Building a database for brain 18 kDa translocator protein imaged using [11C]PBR28 in healthy subjects

Translocator protein 18 kDa (TSPO) has been widely imaged as a marker of neuroinflammation using several radioligands, including [11C]PBR28. In order to study the effects of age, sex, and obesity on TSPO binding and to determine whether this binding can be accurately assessed using fewer radio high-performance liquid chromatography (radio-HPLC) measurements of arterial blood samples, we created a database of 48 healthy subjects who had undergone [11C]PBR28 scans (23 high-affinity binders (HABs) and 25 mixed-affinity binders (MABs), 20 F/28 M, age: 40.6 ± 16.8 years). After analysis by Logan plot using 23 metabolite-corrected arterial samples, total distribution volume ( VT) was found to be 1.2-fold higher in HABs across all brain regions. Additionally, the polymorphism plot estimated nondisplaceable uptake ( VND) as 1.40 mL · cm−3, which generated a specific-to-nondisplaceable ratio ( BPND) of 1.6 ± 0.6 in HABs and 1.1 ± 0.6 in MABs. VT increased significantly with age in nearly all regions and was well estimated with radio-HPLC measurements from six arterial samples. However, VT did not correlate with body mass index and was not affected by sex. These results underscore which patient characteristics should be accounted for during [11C]PBR28 studies and suggest ways to perform such studies more easily and with fewer blood samples.

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Noninvasive Blood-Free Full Quantification of Positron Emission Tomography Radioligand Binding

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2014.191 ◽

2014 ◽

Vol 35 (1) ◽

pp. 148-156 ◽

Cited By ~ 7

Author(s):

Francesca Zanderigo ◽

R Todd Ogden ◽

Ramin V Parsey

Keyword(s):

Positron Emission Tomography ◽

Radioligand Binding ◽

Partial Agonist ◽

Brain Regions ◽

Emission Tomography ◽

Simultaneous Estimation ◽

Arterial Line ◽

Blood Samples ◽

Arterial Blood ◽

Positron Emission

Full quantification of a positron emission tomography (PET) radioligand binding to its target is preferred because it requires the fewest assumptions, but generally involves measuring the concentration of free radioligand in the arterial plasma by collecting blood samples from the subject's radial artery during the scan, and performing metabolite analysis. This invasive, costly procedure deters subjects’ participation, and requires specialized staff and equipment. Simultaneous estimation (SIME) can fully quantify binding using only PET data from multiple brain regions and one individual anchor value, which is based on a single arterial blood sample. Drawing this sample can still be challenging in clinical settings, particularly when using simultaneous PET/magnetic resonance scanners. Here we propose a methodology for full quantification of binding that does not require any blood samples. The methodology substitutes the SIME blood-based anchor with a value predicted using multiple linear regression of noninvasive, easy-to-collect variables related to the radioligand blood concentration, and individual metabolism, such as injected dose, body mass index, or body surface area. As a study case, we show here the methodology in comparison to analysis with full arterial-line blood sampling in a cohort of 23 available scans with [11C]CUMI-101, a partial agonist of the serotonin 5-HT1A receptors.

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First in-human PET study of 3 novel tau radiopharmaceuticals: [11C]RO6924963, [11C]RO6931643, and [18F]RO6958948

10.1101/296764 ◽

2018 ◽

Author(s):

Dean F. Wong ◽

Robert A. Comley ◽

Hiroto Kuwabara ◽

Paul B. Rosenberg ◽

Susan M. Resnick ◽

...

Keyword(s):

Healthy Subjects ◽

Regional Analysis ◽

Brain Regions ◽

Whole Body ◽

Kinetic Properties ◽

Amyloid Pet ◽

Significant Group ◽

Pet Tracers ◽

Arterial Blood

AbstractBackground[11C]RO-963, [11C]RO-643 and [18F]RO-948 (previously referred as [11C]RO6924963, [11C]RO6931643, and [18F]RO6958948, respectively) have been reported as promising PET tracers for tau imaging based on in vitro and preclinical PET data (1,2). Here we describe the first human evaluation of these novel radiotracers.MethodsAmyloid PET positive Alzheimer’s disease (AD) patients and young healthy subjects (YC) each received two different tau tracers. Dynamic 90 min scans were obtained after bolus injection of [11C]RO-963, [11C]RO-643 or [18F]RO-948. Arterial blood sampling was performed in 11 healthy controls (HC) and 11 AD. Regions were defined on MRI, and PET data were quantified by plasma reference graphical analysis (for VT) and target cerebellum ratio (SUVR60-90). SUVR images were also analyzed voxelwise. Five older healthy subjects (OC) each received two scans with [18F]RO-948 for evaluation of test-retest variability. Four AD subjects received a repeat [18F]RO-948 scan over about 1 year. Six additional HC (3M: 3F; 41-67y) each received one whole body dosimetry scan with [18F]RO-948.ResultsIn YC, peak SUV values were observed in the temporal lobe with values of approximately 3.0 for [11C]RO-963, 1.5 for [11C]RO-643 and 3.5 for [18F]RO-948. Over all brain regions and subjects, the trend was that [18F]RO-948 had the highest peak SUV value, followed by [11C]RO-963, and then [11C]RO-643. Regional analysis of SUVR and VT for [11C]RO-643 and [18F]RO-948 clearly discriminated AD and HC groups. Compartmental modeling confirmed that [11C]RO-643 had lower brain entry than both [18F]RO-963 and [18F]RO-948, and [18F]RO-948 showed a better contrast between (predicted) areas of high vs low tau accumulation. Thus, our subsequent analysis focused on [18F]RO-948. Both voxelwise and region-based analysis of [18F]RO-948 binding in HC vs AD revealed multiple areas where AD and HC significantly differed. Of 22 high-binding regions, 13 showed significant group difference (following ANOVA, F=45, p<10-5). Voxelwise analysis also revealed a set of symmetrical clusters where AD>HC (threshold of p<0.001, cluster size k>50).Conclusions[18F]RO-948 demonstrates superior characteristics to [11C]RO-643 and [18F]RO-963 for characterization of tau pathology in AD. Regional binding data and kinetic properties of RO-948 compare favorably with existing other tau PET tracers.

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11C-DPA-713 has much greater specific binding to translocator protein 18 kDa (TSPO) in human brain than 11C-(R)-PK11195

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17699223 ◽

2017 ◽

Vol 38 (3) ◽

pp. 393-403 ◽

Cited By ~ 23

Author(s):

Masato Kobayashi ◽

Teresa Jiang ◽

Sanjay Telu ◽

Sami S Zoghbi ◽

Roger N Gunn ◽

...

Keyword(s):

Second Generation ◽

Specific Binding ◽

Translocator Protein ◽

Emission Tomography ◽

Binding Potential ◽

Arterial Blood ◽

Plot Analysis ◽

Positron Emission ◽

Translocator Protein 18 Kda ◽

Pet Scans

Positron emission tomography (PET) radioligands for translocator protein 18 kDa (TSPO) are widely used to measure neuroinflammation, but controversy exists whether second-generation radioligands are superior to the prototypical agent 11C-( R)-PK11195 in human imaging. This study sought to quantitatively measure the “signal to background” ratio (assessed as binding potential ( BPND)) of 11C-( R)-PK11195 compared to one of the most promising second-generation radioligands, 11C-DPA-713. Healthy subjects had dynamic PET scans and arterial blood measurements of radioligand after injection of either 11C-( R)-PK11195 (16 subjects) or 11C-DPA-713 (22 subjects). To measure the amount of specific binding, a subset of these subjects was scanned after administration of the TSPO blocking drug XBD173 (30–90 mg PO). 11C-DPA-713 showed a significant sensitivity to genotype in brain, whereas 11C-( R)-PK11195 did not. Lassen occupancy plot analysis revealed that the specific binding of 11C-DPA-713 was much greater than that of 11C-( R)-PK11195. The BPND in high-affinity binders was about 10-fold higher for 11C-DPA-713 (7.3) than for 11C-( R)-PK11195 (0.75). Although the high specific binding of 11C-DPA-713 suggests it is an ideal ligand to measure TSPO, we also found that its distribution volume increased over time, consistent with the accumulation of radiometabolites in brain.

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Stability of ascorbic acid in serum and plasma prior to analysis

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1258/000456302320314566 ◽

2002 ◽

Vol 39 (5) ◽

pp. 518-520 ◽

Cited By ~ 22

Author(s):

Simon YL Ching ◽

Alex W Prins ◽

John P Beilby

Keyword(s):

Ascorbic Acid ◽

High Performance Liquid Chromatography ◽

Liquid Chromatography ◽

Perchloric Acid ◽

Healthy Subjects ◽

High Performance ◽

Minimum Loss ◽

Blood Samples ◽

The Stability

Introduction: The stability of ascorbic acid in serum and plasma prior to analysis was studied. Methods: Blood samples were collected from ten healthy subjects into Vacutainer tubes containing either dipotassium EDTA, lithium-heparin or no additive. Ascorbic acid was analysed following immediate separation and preservation of samples, following delayed separation for 2 h and after delayed deproteinization and preservation for 2, 5 and 8 h. Deproteinization and preservation were achieved using a solution containing perchloric acid, EDTA and dithiothreitol. Ascorbic acid was analysed by high-performance liquid chromatography. Results: Blood collected into EDTA and separated, deproteinized and preserved immediately gave the highest yield of ascorbic acid. Loss of analyte after delayed separation was least for EDTA tubes (median 7%, range 4-13%), followed by lithium-heparin (median 18%, range 10-32%) and serum (median 26%, range 14-50%). Immediate separation of samples but delayed deproteinization and preservation also resulted in substantial losses of ascorbic acid. Conclusion: Minimum loss of ascorbic acid is achieved if blood is collected into tubes containing dipotassium EDTA and separated within 2 h, followed by immediate deproteinization and preservation.

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Stability of antioxidant vitamins in whole human blood during overnight storage at 4°C and frozen storage up to 6 months

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000485 ◽

2018 ◽

Vol 88 (3-4) ◽

pp. 151-157 ◽

Cited By ~ 3

Author(s):

Scott W. Leonard ◽

Gerd Bobe ◽

Maret G. Traber

Keyword(s):

Ascorbic Acid ◽

Whole Blood ◽

Healthy Subjects ◽

Frozen Storage ◽

Blood Collection ◽

Plasma Samples ◽

Optimal Conditions ◽

Plasma Ascorbic Acid ◽

Blood Samples ◽

Sample Handling

Abstract. To determine optimal conditions for blood collection during clinical trials, where sample handling logistics might preclude prompt separation of erythrocytes from plasma, healthy subjects (n=8, 6 M/2F) were recruited and non-fasting blood samples were collected into tubes containing different anticoagulants (ethylenediaminetetra-acetic acid (EDTA), Li-heparin or Na-heparin). We hypothesized that heparin, but not EDTA, would effectively protect plasma tocopherols, ascorbic acid, and vitamin E catabolites (α- and γ-CEHC) from oxidative damage. To test this hypothesis, one set of tubes was processed immediately and plasma samples were stored at −80°C, while the other set was stored at 4°C and processed the following morning (~30 hours) and analyzed, or the samples were analyzed after 6 months of storage. Plasma ascorbic acid, as measured using HPLC with electrochemical detection (LC-ECD) decreased by 75% with overnight storage using EDTA as an anticoagulant, but was unchanged when heparin was used. Neither time prior to processing, nor anticoagulant, had any significant effects upon plasma α- or γ-tocopherols or α- or γ-CEHC concentrations. α- and γ-tocopherol concentrations remained unchanged after 6 months of storage at −80°C, when measured using either LC-ECD or LC/mass spectrometry. Thus, refrigeration of whole blood at 4°C overnight does not change plasma α- or γ-tocopherol concentrations or their catabolites. Ascorbic acid is unstable in whole blood when EDTA is used as an anticoagulant, but when whole blood is collected with heparin, it can be stored overnight and subsequently processed.

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Arterio-Venous Differences in the Components of the Fibrinolytic Enzyme System

Thrombosis and Haemostasis ◽

10.1055/s-0038-1655624 ◽

1966 ◽

Vol 16 (01/02) ◽

pp. 032-037 ◽

Cited By ~ 5

Author(s):

D Ogston ◽

C. M Ogston ◽

N. B Bennett

Keyword(s):

Plasminogen Activator ◽

Enzyme System ◽

Venous Blood ◽

Fibrinolytic Enzyme ◽

Blood Levels ◽

Activator Concentration ◽

Blood Samples ◽

Arterial Blood ◽

Male Subjects

Summary1. The concentration of the major components of the fibrinolytic enzyme system was compared in venous and arterial blood samples from male subjects.2. The plasminogen activator concentration was higher in venous blood and the arterio-venous difference increased as its concentration rose, but the ratio of the arterial to venous level remained constant.3. No arterio-venous difference was found for anti-urokinase activity, antiplasmin, plasminogen and fibrinogen.4. It is concluded that venous blood determinations of the components of the fibrinolytic enzyme system reflect satisfactorily arterial blood levels.

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