al. 2017

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PurposeThis study evaluates the performance of several parametric methods for assessing [11C]flumazenil binding distribution in the rat brain.ProceduresDynamic (60 min) positron emission tomography data with metabolite-corrected plasma input function were retrospectively analyzed (male Wistar rats, n = 10). Distribution volume (V T) images were generated from basis function method (BFM), Logan graphical analysis (Logan), and spectral analysis (SA). Using the pons as pseudo-reference tissue, binding potential (BP ND and DVR–1) images were obtained from receptor parametric imaging algorithms (RPM and SRTM2) and reference Logan (RLogan). Standardized uptake value images (SUV and SUVR) were also computed for different intervals post-injection. Next, regional averages were extracted from the parametric images, using pre-defined volumes of interest, which were also applied to the regional time-activity curves from the dynamic data. Parametric data were compared to their regional counterparts and to two-tissue compartment model (2TCM)-based values (previously defined as the model of choice for rats). Parameter agreement was assessed by linear regression analysis and Bland-Altman plots.ResultsAll parametric methods strongly correlated to their regional counterparts (R 2 > 0.97) and to the 2TCM values (R 2 ≥ 0.95). SA and RLogan underestimated V T and BP ND (slope of 0.93 and 0.86, respectively), while SUVR-1 overestimated BP ND (slope higher than 1.07 for all intervals). While BFM and SRTM2 had the smallest bias to 2TCM values (0.05 for both), ratio Bland-Altman plots showed Logan and RLogan displayed relative errors which were comparable between different regions, in contrast with the other methods. Although SUV consistently underestimated V T, the bias in this method was also constant across regions.ConclusionsAll parametric methods performed well for the analysis of [11C]flumazenil distribution and binding in the rat brain. However, Logan and RLogan slightly outperformed the other methods in terms of precision, providing robust parameter estimation and constant bias. Yet, other methods can be of interest, because they can provide tissue perfusion (i.e., K 1 with BFM and SA), relative flow (i.e., R 1 with RPM and SRTM2), and model order (SA) images.

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Validation of reference tissue modelling for [11C]flumazenil positron emission tomography following head injury

Abstract: These results indicate that reference tissue modelling with the pons as the reference region is valid for [(11)C]FMZ PET in head-injured patients at 6 months following injury within both normal appearing and peri-lesional brain regions.

Cited by 20 publications

References 36 publications

Noninvasive Quantification of Metabotropic Glutamate Receptor Type 1 with [¹¹C]ITDM: a Small-Animal PET Study

Noninvasive Quantification of Metabotropic Glutamate Receptor Type 1 with [¹¹C]ITDM: a Small-Animal PET Study

Pharmacokinetic modeling of [11C]flumazenil kinetics in the rat brain

Parametric Imaging of [11C]Flumazenil Binding in the Rat Brain

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Validation of reference tissue modelling for [11C]flumazenil positron emission tomography following head injury

Abstract: These results indicate that reference tissue modelling with the pons as the reference region is valid for [(11)C]FMZ PET in head-injured patients at 6 months following injury within both normal appearing and peri-lesional brain regions.

Cited by 20 publications

References 36 publications

Noninvasive Quantification of Metabotropic Glutamate Receptor Type 1 with [11C]ITDM: a Small-Animal PET Study

Noninvasive Quantification of Metabotropic Glutamate Receptor Type 1 with [11C]ITDM: a Small-Animal PET Study

Pharmacokinetic modeling of [11C]flumazenil kinetics in the rat brain

Parametric Imaging of [11C]Flumazenil Binding in the Rat Brain

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Noninvasive Quantification of Metabotropic Glutamate Receptor Type 1 with [¹¹C]ITDM: a Small-Animal PET Study

Noninvasive Quantification of Metabotropic Glutamate Receptor Type 1 with [¹¹C]ITDM: a Small-Animal PET Study