Quantitative Analysis of Peripheral Benzodiazepine Receptor in the Human Brain Using PET with 11C-AC-5216 (original) (raw)
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Glia, 2007
The peripheral benzodiazepine receptor (PBR) is expressed by microglial cells in many neuropathologies involving neuroinflammation. PK11195, the reference compound for PBR, is used for positron emission tomography (PET) imaging but has a limited capacity to quantify PBR expression. Here we describe the new PBR ligand CLINME as an alternative to PK11195. In vitro and in vivo imaging properties of [ 11 C]CLINME were studied in a rat model of local acute neuroinflammation, and compared with the reference compound [ 11 C]PK11195, using autoradiography and PET imaging. Immunohistochemistry study was performed to validate the imaging data. [ 11 C]CLINME exhibited a higher contrast between the PBR-expressing lesion site and the intact side of the same rat brain than [ 11 C]PK11195 (2.14 6 0.09 vs. 1.62 6 0.05 fold increase, respectively). The difference was due to a lower uptake for [ 11 C]CLINME than for [ 11 C]PK11195 in the non-inflammatory part of the brain in which PBR was not expressed, while uptake levels in the lesion were similar for both tracers. Tracer localization correlated well with that of activated microglial cells, demonstrated by immunohistochemistry and PBR expression detected by autoradiography. Modeling using the simplified tissue reference model showed that R 1 was similar for both ligands (R 1 1), with [ 11 C]CLINME exhibiting a higher binding potential than [ 11 C]PK11195 (1.07 6 0.30 vs. 0.66 6 0.15). The results show that [ 11 C]CLINME performs better than [ 11 C]PK11195 in this model. Further studies of this new compound should be carried out to better define its capacity to overcome the limitations of [ 11 C]PK11195 for PBR PET imaging.
Evaluation of the Reference Tissue Models for PET and SPECT Benzodiazepine Binding Parameters
NeuroImage, 2002
Recently, reference tissue methods have been proposed to estimate binding potential from PET data. A reference region without specifically bound ligand is used as an indirect input function to enable the expression of the time-concentration curve of a region of interest using a compartment model. However, PET dopaminergic and serotoninergic studies have shown differences between binding potential (BP) values obtained with reference tissue methods and those obtained with conventional kinetic modeling using an arterial input function. In this study, we measured the BP values for the benzodiazepine receptors in seven subjects using PET [ 11 C]flumazenil and SPECT [ 123 I]iomazenil radioligands. We compared the BP values obtained using the reference tissue methods with those obtained using the conventional kinetic method. These values were also compared with the absolute value of receptor density, B max. For the PET studies, a multi-injection approach employing labeled and unlabeled flumazenil was used to estimate the main binding parameters, BP and B max. For SPECT studies, a single injection protocol of [ 123 I]iomazenil was used to estimate BP values. The BP values were estimated using one-and two-tissue compartment models for the target region. Similar BP values were obtained using either the one-or two-tissue compartment model. This is probably due to the rapid equilibrium between tissue compartments reached with these radioligands. For PET and SPECT, these BP values were highly correlated (r > 0.960) to the BP values obtained using the arterial input function. We also found high correlations between the BP values obtained using the simplified reference tissue method and the receptor density parameter B max (r > 0.884). However, the reference tissue methods yielded lower BP values than those obtained using the conventional approach. Moreover, there was a bias on BP values that was not a simple scaling. It seems that the physiological values found in gray matter structures using these radioligands give acceptable BP values. We conclude that the reference tissue methods should be carefully evaluated for each radioligand.
Journal of Cerebral Blood Flow & Metabolism, 2012
This positron emission tomography (PET) study aimed to further define selectivity of [ 11 C]Ro15-4513 binding to the GABARa5 relative to the GABARa1 benzodiazepine receptor subtype. The impact of zolpidem, a GABARa1-selective agonist, on [ 11 C]Ro15-4513, which shows selectivity for GABARa5, and the nonselective benzodiazepine ligand [ 11 C]flumazenil binding was assessed in humans. Compartmental modelling of the kinetics of [ 11 C]Ro15-4513 time-activity curves was used to describe distribution volume (V T ) differences in regions populated by different GABA receptor subtypes. Those with low a5 were best fitted by one-tissue compartment models; and those with high a5 required a more complex model. The heterogeneity between brain regions suggested spectral analysis as a more appropriate method to quantify binding as it does not a priori specify compartments. Spectral analysis revealed that zolpidem caused a significant V T decrease (B10%) in [ 11 C]flumazenil, but no decrease in [ 11 C]Ro15-4513 binding. Further analysis of [ 11 C]Ro15-4513 kinetics revealed additional frequency components present in regions containing both a1 and a5 subtypes compared with those containing only a1. Zolpidem reduced one component (mean ± s.d.: 71%±41%), presumed to reflect a1-subtype binding, but not another (13%±22%), presumed to reflect a5. The proposed method for [ 11 C]Ro15-4513 analysis may allow more accurate selective binding assays and estimation of drug occupancy for other nonselective ligands.
Kinetic analysis and test-retest variability of the radioligand 11C-PK11195 binding to TSPO in the human brain - a PET study in control subjects
EJNMMI research, 2012
Positron-emission tomography and the radioligand [11C](R)-PK11195 have been used for the imaging of the translocator protein (TSPO) and applied to map microglia cells in the brain in neuropsychiatric disorders. [11C](R)-PK11195 binding has been quantified using reference region approaches, with the reference defined anatomically or using unsupervised or supervised clustering algorithms. Kinetic compartment modelling so far has not been presented. In the present test-retest study, we examine the characteristics of [11C](R)-PK11195 binding in detail, using the classical compartment analysis with a metabolite-corrected arterial input function. [11C](R)-PK11195 binding was examined in six control subjects at two separate occasions, 6 weeks apart. Results of one-tissue and two-tissue compartment models (1TCM, 2TCM) were compared using the Akaike criteria and F-statistics. The reproducibility of binding potential (BPND) estimates was evaluated by difference in measurements (error in perce...
Synapse, 2007
Peripheral benzodiazepine receptors (PBRs) are upregulated on activated microglia and are, thereby, biomarkers of cellular inflammation in brain. We recently developed two PET ligands with an aryloxyanilide structure to image PBRs and now evaluate the kinetics of these radiotracers in monkey to determine whether they are suitable to explore in human. Baseline and receptor-blocking scans were performed with [ 11 C]PBR01 and [ 18 F]PBR06 in conjunction with serial measurements of the arterial plasma concentration of parent radiotracer separated from radiometabolite. We used brain and plasma data with compartmental modeling to calculate regional brain distribution volume, which is equal to the ratio at equilibrium of the concentration of radioligand in brain to that of plasma. The distribution volume of [ 11 C]PBR01 was inaccurately estimated in the baseline scans, possibly because of the short half-life of 11 C or the presence of radiometabolite in brain. In contrast, the distribution volume of [ 18 F]PBR06 was stably determined within 200 min of scanning, and nondisplaceable uptake was only 1010% of total brain uptake. [ 18 F]PBR06 is promising for use in human because brain activity could be quantified with standard compartmental models and showed higher ratios (1010:1) of specific to nonspecific uptake. A critical factor for human use will be whether the tracer has adequately fast wash out from brain relative to the half-life of the radionuclide to obtain stable values of distribution volume. Synapse 61:595-605,
Neuroscience Letters, 2007
Peripheral benzodiazepine receptors (PBRs) are upregulated on activated microglia. We recently developed a promising positron emission tomography (PET) ligand, [ 11 C]PBR28, with high affinity and excellent ratio of specific to nonspecific binding. We assessed the ability of [ 11 C]PBR28 PET to localize PBRs in a rat permanent middle cerebral artery occlusion (MCAO) model of neuroinflammation. [ 11 C]PBR28 was intravenously administered to rats at 4 and 7 days after permanent MCAO. In all experiments, arterial blood was sampled for compartmental modeling of regional distribution volumes, and rat brains were sampled after imaging for in vitro [ 3 H]PK 11195 autoradiography and histological evaluation. [ 11 C]PBR28 PET and [ 3 H]PK 11195 autoradiography showed similar areas of increased PBRs, especially in the peri-ischemic core. Results from these in vivo and in vitro methods were strongly correlated. In this first study to demonstrate neuroinflammation in vivo with small animal PET, [ 11 C]PBR28 had adequate sensitivity to localize and quantify the associated increase in PBRs. Published by Elsevier Ireland Ltd.