Browsing by Subject "PET imaging"
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Item Open Access ABSOLUTE QUANTIFICATION IN SMALL PLANT RADIOTRACER STUDIES(2017) Cumberbatch, LaurieThe main objective of this dissertation research is to develop measurement and data-analysis tools for improving the quantitative accuracy of radiotracer studies of small plants, e.g., grasses in their early growth stages and tree seedlings. Improved accuracy is needed due to the thin nature of plant organs, e.g., leafs and stem. In addition, the methods developed in this thesis are applied to study the plant-environment interface of barley. Some of the approaches explored have potential to increase the statistical accuracy of counting data using PET imaging techniques. Improving the statistical precision of radionuclide tracking data will add to the analysis options. Another important goal is to measure the absolute photosynthetic rate. The standard approach in plant radiotracer experiments is to perform measurements of the relative distribution of radioactivity in various parts of the plant being studied. A limitation of this approach is that it does not take into account differences in the amount of radioisotope assimilated that are available for transport and allocation to the various sinks, that is, absolute CO2 uptake and photosynthetic rates are important factors in understanding the holistic physiological responses of plants to external conditions. For example, monitoring the movement of carbon-11 (11C) tagged carbohydrates in a plant requires an estimate of the average photosynthetic rate to determine the actual quantity of carbohydrates in each plant region (e.g. leaf, shoot, and root).
Radiotracing provides a method for real-time measurements of substance absorption, allocation and metabolic consumption and production in living organisms. Application of radioactive labelling in plants enables measurements associated with core physiological processes, e.g., photosynthesis, water uptake and nitrogen absorption and utilization. Plant uptake of radiotracers allows for tracking spatial and temporal distribution of substances, which enables studies of the plant-environment interface and the mechanisms involved in the allocation of resources (e.g., sugars, nutrients, and water). As such, these techniques are increasingly becoming an important tool for investigating the processes involved in the physiological responses of plants to changes in their local environmental conditions.
This dissertation has two major components: (1) development of experiment techniques for absolute photosynthetic rate measurements in plants using radio-isotope labeling, and (2) application of radioisotope tracing techniques to study the plant-environment interface in barley. The first component is covered in chapters one through three. The second component is presented in chapter four. An introduction into radio-tracing techniques is provided in chapter one. Chapter two describes radio-isotope production, radio-labelled compound preparation and delivery of labels to plant measurements. Chapter three outlines methods that can be employed to measure the absolute photosynthetic rate (µmol/m2/s) for a closed-loop system with [CO2] monitoring capabilities. Chapter four describes the background and results of our study on changing environmental conditions on a model system, barley seedlings. Chapter 5 will introduce the use of Monte-Carlo modeling for scaling the collected data to adjust the detected coincidence counts for losses due to positron escape from plant tissue. Chapter 6 describes the development of a novel imaging technique using direct positron detection that takes advantage of the high fraction of positrons escaping thin plant tissue.
In this dissertation, we have performed the most extensive measurements of carbohydrate allocation and translocation in a plant species using radio-isotope tracing techniques. A major practical limitation of studies based on radio-isotope labeling is the number of samples that can be measured in a single project. Our study on barley (Hordeum distichum) includes measurements on more than 30 plants. The short-lived radionuclide, 11C, was used to determine the real-time response to metabolite transport in barley. Sugars are photosynthesized and tagged with a positron-emitting radioisotope by flowing carbon dioxide (11CO2) tagged air over an active leaf. Data analysis of measurements taken in this dissertation indicates that the fraction of carbohydrates allocated to below ground sinks decreased, by 31% ± 9% in ambient [CO2] and by 37% ± 14% in elevated [CO2], when the nutrient conditions were rapidly changed from high to low nutrient.
Item Open Access An Investigation of MR Sequences for Partial Volume Correction in PET Image Reconstruction(2019) Wang, GongBrain Positron emission tomography (PET) has been widely employed for the clinic diagnosis of Alzheimer's disease (AD). Studies have shown that PET imaging is helpful in differentiating healthy elderly individuals, mild cognitive impairment (MCI) individuals, and AD individuals (Nordberg, Rinne, Kadir, & Långström, 2010). However, PET image quality and quantitative accuracy is degraded from partial volume effects (PVEs), which are due to the poor spatial resolution of PET. As a result, the compensation of PVEs in PET may be of great significance in the improvement of early diagnosis of AD. There are many different approaches available to address PVEs including region-based methods and voxel-based methods. In this study, a voxel-based PVE compensation technique using high-resolution anatomical images was investigated. The high-resolution anatomical images could be computed tomography (CT) or magnetic resonance imaging (MRI) images. Such methods have been proposed and investigated in many studies (Vunckx et al., 2012). However, relatively little research has been done on comparing the effects of different MRI images on voxel-based PVE correction methods. In this study, we compare the effect of 6 different MRI image protocols on PVE compensation in PET images. The MRI protocols compared in this study are T1-, T2-, proton-density (PD)-weighted and 3 different inversion recovery MRI protocols.
Results: OSEM and MAP/ICD images with isotropic prior are blurry and/or noisy. Compared with the OSEM and MAP/ICD images obtained by using an isotropic prior, the PET image reconstructed using anatomical information show better contrast and less noise. Visually, the PET image reconstructed with the ZeroCSF prior gave the PET image that visually appears to match best with the PET phantom. PET images reconstructed with T2, PD and ZeroWM image are similar to one another in image quality, but relative to the PET phantom and the ZeroCSF PET image, these images have poor contrast between CSF pockets and surrounding GM tissue, and they have less contrast between GM and WM. PET image reconstructed with T1 image had a better GM and CSF contrast, some of the CSF pockets in GM were reconstructed, but the WM region was very noisy. PET images reconstructed with ZeroGM image had noticeably worse performance on the GM reconstruction. Analysis suggest that these effects are caused by differences in tissue contrast with different MRI protocols
Keywords: PET, MRI, partial volume effect, image reconstruction, SPECT, Alzheimer's disease.
Item Open Access Radiolabeled inhibitors as probes for imaging mutant IDH1 expression in gliomas: Synthesis and preliminary evaluation of labeled butyl-phenyl sulfonamide analogs.(Eur J Med Chem, 2016-08-25) Chitneni, Satish K; Reitman, Zachary J; Gooden, David M; Yan, Hai; Zalutsky, Michael RINTRODUCTION: Malignant gliomas frequently harbor mutations in the isocitrate dehydrogenase 1 (IDH1) gene. Studies suggest that IDH mutation contributes to tumor pathogenesis through mechanisms that are mediated by the neomorphic metabolite of the mutant IDH1 enzyme, 2-hydroxyglutarate (2-HG). The aim of this work was to synthesize and evaluate radiolabeled compounds that bind to the mutant IDH1 enzyme with the goal of enabling noninvasive imaging of mutant IDH1 expression in gliomas by positron emission tomography (PET). METHODS: A small library of nonradioactive analogs were designed and synthesized based on the chemical structure of reported butyl-phenyl sulfonamide inhibitors of mutant IDH1. Enzyme inhibition assays were conducted using purified mutant IDH1 enzyme, IDH1-R132H, to determine the IC50 and the maximal inhibitory efficiency of the synthesized compounds. Selected compounds, 1 and 4, were labeled with radioiodine ((125)I) and/or (18)F using bromo- and phenol precursors, respectively. In vivo behavior of the labeled inhibitors was studied by conducting tissue distribution studies with [(125)I]1 in normal mice. Cell uptake studies were conducted using an isogenic astrocytoma cell line that carried a native IDH1-R132H mutation to evaluate the potential uptake of the labeled inhibitors in IDH1-mutated tumor cells. RESULTS: Enzyme inhibition assays showed good inhibitory potency for compounds that have iodine or a fluoroethoxy substituent at the ortho position of the phenyl ring in compounds 1 and 4 with IC50 values of 1.7 μM and 2.3 μM, respectively. Compounds 1 and 4 inhibited mutant IDH1 activity and decreased the production of 2-HG in an IDH1-mutated astrocytoma cell line. Radiolabeling of 1 and 4 was achieved with an average radiochemical yield of 56.6 ± 20.1% for [(125)I]1 (n = 4) and 67.5 ± 6.6% for [(18)F]4 (n = 3). [(125)I]1 exhibited favorable biodistribution characteristics in normal mice, with rapid clearance from the blood and elimination via the hepatobiliary system by 4 h after injection. The uptake of [(125)I]1 in tumor cells positive for IDH1-R132H was significantly higher compared to isogenic WT-IDH1 controls, with a maximal uptake ratio of 1.67 at 3 h post injection. Co-incubation of the labeled inhibitors with the corresponding nonradioactive analogs, and decreasing the normal concentrations of FBS (10%) in the incubation media substantially increased the uptake of the labeled inhibitors in both the IDH1-mutant and WT-IDH1 tumor cell lines, suggesting significant non-specific binding of the synthesized labeled butyl-phenyl sulfonamide inhibitors. CONCLUSIONS: These data demonstrate the feasibility of developing radiolabeled probes for the mutant IDH1 enzyme based on enzyme inhibitors. Further optimization of the labeled inhibitors by modifying the chemical structure to decrease the lipophilicity and to increase potency may yield compounds with improved characteristics as probes for imaging mutant IDH1 expression in tumors.