Semiquantification of the peripheral-type benzodiazepine ligand [11C]PK11195 in normal human brain and application in multiple sclerosis patients (original) (raw)
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Whole-body distribution and metabolism of N-methyl-11C-1-(2-chlorophenyl)-N-(1-methylpropyl)-3-isoquinolinecarboxamide in humans; an imaging agent for in vivo assessment of peripheral benzodiazepine receptor activity with positron emission tomography
European Journal of Nuclear Medicine and Molecular Imaging, 2009
Purpose 11 C-PK11195 is a radiopharmaceutical for in vivo assessment of peripheral benzodiazepine receptor (PBR) activity using PET. We sought to clarify the metabolic fate of 11 C-PK11195 in a test-retest setting using radio-HPLC in comparison with radio-TLC, and the whole-body distribution in humans. Materials and methods In order to evaluate the reproducibility of radio-HPLC metabolite analyses, ten patients with Alzheimer's disease (AD) underwent two successive 11 C-PK11195 examinations on separate days. For comparison of different analytical methods, plasma samples from seven patients were also analysed by radio-TLC. In addition, we evaluated the whole-body distribution of 11 C-PK11195 and its uptake in the brain. Results The level of unmetabolized 11 C-PK11195 decreased slowly from 96.3±1.6% (mean±SD) at 5 min to 62.7±8.3% at 40 min after injection. Large individual variation was observed in the amount of plasma 11 C-PK11195 radiometabolites. The whole-body distribution of 11 C-PK11195 showed the highest radioactivity levels in urinary bladder, adrenal gland, liver, salivary glands, heart, kidneys, and vertebral column. In addition, the hip bone and breast bone were clearly visualized by PET. In patients with AD, 11 C-PK11195 uptake in the brain was the highest in the basal ganglia and thalamus, followed by the cortical grey matter regions and the cerebellum. Low 11 C-PK11195 uptake was observed in the white matter. Conclusion Our results indicate that 11 C-PK11195 is eliminated both through the renal and hepatobiliary systems. Careful analysis of plasma metabolites is required to determine the accurate arterial input function for quantitative PET measurement.
Reduction of PK11195 uptake observed in multiple sclerosis lesions after natalizumab initiation
Multiple sclerosis and related disorders, 2017
The objective of this study is to longitudinally analyze the uptake of [(11)C]PK11195-PET in multiple sclerosis patients after 3 and 6 months of natalizumab treatment. Eighteen MS patients, starting treatment with monocloncal anti-VLA-4, were enrolled in a longitudinal PK-PET study. PK uptake was quantified by volume of distribution (VT) calculation using image-derived input function at baseline, 3 and 6 months. Pharmacokinetic quantification was done using a segmented MRI, and selected areas included white matter, gadolinium enhancing lesions, non-enhancing lesions, cortical grey matter and thalamus. VTs of lesions were calculated in reference to each patient's white matter (VT ratio=VTr), to consider physiologic variability. Test-retest variability was stable for healthy control (HC). Quantification of PK uptake was completed in 18 patients, and baseline uptake was compared to 6-month uptake. After the start of natalizumab VTr significantly decreased in 13 individual enhancing...
Journal of Nuclear Medicine, 2009
Peripheral benzodiazepine receptor (PBR) is upregulated in activated glial cells and is therefore a useful biomarker for inflammation in the brain and neurodegenerative disorders. We developed a new PET radioligand, 11 C-AC-N-benzyl-N-ethyl-2-(7-methyl-8-oxo-2-pheyl-7,8-dihydro-9H-purin-9-yl)acetamide ( 11 C-AC-5216), that allows the imaging and quantification of PBRs in monkey and mouse brains. The aim of this study was to evaluate a quantification method of 11 C-AC-5216 binding in the human brain. Methods: A 90-min dynamic PET scan was obtained for each of 12 healthy men after an intravenous injection of 11 C-AC-5216. Regions of interest were drawn on several brain regions. Binding potential, compared with nondisplaceable uptake (BP ND ), was calculated by a nonlinear least-squares fitting (NLS) method with the 2-tissue-compartment model, and total volume of distribution (V T ) was estimated by NLS and graphical analysis methods. Results: BP ND was highest in the thalamus (4.6 6 1.0) and lowest in the striatum (3.5 6 0.7). V T obtained by NLS or graphical analysis showed regional distribution similar to BP ND . However, there was no correlation between BP ND and V T because of the interindividual variation of K 1 /k 2 . BP ND obtained with data from a scan time of 60 min was in good agreement with that from a scan time of 90 min (r 5 0.87). Conclusion: Regional distribution of 11 C-AC-5216 was in good agreement with previous PET studies of PBRs in the human brain. BP ND is more appropriate for estimating 11 C-AC-5216 binding than is V T because of the interindividual variation of K 1 /k 2 . 11 C-AC-5216 is a promising PET ligand for quantifying PBR in the human brain.
2017
PET brain images with [C]-(R)-PK11195 are being widely used to visualize microglial activation in vivo in neurodegenerative diseases, such as multiple sclerosis (MS). The aim of this study is to investigate the uptake behavior in juxtacortical and periventricular regions of [C]-(R)-PK11195 PET brain images reformatted in different time intervals by applying three methods, seeking method and time interval that significantly differentiate MS patients from healthy controls. Semiquantitative SUV and SUVR methods were applied to PET images from different time intervals acquired from 10 patients with MS and 5 healthy controls. The results show significant difference between groups for SUV (p = 0.01) in 40 to 60 min interval, and SUVR with white matter as reference (p < 0.01) in 10 to 60 min interval, measured in the juxtacortical and periventricular regions.
Semiquantification Study of [11C]-(R)-PK11195 PET Brain Images in Multiple Sclerosis
Revista Brasileira de Física Médica
PET brain images with [11C]-(R)-PK11195 are being widely used to visualize microglial activation in vivo in neurodegenerative diseases, such as multiple sclerosis (MS). The aim of this study is to investigate the uptake behavior in juxtacortical and periventricular regions of [11C]-(R)-PK11195 PET brain images reformatted in different time intervals by applying three methods, seeking method and time interval that significantly differentiate MS patients from healthy controls. Semiquantitative SUV and SUVR methods were applied to PET images from different time intervals acquired from 10 patients with MS and 5 healthy controls. The results show significant difference between groups for SUV (p = 0.01) in 40 to 60 min interval, and SUVR with white matter as reference (p < 0.01) in 10 to 60 min interval, measured in the juxtacortical and periventricular regions.
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...
Journal of Nuclear Medicine, 2010
The PET tracer 11 C-(R)-PK11195 (PK) is an antagonist of the peripheral-type benzodiazepine binding site and allows the noninvasive imaging of microglial activation seen in several neurologic disorders affecting the mature and developing brain. The objective of this study was to derive the biodistribution and in vivo radiation dose estimates of PK in children studied for brain inflammatory conditions and in healthy adults. Methods: Twenty-two children (mean age 6 SD, 9.5 6 4 y; range, 4-17 y; 10 girls) who underwent dynamic PK PET for conditions involving brain inflammation were studied. Seven healthy adults (age, 27.4 6 7.5 y; range, 22-41 y; 3 women) were evaluated using the same protocol. Normal-organ time-activity curves and residence times were derived and absorbed doses then calculated using the OLINDA software. Two other healthy young adults (1 man, 1 woman) also underwent sequential whole-body PET using a PET/CT scanner to obtain corresponding CT images and PK pharmacokinetics. Results: PK uptake was highest in the gallbladder and urinary bladder, followed by the liver, kidney, bone marrow, salivary gland, and heart wall, with minimal localization in all other organs including normal brain and lungs. PK was excreted through the hepatobiliary and renal systems. The average effective dose equivalent was 11.6 6 0.6 mSv/MBq (mean 6 SD) for young children (age, 4-7 y), 7.7 6 1.0 mSv/ MBq for older children (age, 8-12 y), 5.3 6 0.5 mSv/MBq for adolescents (age, 13-17 y), and 4.6 6 2.7 mSv/MBq for adults. The gallbladder wall received the highest radiation dose in children younger than 12 y, whereas the urinary bladder wall received the highest dose in older children and adults. For an administered activity of 17 MBq/kg (0.45 mCi/kg), the effective dose equivalent was about 5 mSv or below for all age groups. Conclusion: At clinically practical administered activities, the radiation dose from 11 C-PK11195 in both children and adults is comparable to that from other clinical PET tracers and diagnostic radiopharmaceuticals in routine clinical use.
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.
Journal of the Neurological Sciences, 2008
With the purpose of demonstrating the use of positron emission tomography (PET) and radiolabelled glia markers to indicate regional cerebral damage, we measured with PET in four young multiplex sclerosis (MS) patients in two consecutive measurements the global and regional brain uptake as well as regional distribution and binding potential (BP) of [ 11 C]vinpocetine and [ 11 C]PK11195. Both ligands showed increased uptake and BP in the regions of local brain damage. However, regional BP values for [ 11 C]vinpocetine were markedly higher than those for [ 11 C]PK11195. This feature of the former radioligand may be related to its high brain uptake and marked affinity to the peripheral benzodiazepine receptor binding sites (PBBS), characteristic for glia cells. As local brain traumas entail reactive glia accumulation in and around the site of the damage, the present findings may indicate that [ 11 C]vinpocetine marks the place or boundaries of local brain damage by binding to the PBBS present in glia cells, which, in turn, accumulate in the region of the damage.