Thesis (Ph. D.)--University of Wisconsin--Madison, 1968. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

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The expansion of [¹⁸F]-radiolabelling methodologies is vital for the advancement of Positron Emission Tomography (PET) as a medical imaging tool. Novel protocols will simplify access to current PET tracers and allow development of original tracers, potentially enhancing the imaging quality or permit imaging of a wider range of clinical problems. A general introduction is presented in <b>Chapter 1</b>, covering PET, application of fluorine-19 in the pharmaceutical industry, the production of fluorine-18 and the current state-of -art for [¹⁸F]-radiolabelling. The results chapters are divided in to two parts; <b>Part 1</b> (<b>Chapters 2 - 4</b>) concern the synthesis of [18F]fluoroarenes and <b>Part II</b> (<b>Chapters 5</b> and <b>6</b>) discuss diversity oriented radiofluorination techniques, targeting novel [¹⁸F]motifs. In <b>Part I</b>, Chapter 2 describes the use of hypervalent iodine reagents to meditate an umpolung approach for fluorination and radiofluorination of N-arylsulfonamides and anilides. <b>Chapter 3</b> again utilises hypervalent iodine reagents, but as spirocyclic iodonium(III) ylide precursors, being applied to semi-automated and automated microfluidic conditions. <b>Chapter 4</b> discusses the development of conditions for the production and isolation of radiopharmaceuticals employing Cu(II)-mediated radiofluorination of aryl boronic pinacol esters. In <b>Part II, Chapter 5</b> discusses the applicability of halogen exchange reactions to reach polyfluorinated motfis and <b>Chapter 6</b> focuses on the application of a single diazo precursor to access three polyfluorinated motifs with single-step reactions. Finally, <b>Chapter 7</b> provides experimental data for compounds discussed in this thesis.

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M.Sc. (Chemistry) / The storage as solid Ag12BI(s) of reactor produced 12BI (t~ = 1.6 x 107 a) in underground respositories can present an environmental problem due to the potential release of radioactive 12BI into the environment over extended storage periods. One process that causes concern is the solubilization of AgI through complexation when brought into contact with underground water, particularly those with high salt content. In this work the charaqterization of the complexation equilibria in the AgI(s)/I-(aq),CI-(aq) system was studied. Solu- I tions containing high CI- and low 1- concentrations were of special interest with regard to the possible formation of ternary complexes. The presence of AgICI22- was indicated experimentally but no evidence of other ternary species like AgI2CI2- or AgIsCIS- could be established. Solubilities were determined radiochemically by using specially prepared 110mAgI. Solubility curves for AgI in different I-/CI- mixtures were adequately explained in terms of models consisting of the species AgCls2-, AgC14S-, AgIs2-, AgI4s- and AgICI22-. Distribution curves were calculated for different I-/CI- mixtures. As an alternative detection mode for silver-determination a flow injection system incorporating a micro-column of activated alumina was used in conjuntion with flame atomic absorption spectrometry for the pre-concentration and determination of silver in water. The procedure was successfully applied to a range of water samples, but no determination of silver in halide or perchlorate media was possible. The limit of detection based on a sample volume of 15 cms was 4.5 ~gdm-3 and the relative standard deviations at 50 and 5 ~gdm-3 were 5.4 and 19%, respectively. In part B of this work a method for the determination of chloride in organic compounds (oils provided by the Atomic Energy Corporation) by using an Parr oxygen bomb and ion chromatography was studied. The combustion products were absorbed in H20. The solution was injected into an ion chromatograph equipped with an anion analytical column, membrane suppressor and conductivity detector. The instrument response was calibrated using different standard solutions. These were prepared from several organic solutions, an organic salt and from sodiumchloride. Calibration curves were linear over a wide range and presented good reproducibility. It differed however according to the type of standard solution used. The limit of detection was 255 ~gdm-3 and the relative standard deviations at 10, 1 and 0.5 ugcm-3 were 0.52, 1.64 and 3.5%, respectively. As an alternative decomposition method wet decomposition within a sealed system (autoclave) was used. Due to the high blank values in this method no analysis of substances could be made in the lower ugcm-3 range.

D.Sc. (Chemistry) / Please refer to full text to view abstract

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Recently discovered methods for both diagnosis and treatment management of heart failure (HF) and other cardiovascular diseases include the use of molecular imaging modalities such as positron emission tomography (PET). As such, PET radiotracers have been developed and show strong evidence for quantifiable sympathetic nervous system (SNS) imaging in animals and humans using radioligands that target the norepinephrine transporter (NET). In this study, the cardiac sympathetic nervous system imaging probe [¹⁸F]meta-fluorobenzylguanidine ([¹⁸F]mFBG) was evaluated in Sprague Dawley (SD) rats and hypothesized to i) have measurable NET-dependent uptake kinetics; ii) possess measurable NET reuptake, iii) be stored into vesicles, and remain metabolically stable within the myocardium, iv) be sensitive to changes in sympathetic tone, and v) discriminate between healthy and diseased animals. Using the selective NET inhibitor desipramine (DMI) and nonselective extraneural and neural uptake inhibitor phenoxybenzamine (PBZ) we observed 30-35% and ~70% reduced uptake in the myocardium, respectively. Neuronal ablation with 6-hydroxydopamine (6-OHDA) resulted in a 36% loss of myocardial retention. DMI and PBZ chase dosing revealed no change in myocardial washout by PET, suggesting minimal reuptake of the tracer and preferential clearance into blood. Pretreatment with the vesicular monoamine transporter (VMAT) inhibitor reserpine (RSP) reduced myocardial retention by 34% within 5 minutes in comparison to baseline, providing evidence for intraneural vesicular retention. Dahl salt-sensitive (DSS) rats were induced with HF via high salt (HS, 8%) diet. After 16 weeks, rats kept on HS diet showed ~32% reduced myocardial uptake in comparison to low salt (LS) controls. Non-invasive PET imaging of HF is therefore sensitive to the expected changes in myocardial uptake in small animal imaging. The myocardial cholinergic system was evaluated using the vesicular acetylcholine transporter (VAChT) ligand [¹⁸F]fluoroethoxybenzylvesamicol ([¹⁸F]FEOBV) in CD-1 mice. We hypothesized that i) [¹⁸F]FEOBV uptake in the myocardium is VAChT dependent; and more specific in the absence of isoflurane anesthesia. Baseline uptake was observed in the ventricles. However, pretreatment with vesamicol in the presence and absence of isoflurane did not reduce myocardial activity. Analysis of PET images in mice with differential cardiac VAChT expression showed minimal changes in blood and cardiac activity. These studies have demonstrated a lack of specific binding of [¹⁸F]FEOBV in the myocardium of mice, rendering this imaging probe unfit in interpreting cholinergic function in small animals. The second half of the thesis is focused on the development of a radiolabeling technique using novel iminophosphorane precursors, and their subsequent reactivity and application using the naturally abundant (99% carbon-12) and positron emission tomography (PET) imaging isotope (carbon-11). We hypothesized that the reaction of iminophosphorane precursors with [¹¹C]CO₂ with allow us to i) synthesize a myriad of labelled isocyanate derived functional groups ii) apply this chemistry to label relevant radiopharmaceuticals in high yield and molar activity. Optimization of reaction conditions was performed, and a substrate scope was developed. Using the naturally abundant carbon isotope, we synthesized isocyanate derived functional groups such as carbamates, thiocarbamates, ureas, and amides in 63-94% yield. Pharmaceuticals such as regorafenib, URB694, and melatonin were synthesized in 60-72% yield. When applied to carbon-11 radiochemistry, labelled products were produced in 32-84% radiochemical yield (RCY). Radiopharmaceuticals such as [¹¹C]URB694 and [¹¹C]glibenclamide were synthesized in high yield and molar activity suitable for preclinical evaluation. We have demonstrated the utility of iminophosphorane precursors in synthesizing labelled functional groups and relevant radiopharmaceuticals in high yields, enabling their use for future preclinical or clinical studies. The recent development of the potent and selective nod-like receptor protein-3 (NLRP3) inhibitor MCC950 has demonstrated remarkable application as a therapeutic in reducing macrophage infiltration and aortic lesion area, but has yet to be applied to PET imaging due to poor synthesis yields. We hypothesized that i) using our previously established iminophosphorane chemistry we can synthesize [¹¹C]MCC950, and ii) selective uptake of [¹¹C]MCC950 occurs in aortic atherosclerotic lesions. We successfully radiolabeled [¹¹C]MCC950 in 45 ± 4 % RCY (27 ± 2 GBq/µmol). Plasma metabolite analysis revealed 94% intact tracer after 15 minutes, and ex vivo autoradiography on excised aortas showed heterogeneous uptake in atherosclerotic plaques of ApoE⁻ᐟ⁻ mice. Pretreatment with nonradioactive MCC950 resulted in significantly increased uptake in aortic lesions (48 ± 17 %ID/m² vs 104 ± 15 %ID/m²), without significantly increasing plasma free fraction (1.3 ± 0.4% vs 1.7 ± 0.8%). The data suggests increased specific binding following blockade which may be due to biochemical mechanisms such as disaggregation of NLRP3 oligomers, artificially increasing the available number of binding sites. Thus, the data suggest [¹¹C]MCC950 uptake demonstrates specific binding and may therefore prove useful as an in vivo imaging probe to detect NLRP3-mediated inflammation in atherosclerosis.