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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Characterization of [18F]flutemetamol binding properties : A β-amyloid PET imaging ligand

Heurling, Kerstin January 2015 (has links)
The criteria for diagnosing Alzheimer’s disease (AD) have recently been revised to include the use of biomarkers for the in vivo presence of β-amyloid, one of the neuropathological hallmarks of AD. Examples of such biomarkers are positron emission tomography (PET) β-amyloid specific ligands, including [18F]flutemetamol. The aim of this thesis was to characterize the binding properties of [18F]flutemetamol from a tracer kinetic perspective as well as by validating binding measures through comparison with tissue pathology assessments. The applicability of previously developed kinetic models of tracer binding for voxel-based analysis was examined and compared to arterial input compartment modelling, the “gold standard” for PET quantification. Several voxel-based methods were found to exhibit high correlations with compartment modelling, including the semi-quantitative standardized uptake value ratio (SUVR). The kinetic components of [18F]flutemetamol uptake were also investigated without model assumptions using the data driven method spectral analysis, with binding to β-amyloid shown to relate to a slow kinetic component. The same component was also found to predominate in the uptake of white matter, known to be free of β-amyloid accumulation. White matter uptake was however possible to separate from β-amyloid binding based on the relative contribution of the slow component to the total volume of distribution. Uptake of [18F]flutemetamol as quantified using SUVR or assessed visually was found to correlate well with tissue pathology assessments. Classifying the brains of 68 deceased subjects who had undergone [18F]flutemetamol PET scanning ante mortem, based on the spatial distribution of β-amyloid according to pre-defined phases, revealed that abnormal uptake patterns of [18F]flutemetamol were only certain to be found in the last phase of β-amyloid accumulation. In the same cohort however, [18F]flutemetamol was also shown to accurately distinguish between subjects with AD and non-AD dementia. While this supports the use of [18F]flutemetamol in clinical settings for ruling out AD, the association of abnormal [18F]flutemetamol uptake to late phases of β-amyloid accumulation may limit the detection of early accumulation and pre-clinical stages of AD. It remains to be investigated whether application of voxel-based methods and slow component filtering may increase sensitivity, particularly in the context of clinical trials.
2

Imaging and Quantification of Brain Serotonergic Activity using PET

Lundquist, Pinelopi January 2006 (has links)
<p>This thesis investigates the potential of using positron emission tomography (PET) to study the biosynthesis and release of serotonin (5HT) at the brain serotonergic neuron. As PET requires probe compounds with specific attributes to enable imaging and quantification of biological processes, emphasis was placed on the evaluation of these attributes. </p><p>The experiments established that the 5HT transporter radioligand [<sup>11</sup>C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile, [<sup>11</sup>C]DASB, is suitable for imaging and quantification of transporters in rats and rhesus monkeys. In addition, the binding of [<sup>11</sup>C]DASB in brain tissue is decreased when 5HT concentrations are increased by tranylcypromine administration. The sensitivity of [<sup>11</sup>C]DASB binding, under these experimental conditions, to increased endogenous 5HT concentrations demonstrates the potential of in vivo monitoring of 5HT release in rat and monkey models.</p><p>The irreversible binding of 5-hydroxy-L-[β-<sup>11</sup>C]tryptophan, [<sup>11</sup>C]HTP, in the monkey brain was lower in the presence of NSD1015, which was used to inhibit the decarboxylase step in 5HT synthesis. [<sup>11</sup>C]HTP seems thus to have potential for tracking changes in the activity of this biosynthesis enzyme. In contrast, the accumulation of [<sup>11</sup>C]HTP was unaffected by clorgyline, which was used to inhibit metabolism of the probe in the brain. This appears to indicate that elimination of the main metabolite from the brain could be negligible and thus will not alter [<sup>11</sup>C]HTP quantification. The extent and distribution of the irreversible binding of a substrate for the first enzyme in 5HT formation, α-[<sup>11</sup>C]methyl-L-tryptophan, [<sup>11</sup>C]AMT, was different from those for [<sup>11</sup>C]HTP. This suggests that the two studied probe compounds provide estimates related to the enzyme activity of different steps in the 5HT biosynthesis pathway. </p><p>A reference tissue version of the Patlak method for the analysis of data obtained by PET was also developed. This approach takes into account irreversible binding in the reference region and appears, therefore, to yield more reliable parameter estimates than the conventional reference Patlak analysis. The method is recommended for parameter estimation of [<sup>11</sup>C]HTP data when no metabolite-corrected plasma curve is available. </p><p>Knowledge of altered 5HT synthesis and release in disease states and the consequences for effective pharmacotherapy can improve our knowledge of the aetiology of certain psychiatric and neurological diseases and enhance our ability to design more effective drugs.</p>
3

Imaging and Quantification of Brain Serotonergic Activity using PET

Lundquist, Pinelopi January 2006 (has links)
This thesis investigates the potential of using positron emission tomography (PET) to study the biosynthesis and release of serotonin (5HT) at the brain serotonergic neuron. As PET requires probe compounds with specific attributes to enable imaging and quantification of biological processes, emphasis was placed on the evaluation of these attributes. The experiments established that the 5HT transporter radioligand [11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile, [11C]DASB, is suitable for imaging and quantification of transporters in rats and rhesus monkeys. In addition, the binding of [11C]DASB in brain tissue is decreased when 5HT concentrations are increased by tranylcypromine administration. The sensitivity of [11C]DASB binding, under these experimental conditions, to increased endogenous 5HT concentrations demonstrates the potential of in vivo monitoring of 5HT release in rat and monkey models. The irreversible binding of 5-hydroxy-L-[β-11C]tryptophan, [11C]HTP, in the monkey brain was lower in the presence of NSD1015, which was used to inhibit the decarboxylase step in 5HT synthesis. [11C]HTP seems thus to have potential for tracking changes in the activity of this biosynthesis enzyme. In contrast, the accumulation of [11C]HTP was unaffected by clorgyline, which was used to inhibit metabolism of the probe in the brain. This appears to indicate that elimination of the main metabolite from the brain could be negligible and thus will not alter [11C]HTP quantification. The extent and distribution of the irreversible binding of a substrate for the first enzyme in 5HT formation, α-[11C]methyl-L-tryptophan, [11C]AMT, was different from those for [11C]HTP. This suggests that the two studied probe compounds provide estimates related to the enzyme activity of different steps in the 5HT biosynthesis pathway. A reference tissue version of the Patlak method for the analysis of data obtained by PET was also developed. This approach takes into account irreversible binding in the reference region and appears, therefore, to yield more reliable parameter estimates than the conventional reference Patlak analysis. The method is recommended for parameter estimation of [11C]HTP data when no metabolite-corrected plasma curve is available. Knowledge of altered 5HT synthesis and release in disease states and the consequences for effective pharmacotherapy can improve our knowledge of the aetiology of certain psychiatric and neurological diseases and enhance our ability to design more effective drugs.

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