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O aumento nos casos de obesidade em todo o mundo tem gerado grande preocupação e estimulado pesquisas na prevenção e tratamento dessa condição patológica. A combinação de diabetes tipo 2 ou resistência insulínica com obesidade agrava o potencial evolutivo da enfermidade. Mesmo pacientes submetidos com sucesso à cirurgia bariátrica ou metabólica, podem não se curar do diabetes, pois a melhora das taxas circulantes de glicose e insulina nem sempre corresponde à recuperação da massa beta pancreática. Até o momento, não há consenso sobre como medir a massa de células beta in vivo. As ferramentas disponíveis padecem de baixa sensibilidade e especificidade, muitas vezes revelando-se também complexas e dispendiosas. Incretinas radiomarcadas ,como os análogos do peptídeo glucagon-like-peptide-1 / GLP-1, têm-se revelado promissoras para avaliação de células beta pancreáticas, em diabetes e insulinoma. O objetivo do presente trabalho foi o desenvolvimento de dois conjugados de análogo de incretina GLP-1, marcados com tecnécio-99m, a fim de propor um método não invasivo de imagem, para monitoração da massa de células beta pancreáticas, em organismos afetados por obesidade. O estudo foi conduzido em diferentes modelos animais, incluindo obesidade induzida por dieta hiperlipídica, estado pós-obesidade em que o distúrbio inicialmente gerado foi parcialmente corrigido, e como controle, diabetes induzido com aloxana. Nos resultados, os radiotraçadores alcançaram um rendimento radioquímico superior a 97%. O melhor radiomarcador, dentre os dois análogos ensaiados, foi o 99mTc-HYNIC-βAla-Exendin-4. Animais com obesidade induzida por dieta revelaram captação reduzida nas células beta pancreáticas. A restrição dietética (estado pós-obesidade) não se seguiu de recuperação completa, embora notável melhora de glicemia haja sido observada. Estudos futuros são indicados em modelos de obesidade, diabetes tipo 2 e tratamento dietético, incluindo cirurgia bariátrica e metabólica. / Increased prevalence of obesity worldwide, has become a vast concern, stimulating investigations focusing prevention and therapy of this condition. The association of type 2 diabetes or insulin resistance aggravates the prognosis of obesity. Even patients successfully submitted to bariatric or metabolic surgery, may not be cured of diabetes, as improvement of circulating values of glucose and insulin not necessarily reflects recovery of pancreatic beta cell mass. There is no consensus about how to estimate beta cell mass in vivo. Available tools suffer from low sensitivity and specificity, often being as well cumbersome and expensive. Radiolabeled incretins, such as glucagon-like-peptide 1 (GLP-1) analogs, seem to be promising options for the measurement of beta cell mass in diabetes and insulinoma. The objective of this study was the development of two conjugates of GLP-1 analog, radiolabeled with 99m Technetium, as a noninvasive imaging method for the estimation of pancreatic beta cell mass, in the presence of obesity. Animal models were selected, including hyperlipidic diet-induced obesity, diet restricted obesity, and as controls, alloxan diabetes. Results indicated that both radiotracers achieved over 97% radiochemical yield. The most successful product was 99mTc-HYNIC-βAla-Exendin-4. Low beta cell mass uptake occurred in diet-induced obesity. Diet-restricted obesity, with substantial shedding of excess body weight, was followed by remarkable decrease of fasting blood glucose, however beta cell mass uptake was only mildly improved. Future studies are recommended in obesity, type 2 diabetes, and dieting, including bariatric and metabolic operations.

Methotrexate (MTX), as a pharmaceutical, is frequently used in tumor chemotherapy and is also a part of the established treatment of a number of autoimmune inflammatory disorders. Radiolabeled MTX has been studied as a tumor-diagnostic agent in a number of published studies. In the present study, the potential use of technetium-99m-labelled MTX (Tc-99m-MTX) as a radiotracer was investigated for the identification of inflammatory target sites. The labelling of MTX was carried out via a Tc-99m-gluconate precursor. Evaluation studies included in vitro stability, plasma protein binding assessment, partition-coefficient estimation, in vivo scintigraphic imaging and ex vivo animal experiments in an animal inflammation model. MTX was successfully labelled with Tc-99m, with a radiochemical purity of >95%. Stability was assessed in plasma, where it remained intact up to 85% at 4 h post-incubation, while protein binding of the radiotracer was observed to be similar to 50% at 4 h. These preclinical ex vivo and in vivo studies indicated that Tc-99m-MTX accumulates in inflamed tissue, as well as in the spinal cord, joints and bones; all areas with relatively high remodeling activity. The results are promising, and set the stage for further work on the development and application of Tc-99m-MTX as a radiotracer for inflammation associated with rheumatoid arthritis.

O aumento nos casos de obesidade em todo o mundo tem gerado grande preocupação e estimulado pesquisas na prevenção e tratamento dessa condição patológica. A combinação de diabetes tipo 2 ou resistência insulínica com obesidade agrava o potencial evolutivo da enfermidade. Mesmo pacientes submetidos com sucesso à cirurgia bariátrica ou metabólica, podem não se curar do diabetes, pois a melhora das taxas circulantes de glicose e insulina nem sempre corresponde à recuperação da massa beta pancreática. Até o momento, não há consenso sobre como medir a massa de células beta in vivo. As ferramentas disponíveis padecem de baixa sensibilidade e especificidade, muitas vezes revelando-se também complexas e dispendiosas. Incretinas radiomarcadas ,como os análogos do peptídeo glucagon-like-peptide-1 / GLP-1, têm-se revelado promissoras para avaliação de células beta pancreáticas, em diabetes e insulinoma. O objetivo do presente trabalho foi o desenvolvimento de dois conjugados de análogo de incretina GLP-1, marcados com tecnécio-99m, a fim de propor um método não invasivo de imagem, para monitoração da massa de células beta pancreáticas, em organismos afetados por obesidade. O estudo foi conduzido em diferentes modelos animais, incluindo obesidade induzida por dieta hiperlipídica, estado pós-obesidade em que o distúrbio inicialmente gerado foi parcialmente corrigido, e como controle, diabetes induzido com aloxana. Nos resultados, os radiotraçadores alcançaram um rendimento radioquímico superior a 97%. O melhor radiomarcador, dentre os dois análogos ensaiados, foi o 99mTc-HYNIC-βAla-Exendin-4. Animais com obesidade induzida por dieta revelaram captação reduzida nas células beta pancreáticas. A restrição dietética (estado pós-obesidade) não se seguiu de recuperação completa, embora notável melhora de glicemia haja sido observada. Estudos futuros são indicados em modelos de obesidade, diabetes tipo 2 e tratamento dietético, incluindo cirurgia bariátrica e metabólica. / Increased prevalence of obesity worldwide, has become a vast concern, stimulating investigations focusing prevention and therapy of this condition. The association of type 2 diabetes or insulin resistance aggravates the prognosis of obesity. Even patients successfully submitted to bariatric or metabolic surgery, may not be cured of diabetes, as improvement of circulating values of glucose and insulin not necessarily reflects recovery of pancreatic beta cell mass. There is no consensus about how to estimate beta cell mass in vivo. Available tools suffer from low sensitivity and specificity, often being as well cumbersome and expensive. Radiolabeled incretins, such as glucagon-like-peptide 1 (GLP-1) analogs, seem to be promising options for the measurement of beta cell mass in diabetes and insulinoma. The objective of this study was the development of two conjugates of GLP-1 analog, radiolabeled with 99m Technetium, as a noninvasive imaging method for the estimation of pancreatic beta cell mass, in the presence of obesity. Animal models were selected, including hyperlipidic diet-induced obesity, diet restricted obesity, and as controls, alloxan diabetes. Results indicated that both radiotracers achieved over 97% radiochemical yield. The most successful product was 99mTc-HYNIC-βAla-Exendin-4. Low beta cell mass uptake occurred in diet-induced obesity. Diet-restricted obesity, with substantial shedding of excess body weight, was followed by remarkable decrease of fasting blood glucose, however beta cell mass uptake was only mildly improved. Future studies are recommended in obesity, type 2 diabetes, and dieting, including bariatric and metabolic operations.

The radiopharmaceutical methylene diphosphonate (MDP) is a relatively new diagnostic tool and currently in widespread use as a gone imaging agent to delineate areas of altered osteogenesis. MDP is chelated with radioactive technetium-99m (Tc99m) and injected into the venous system of the body. It quickly clears from the bloodstream and is deposited into areas of bone transformation. Osteoporosis, primary carcinoma, bony metastases, osteomyelitis, and stress fractures are diagnosed with the use of Tc99m-MDP (1). In the presence of disease, the biodistribution of Tc99m-MDP is altered and this change is reflected in the images or scans. Ideally, the product would show a high ration of radioactivity in the target organ tot that of the surrounding tissue, with a minimization of radiation exposure to the patient. The purpose of this study will be to investigate Methylene Diphosphonate radiopharmaceuticals for their binding efficiencies, stability, and subsequent changes due to varying technetium levels.

Page 39 was included twice in the thesis. / <p> This thesis describes reactions involving low valent technetium nitrosyl complexes. O-Substituted hydroxylamines were reacted with [TcOCl4]- in methanol producing [Tc(NO)Cl4]-. NMR studies have shown that two species are present besides the starting material during this reaction. One of these species was confirmed by NMR to be the corresponding alcohol of the O-substituted hydroxylamine. The other species is believed to be a hydroxylamine intermediate that is in equilibrium with the final product, [Tc(NO)Cl4]-. A plausible mechanism for this reaction was proposed that included an oxo group attack of the α-carbon of the O-substituted hydroxylamine which would lead to the formation of the corresponding alcohol. In an attempt to confirm the mechanism, O-18 labeled [TcOCl4]- was synthesized, however, there is no conclusive evidence that the label is transferred to the corresponding alcohol at the present time. Substitution reactions of [Tc(NO)Cl4]- with phenanthroline and bipyridyl ligands were also investigated. Reactions with these ligands produced [Tc^(II)(NO)Cl3phen] (4a) and [Tc^(II)(NO)Cl3bipy] (5), respectively. The crystal structures of these complexes showed that the meridonial isomer is produced with one nitrogen atom of the bidentate ligand trans to the nitrosyl moiety. EPR spectra of these compounds confirm the Tc(II) oxidation state of the metal. All of the chloride ligands of 4a and 5 can be displaced using AgBF4 in acetonitrile solvent, which, in the case of bipyridyl, produces [Tc^(I)(NO)(bipy)2(MeCN)]2+ (6). Other technetium nitrosyl containing complexes are formed in these reactions and are currently awaiting x-ray structure determination.</p> / Thesis / Master of Science (MSc)

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