Measurement of extrastriatal D2-like receptor binding with [11C]FLB 457 – a test-retest analysis (original) (raw)
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Journal of Cerebral Blood Flow & Metabolism, 2007
The very high-affinity position emission tomography (PET) radioligand [ 11 C]FLB 457 was developed in order to study extrastriatal tissues, where the density of dopamine D 2 /D 3 receptors is one to two orders of magnitude lower than in the striatum. The present study investigated the validity of using the cerebellum as a reference region. Ten healthy volunteers underwent a 90-min dynamic PET study after the bolus injection of [ 11 C]FLB 457. The total volume of distribution (VD t) was estimated for the thalamus, hippocampus, frontal cortex, and cerebellum using a two-tissue compartmental model with a metabolite-corrected arterial plasma input function. VD t was sensitive to co-injected stable FLB 457 in all regions, including the cerebellum. Ex vivo saturation studies were also conducted in 17 rats where the dose of stable ligand was varied over five orders of magnitude. Specific binding was estimated to account for more than half of the rat cerebellar uptake of [ 11 C]FLB 457, questioning the latter as an estimate of nonspecific binding in human PET studies. To check whether the cerebellum is a reference region, the binding potential (BP) was calculated either from the VD t ratio or using the simplified reference tissue model (SRTM). A non-negligible density of D 2 /D 3 receptors in the cerebellum was shown to lead to underestimation of BP as well as erroneous estimation of differential occupancies. Binging potential estimates from the SRTM were found to be sensitive to changes in cerebral blood flow, providing further evidence for caution in the use of the cerebellum as a reference region in measures of [ 11 C]FLB 457 binding.
NeuroImage, 2004
Dopaminergic neurotransmission in extrastriatal regions may play a crucial role in the pathophysiology and treatment of neuropsychiatric disorders. The high-affinity radioligands [ 11 C]FLB 457, [ 123 I]epidepride, and [ 18 F]fallypride are now used in clinical studies to measure these low-density receptor populations in vivo. However, a single determination of the regional binding potential (BP) does not differentiate receptor density (B max ) from the apparent affinity (K D ). In this positron emission tomography (PET) study, we measured extrastriatal dopamine D2 receptor density (B max ) and apparent affinity (K D ) in 10 healthy subjects using an in vivo saturation approach. Each subject participated in two to three PET measurements with different specific radioactivity of [ 11 C]FLB 457. The commonly used simplified reference tissue model (SRTM) was used in a comparison of BP values with the B max values obtained from the saturation analysis. The calculated regional receptor density values were of the same magnitude (0.33 -1.68 nM) and showed the same rank order as reported from postmortem studies, that is, in descending order thalamus, lateral temporal cortex, anterior cinguli, and frontal cortex. The affinity ranged from 0.27 to 0.43 nM, that is, approximately 10 -20 times the value found in vitro (20 pM). The area under the cerebellar time activity curve (TAC) was slightly lower (11 F 8%, mean F SD, P = 0.004, n = 10) after injection of low as compared with high specific radioactivity, indicating sensitivity to the minute density of dopamine D2 receptors in the this region. The results of the present study support that dopamine D2 receptor density and affinity can be differentiated in low-density regions using a saturation approach. There was a significant ( P < 0.001) correlation between the binding potential calculated with SRTM and the receptor density (B max ), which supports the use of BP in clinical studies where differentiation of B max and K D is not required. In such studies, the mass of FLB 457 has to be less than 0.5 Mg injected to avoid a mass effect of the radioligand itself. D 2004 Elsevier Inc. All rights reserved.
2000
This study evaluated the test-retest reproducibility of D2receptor quantification in the thalamus and temporal cortex using [123l]epidepride SPECT. Methods: Ten healthy volunteers (4 men, 6 women; age range, 19-46 y) underwent 2 SPECT studies (interval, 2-26 d) using a bolus-plus-constant-infusion paradigm (bolus-to-infusion ratio = 6 h; infusion time = 9 h). Plasma clearance (in liters per hour) and free fraction (f,) of the parent tracer were measured. Radioactivity (in becquerels per gram) in the thalamus, temporal cortex, and cerebellum were normalized to the infusion rate (in becquerels per hour). Normalized striatal radioactivity was also measured to assess reproducibility in regions with a high density of receptors and better counting statistics. The outcome measures obtained were V3 (receptor density [Bmax]/equilibrium dissociation constant [KD]), V3' (f, x Bmax/KD), and RT (specific-to-nondisplaceable tissue ratio). Re sults: Test-retest variabilityand reliability(intraclasscorrelation coefficient) were 10.8% and 0.88, respectively, for plasma clear ance and 15.3% and 0.77, respectively, for f,. The test-retest variability of brain-specific (target minus nondisplaceable) radio activity was higher in the thalamus and temporal cortex than in the striatum, although reliability was comparable. Among the outcome measures, V3' showed better test-retest variability and reliability in the thalamus (13.3% and 0.75, respectively) and temporal cortex (13.4% and 0.86, respectively). Conclusion: Brain radioactivity was the main source of variability for quantifi cation of extrastriatal D2 receptors with [123l]epidepride. The reproducibility of outcome measures in extrastriatal regions was good. However, because receptor density was lower in extrastria tal regions than in the striatum, the counting statistics in these regions were low and reproducibility was affected by the higher test-retest variability of brain-specific radioactivity. Compared with V3 and V3', RT showed less test-retest variability in the thalamus and temporal cortex but lower reliability. Moreover, measurement of RTmay be affected by the presence of potential lipophilic metabolites entering the brain.
Molecular imaging, 2014
Defluorination of [18F]fallypride and accumulation of 18F in skull and glands leads to the contamination of brain structures with spillover activity due to partial volume effects, leading to considerable errors in binding potential estimations. Here we propose a modification of the simplified reference tissue model (SRTM) to take into account the contribution of skull activity to the radioactivity kinetic pattern in cerebellum and target regions. It consists of the introduction of an additional parameter for each volume of interest (sT) and one for the cerebellum (sR), corresponding to the fraction of skull activity contaminating these structures. Using five rat positron emission tomography experiments, we applied the modified SRTM (SRTMc), which resulted in excellent fits. As a relative means of comparison of results, we applied factor analysis (FA) to decompose dynamic data into images corresponding to brain and skull activity. With the skull factor images, we estimated the "...
Journal of Cerebral Blood Flow and Metabolism, 2000
11 C]PE2I is a novel positron emission tomography (PET) radiotracer for the dopamine transporter (DAT). The reproducibility and reliability of [ 11 C]PE2I measurements, especially in the small DAT-rich brain regions, is unknown and of critical importance to the interpretation of the data. Five healthy volunteers were scanned twice during the same day using [ 11 C]PE2I and the HRRT PET scanner. Methods based on metabolite-corrected arterial plasma curve and reference region were used to estimate distribution volumes (V T ) and binding potential (BP). Within-subject and between-subject variabilities were compared. [ 11 C]PE2I accumulated in the DAT-rich striatum and the midbrain. Equilibrium of specific binding appeared late in the striatum, whereas it was reached earlier in the midbrain. Plasma metabolite analysis showed that the potentially brain-penetrant 4-hydroxymethyl metabolite represented 15% to 20% of total plasma radioactivity. V T and BP measurements were associated with low within-subject variability. Measurement of DAT binding in small brain regions, including the substantia nigra, is reproducible and reliable using [ 11 C]PE2I and high-resolution research tomograph. A scanning time of more than 70 mins is required for the striatum, while less is sufficient for DAT quantification in the midbrain. The previously suggested involvement of the potentially brain-penetrant radioactive metabolite in the quantification should be further studied. Reproducibility of [ 11 C]PE2I using HRRT PET J Hirvonen et al Abbreviations: BP ND-SRTM , binding potential according to the simplified reference tissue model; DCA, dorsal caudate; DPU, dorsal putamen; ICC, intraclass correlation coefficient; s.d., standard deviation; THA, thalamus; VAR, absolute variability; VST, ventral striatum. Reproducibility of [ 11 C]PE2I using HRRT PET J Hirvonen et al Abbreviations: 2TM, two-tissue compartmental model; CER, cerebellum; DCA, dorsal caudate; DPU, dorsal putamen; ICC, intraclass correlation coefficient; s.d., standard deviation; THA, thalamus; VAR, absolute variability; VST, ventral striatum. Reproducibility of [ 11 C]PE2I using HRRT PET J Hirvonen et al Conclusions In this study, the reproducibility, reliability, and validity of DAT measurements with [ 11 C]PE2I and Reproducibility of [ 11 C]PE2I using HRRT PET J Hirvonen et al Reproducibility of [ 11 C]PE2I using HRRT PET J Hirvonen et al Reproducibility of [ 11 C]PE2I using HRRT PET J Hirvonen et al
NeuroImage, 2004
6-O-(2-[ 18 F]fluoroethyl)-6-O-desmethyldiprenorphine ([ 18 F]FDPN) is a nonselective opiate ligand that binds to postsynaptic M, K and D opiate receptors. Due to the longer half-life of F-18, compared to C-11, labeling DPN with F-18 allows for alternative experimental protocols and potentially the evaluation of endogenous opioid release. The applicability of this compound to assorted experimental protocols motivated the evaluation of [ 18 F]FDPN kinetics with compartmental and non-compartmental models. The results indicate that a two-tissue compartmental model best characterizes the data obtained following a bolus injection of [ 18 F]FDPN (120-min scanning protocol). Estimates of distribution volume (DV) were robust, being highly correlated for the one-tissue compartmental model as well as the invasive Logan model and the basis function method. Furthermore, the DV estimates were also stable under a shortened protocol of 60 min, showing a significant correlation with the full protocol. The binding potential (BP) values showed more variability between methods and in some cases were more sensitive to protocol length. In conclusion, this evaluation of [ 18 F]FDPN kinetics illustrates that DV values can be estimated robustly using compartmental modeling, the basis function method or the invasive Logan modeling approach on a volume of interest level. BP values were also found to correlate with DV values; however, these results should be interpreted with the understanding that specific binding in the reference region (occipital region) may exist.
Molecular Imaging and Biology, 2019
The aim of this study was to evaluate different non-invasive methods for generating (R)-1-((3-([ 11 C]methyl)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one) ([ 11 C]UCB-J) parametric maps using white matter (centrum semi-ovale-SO) as reference tissue. Procedures: Ten healthy volunteers (8 M/2F; age 27.6 ± 10.0 years) underwent a 90-min dynamic [ 11 C]UCB-J positron emission tomography (PET) scan with full arterial blood sampling and metabolite analysis before and after administration of a novel chemical entity with high affinity for presynaptic synaptic vesicle glycoprotein 2A (SV2A). A simplified reference tissue model (SRTM2), multilinear reference tissue model (MRTM2), and reference Logan graphical analysis (rLGA) were used to generate binding potential maps using SO as reference tissue (BP SO). Shorter dynamic acquisitions down to 50 min were also considered. In addition, standard uptake value ratios (SUVR) relative to SO were evaluated for three post-injection intervals (SUVR SO,40-70min , SUVR SO,50-80min , and SUVR SO,60-90min respectively). Regional parametric BP SO + 1 and SUVR SO were compared with regional distribution volume ratios of a 1-tissue compartment model (1TCM DVR SO) using Spearman correlation and Bland-Altman analysis. Results: For all methods, highly significant correlations were found between regional, parametric BP SO + 1 (r = [0.63;0.96]) or SUVR SO (r = [0.90;0.91]) estimates and regional 1TCM DVR SO. For a 90-min dynamic scan, parametric SRTM2 and MRTM2 values presented similar small bias and variability (− 3.0 ± 2.9 % for baseline SRTM2) and outperformed rLGA (− 10.0 ± 5.3 % for baseline rLGA). Reducing the dynamic acquisition to 60 min had limited impact on the bias and variability of parametric SRTM2 BP SO estimates (− 1.0 ± 9.9 % for baseline SRTM2) while a higher variability (− 1.83 ± 10.8 %) for baseline MRTM2 was observed for shorter acquisition times. Both SUVR SO,60-90min and SUVR SO,50-80min showed similar small bias and variability (− 2.8 ± 4.6 % bias for baseline SUVR SO,60-90min). Conclusion: SRTM2 is the preferred method for a voxelwise analysis of dynamic [ 11 C]UCB-J PET using SO as reference tissue, while reducing the dynamic acquisition to 60 min has limited Electronic supplementary material The online version of this article (
Maps of receptor binding parameters in the human brain ? a kinetic analysis of PET measurements
European Journal of Nuclear Medicine, 1990
A kinetic method is described for the estimation of neuroreceptor density as well as the rate constants for association and dissociation of rapidly equilibrating radioligands. The method is exemplified by positron emission tomographic measurements of the human brain using 11C-raclopride, a D2 dopamine receptor antagonist, and 1 a C-Ro 15-1788, a benzodiazepine receptor antagonist. Using a linear non iterative algorithm, regional binding characteristics were calculated and displayed pixel by pixel in brain maps. Data from repeated experiments on the same subject with different amounts of the unlabeled ligand were utilized. The binding characteristics were determined according to a two step procedure in which the time course of the free radioligand concentration was estimated from a reference region considered to be free of specific receptor binding sites. Alternative methods to determine the concentration of free radioligand are discussed.
BMC Veterinary Research, 2015
Background: [ 11 C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile ([ 11 C]DASB) is currently the mostly used radiotracer for positron emission tomography (PET) quantitative studies of the serotonin transporter (SERT) in the human brain but has never been validated in dogs. The first objective was therefore to evaluate normal [ 11 C]DASB distribution in different brain regions of healthy dogs using PET. The second objective was to provide less invasive and more convenient alternative methods to the arterial sampling-based kinetic analysis. Results: A dynamic acquisition of the brain was performed during 90 min. The PET images were coregistered with the magnetic resonance images taken prior to the study in order to manually drawn 20 regions of interest (ROIs). The highest radioactivity concentration of [ 11 C]DASB was observed in the hypothalamus, raphe nuclei and thalamus and lowest levels in the parietal cortex, occipital cortex and cerebellum. The regional radioactivity in those 20 ROIs was quantified using the multilinear reference tissue model 2 (MRTM2) and a semi-quantitative method. The values showed least variability between 40 and 60 min and this time interval was set as the optimal time interval for [ 11 C]DASB quantification in the canine brain. The correlation (R 2) between the MRTM2 and the semi-quantitative method using the data between 40 and 60 min was 99.3 % (two-tailed p-value < 0.01). Conclusions: The reference tissue models and semi-quantitative method provide a more convenient alternative to invasive arterial sampling models in the evaluation of the SERT of the normal canine brain. The optimal time interval for static scanning is set at 40 to 60 min after tracer injection.
NeuroImage, 2006
In positron emission tomography (PET) studies, the detailed mapping of neuroreceptor binding is a trade-off between parametric accuracy and spatial precision. Logan's graphical approach is a straightforward way to quickly obtain binding potential values at the voxel level but it has been shown to have a noise-dependent negative bias. More recently suggested approaches claim to improve parametric accuracy with retained spatial resolution. In the present study, we used PET measurements on regional D 2 dopamine and 5-HT 1A serotonin receptor binding in man to compare binding potential (BP) estimates of six different parametric imaging approaches to the traditional Logan ROI-based approach which was used as a ''gold standard''. The parametric imaging approaches included Logan's reference tissue graphical analysis (PILogan), its version recently modified by Varga and Szabo (PIVarga), two versions of the wavelet-based approach, Gunn's basis function method (BFM) and Gunn et al.'s recent compartmental theory-based approach employing basis pursuit strategy for kinetic modeling (called DEPICT). Applicability for practical purposes in basic and clinical research was also considered. The results indicate that the PILogan and PIVarga approaches fail to recover the correct values, the wavelet-based approaches overcome the noise susceptibility of the Logan fit with generally good recovery of BP values, and BFM and DEPICT seem to produce values with a bias dependent on receptor density. Further investigations on this bias and other phenomena revealed fundamental issues regarding the use of BFM and DEPICT on noisy voxel-wise data.