Several cardiac diseases, including hypertrophy, cardiomyopathy, and myocardial infarction, result in the upregulation of cardiac angiotensin II type-1 receptors (AT1R). Imaging the AT1R in vivo via PET provides the potential to monitor disease progression and guide therapy accordingly. The aim of this research was to develop a novel F-18 labeled losartan analog as an AT1R PET tracer and begin evaluation in rats. Due to the longer half-life and shorter positron range of F-18, we presume that an F-18 labeled tracer will be more beneficial than current C-11 labeled tracers. Prior structure-activity relationship (SAR) studies suggested the addition of substituents to the hydroxyl group of losartan would minimally affect AT1R binding affinity. [18F]Fluoropyridine losartan ([18F]FPyrLos) was synthesized in an automated module through conjugation of [18F]fluoro-3-pent-4-yn-1-yloxypyridine ([18F]FPyKYNE) to azide-modified losartan via the Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) ‘click’ reaction. [18F]FPyrLos was produced in approximately 10% yield (decay-corrected) with > 97.5% purity and specific activities up to 4,200 mCi/µmol. MicroPET (Siemens Inveon) images of normal Sprague Dawley rats displayed high uptake in the kidneys (ratio of 8.3 compared to surrounding tissue at 10 min). Metabolite analysis in the kidneys and plasma by column-switch HPLC revealed that roughly two-thirds of the tracer was unchanged 10 min post-injection and that one labeled hydrophilic metabolite exists, accounting for roughly 6% of the total activity. Both microPET and metabolism studies displayed a dose-dependent reduction in renal uptake upon co-injection with AT1R blocker candesartan indicating specific binding. Further work in rat disease models is required to evaluate the potential of this tracer for imaging cardiac AT1R.

Several cardiac diseases, including hypertrophy, cardiomyopathy, and myocardial infarction, result in the upregulation of cardiac angiotensin II type-1 receptors (AT1R). Imaging the AT1R in vivo via PET provides the potential to monitor disease progression and guide therapy accordingly. The aim of this research was to develop a novel F-18 labeled losartan analog as an AT1R PET tracer and begin evaluation in rats. Due to the longer half-life and shorter positron range of F-18, we presume that an F-18 labeled tracer will be more beneficial than current C-11 labeled tracers. Prior structure-activity relationship (SAR) studies suggested the addition of substituents to the hydroxyl group of losartan would minimally affect AT1R binding affinity. [18F]Fluoropyridine losartan ([18F]FPyrLos) was synthesized in an automated module through conjugation of [18F]fluoro-3-pent-4-yn-1-yloxypyridine ([18F]FPyKYNE) to azide-modified losartan via the Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) ‘click’ reaction. [18F]FPyrLos was produced in approximately 10% yield (decay-corrected) with > 97.5% purity and specific activities up to 4,200 mCi/µmol. MicroPET (Siemens Inveon) images of normal Sprague Dawley rats displayed high uptake in the kidneys (ratio of 8.3 compared to surrounding tissue at 10 min). Metabolite analysis in the kidneys and plasma by column-switch HPLC revealed that roughly two-thirds of the tracer was unchanged 10 min post-injection and that one labeled hydrophilic metabolite exists, accounting for roughly 6% of the total activity. Both microPET and metabolism studies displayed a dose-dependent reduction in renal uptake upon co-injection with AT1R blocker candesartan indicating specific binding. Further work in rat disease models is required to evaluate the potential of this tracer for imaging cardiac AT1R.

Several cardiac diseases, including hypertrophy, cardiomyopathy, and myocardial infarction, result in the upregulation of cardiac angiotensin II type-1 receptors (AT1R). Imaging the AT1R in vivo via PET provides the potential to monitor disease progression and guide therapy accordingly. The aim of this research was to develop a novel F-18 labeled losartan analog as an AT1R PET tracer and begin evaluation in rats. Due to the longer half-life and shorter positron range of F-18, we presume that an F-18 labeled tracer will be more beneficial than current C-11 labeled tracers. Prior structure-activity relationship (SAR) studies suggested the addition of substituents to the hydroxyl group of losartan would minimally affect AT1R binding affinity. [18F]Fluoropyridine losartan ([18F]FPyrLos) was synthesized in an automated module through conjugation of [18F]fluoro-3-pent-4-yn-1-yloxypyridine ([18F]FPyKYNE) to azide-modified losartan via the Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) ‘click’ reaction. [18F]FPyrLos was produced in approximately 10% yield (decay-corrected) with > 97.5% purity and specific activities up to 4,200 mCi/µmol. MicroPET (Siemens Inveon) images of normal Sprague Dawley rats displayed high uptake in the kidneys (ratio of 8.3 compared to surrounding tissue at 10 min). Metabolite analysis in the kidneys and plasma by column-switch HPLC revealed that roughly two-thirds of the tracer was unchanged 10 min post-injection and that one labeled hydrophilic metabolite exists, accounting for roughly 6% of the total activity. Both microPET and metabolism studies displayed a dose-dependent reduction in renal uptake upon co-injection with AT1R blocker candesartan indicating specific binding. Further work in rat disease models is required to evaluate the potential of this tracer for imaging cardiac AT1R.

Simulation of a dynamic system is known to be sensitive to various factors and one of them could be the precision of model parameters. While the sensitivity of flight dynamic simulation to small changes in aerodynamic coefficients is typically not studied, the simulation of aircraft required to operate in nonlinear flight regimes usually at high angles of attack can be very sensitive to such small differences. Determining the significance and impact of the differences in aerodynamic characteristics is critical for understanding the flight dynamics and designing suitable flight control laws. This thesis uses this concept to study the effect of the differences in aerodynamic data for different aerodynamic models provided for a same aircraft which is F-18 HARV combat aircraft. The aircraft was used as a prototype for the high angles of attack technology program. However modeling an aircraft at high angles of attack requires an extensive aerodynamic data which are usually di cult to access. All aerodynamic models were collected from open literature and implemented within a nonlinear six degree of freedom aircraft model. Inspection of aerodynamic data set for these models has shown mismatches for certain aerodynamic derivatives, especially at higher angles of attack where nonlinear dynamics are known to exist. Nonlinear simulations are used to analyse three different types of flight dynamic models that use look-up-tables, arc-tangent formulation and polynomial functions to represent aerodynamic data that are suitable for high angles of attack application. To achieve this, a nonlinear six degree of freedom Simulink model was developed to accommodate these aerodynamic models separately. The trim conditions were obtained for different combinations of angles of attack and airspeed and the models were linearized in each case. Properties of the resulting state matrices such as eigenvalues and eigenvectors were studied to determine the dynamic behaviour of the aircraft at various flight conditions.

La tomographie par émission de positons (TEP) est une modalité d’imagerie nucléaire puissante, permettant des mesures fonctionnelles non-invasive dans les cellules, les animaux et les humains avec une haute sensibilité et résolution. Les exosomes sont des vésicules extracellulaires de 30 à 120 nm qui peuvent transférer leur contenu cytoplasmique entre cellules, mais comprendre leurs cheminements in vivo reste un défi. Les hydrogels thermosensibles à base de chitosane ont été développés et sont sous optimisation pour diverses applications telles que l'embolisation des vaisseaux sanguins, l'administration de médicaments, l’'administration de lymphocytes et la réparation du cartilage et des disques intervertébraux. Il y a un besoin urgent de suivi in vivo à court terme pour évaluer la rétention des hydrogels et des exosomes. Le Hexadécyl-4- [18F]-fluorobenzoate ([18F]HFB) est un radiotraceur lipophile à longue chaîne qui est retenu dans les membranes cellulaires et les biomatériaux. Le but de ce travail était d'automatiser la radiosynthèse de [18F]HFB pour marquer des exosomes et des hydrogels. La radiosynthèse et la purification de [18F]HFB ont été réalisées en utilisant le synthétiseur de chimie commercial IBA Synthera®. [18F]HFB a été préparé via substitution du précurseur d’ammonium quaternaire par [18F]F-. Après une première purification via une cartouche C18, [18F]HFB a été élué avec de l'acétonitrile et purifié par HPLC. [18F]HFB a ensuite été reformulé dans une solution de DMSO (10%) après élimination du solvant HPLC sous azote, filtré et dilué dans une solution saline stérile. [18F]HFB a été obtenu en rendement radiochimique allant de 15 à 45% (corrigé pour désintégration), en haute pureté radiochimique et chimique, et dans un temps de synthèse total de 60 minutes. Les exosomes n'ont pas été marqués avec succès. Cependant, les hydrogels de chitosane ont démontré un marquage élevé, avec une stabilité du complexe >90%, même après 8 heures d’incubation en solution saline. La TEP avec [18F]HFB d'exosomes et de biomatériaux présente une approche novatrice pour déterminer leur distribution in vivo. / Positron emission tomography (PET) is a powerful nuclear imaging modality allowing for non-invasive functional measures in cells, animals and humans with high sensitivity. Exosomes are 30-120 nm extracellular vesicles that can transfer their cytoplasmic contents between cells, however, understanding where exosomes traffic in the body remains a challenge. Chitosan-based thermosensitive hydrogels have been developed and are currently under optimization for various applications such as blood vessel embolization, drug delivery, lymphocyte delivery systems, and cartilage and intervertebral disc repair. There is an urgent need for in vivo, short term follow-up of such procedures to assess the retention of hydrogels and exosomes at the site of injection. Hexadecyl-4-[18F]fluorobenzoate ([18F]HFB) is a long chain lipophilic radiotracer that has been reported to be retained within cell membranes or biomaterials. The aim of this work was to automate the radiosynthesis of [18F]HFB for labeling exosomes and chitosan-based hydrogels. The radiosynthesis and purification of [18F]HFB was done using the commercial IBA Synthera® chemistry synthesiser with the R&D IFP-cassette and HPLC module. As previously reported, [18F]HFB was prepared by [18F]F- substitution of the trimethyl ammonium triflate precursor in DMSO. After removal of unreacted [18F]F- and DMSO via a C18 light cartridge, [18F]HFB was eluted with acetonitrile and purified by semi-prep C18 HPLC. [18F]HFB was then reformulated in DMSO (10%) solution after removal of the HPLC solvent from the radioactive product peak under nitrogen, filtered, and diluted in sterile saline. [18F]HFB was obtained in radiochemical yield (isolated after HPLC and evaporation) ranging from 15 – 45% (decay-corrected), high radiochemical and chemical purities, and within a total synthesis time of 60 mins. Exosomes were not successfully labeled. However, high labeling efficiency was observed with the chitosan hydrogels displaying a stability >90%, even after 8 hours incubation in saline. PET imaging with [18F]HFB of exosomes and biomaterials presents a novel approach to determining their in vivo distribution.

<p>Herein, the development, optimization, and evaluation of quantitative techniques are presented for dynamic PET studies in cancer imaging applications. Dynamic PET image analysis techniques are first applied to 18F-fluoroethyltyrosine (FET) PET imaging of glioma and brain metastasis patients. In a second application, dynamic PET image analysis techniques are applied to 68Ga-PSMA-11 PET imaging for primary prostate cancer patients. Overall, the application of dynamic PET imaging techniques supports improved clinical outcomes and enhanced clinician confidence for treatment modifications. </p>