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.

Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 5 uppsatser.

No description available.

Study of Plasma Protein Binding of Radiopharmaceuticals Summary The purpose of this work is the study of binding of substances (177 Lu-DOTA- [Lys3]bombesin, 177 Lu-NOTA-[Lys3]bombesin, 177 Lu-PCTA-[Lys3]bombesin, and 177 Lu- DOTA-MG47) to plasma proteins by equilibrum dialysis in 37řC, particularly using plasma samples of beef, rabbit, rat and human. Within this group, these substances were compared interspecifically. The substances 177 Lu-DOTA-[Lys3]bombesin, 177 Lu-NOTA-[Lys3]bombesin, 177 Lu- PCTA-[Lys3]bombesin, and 177 Lu-DOTA-MG47 are the newly developed receptor- specific radiolabeled peptides. For all the newly collected data, the interspecific comparison and subsequent statistical evaluation was performed. The indicated bombesin derivates were compared and statistically analyzed even between themselves. During the interspecies comparisons and the determination of the statistical significance of the data, there were found statistically significant and statistically highly significant differences between some of the examined samples. A highly significant difference was found during comparing with samples of 177 Lu-NOTA- [Lys3]bombesin and statistical evaluation, there was found a statistically highly significant difference. Despite the differences found, it is clear that the plasma binding concerning...

The aim of this thesis was to prepare monoamide of macrocycle H3NOTA, which was prepared by multiple step synthesis. Ligand was characterized by NMR, MS and X-ray difraction analysis. Acid-base properties were studied by potentiometric titrations. Four protonation constants pKa`s were found and these protonation constants are lower than pKa`s of H3NOTA. Coordination properties with selected metal ions from the first row of transition metal, metal ions of biological interest and with lithium ions were investigated by potentiometric titration. Stability constants show that monoethylamide derivative of macrocycle H3NOTA forms complexes with lower stability than diethylamide derivative of macrocycle H3NOTA. Stability constants for complexes which contains amide group are lower than for H3NOTA complexes. Kinetics of Ga3+ complexation was investigated at different pH by 71 Ga NMR. The rate constants of and half-lives of complexation were determined at pH = 1. The rate constant was higher and the half-life of complexation was shorter than for H3NOTA ligand. Key words: macrocyclic complexes, thermodynamic stability, formation kinetics, radiopharmaceutical

The aim of this work was to synthesize and study acid-base and coordination properties of ligands bearing a neutral or negative charge on their pendant arms. Acid-base properties of two ligands and thermodynamic stability of their complexes with gallium, copper, and zinc ions were studied using potentiometry, UV-Vis and NMR. Solid state structure of one of the ligands and its complex with copper ion was studied using RTG structural analysis. Structure of complexes in solution was studied using methods of computational chemistry.

Os radiofármacos são preparações farmacêuticas com finalidade diagnóstica ou terapêutica que, quando prontas para o uso, contêm um ou mais radionuclídeos. São utilizados em Medicina Nuclear para diagnóstico e terapia de várias doenças. O tecnécio-99m-mercaptoacetiltriglicina (MAG3-99mTc) foi primeiramente preparado em 1986 na Universidade de Utah pelo Dr. Alan R. Fritzberg e tem sido utilizado para avaliação da filtração glomerular e dos túbulos renais. O objetivo deste trabalho foi definir as condições de preparação de uma formulação para obtenção de MAG3 na forma de um reagente liofilizado comercial, para ser marcado com 99mTc. Inicialmente foram preparados lotes teste baseados nas formulações europeia e americana, com pH final 6 e os resultados foram insatisfatórios. A mudança de pH para 12 resultou em aumento na pureza radioquímica, porém sem estabilidade de marcação com 99mTc em até 4 horas. O teste com a formulação cubana em pH 9,5 resultou em pureza radioquímica (% PRq) maior que 90% até 4 horas de marcação. O limite especificado para % PRq é de 90%. Com base nos resultados anteriores, foram definidos os componentes da formulação IPEN e três lotes do produto liofilizado com 100 frascos cada, foram avaliados quanto à estabilidade radioquímica e biológica até cerca de 9 meses. Quatro lotes piloto produzidos com 230 frascos liofilizados cada, estão em estudo de estabilidade até o presente momento. As atividades de marcação com 99mTc foram 0,74 - 3700 MBq (5 - 100 mCi), em 3 mL de NaCl 0,9%. A % PRq foi determinada em até 240 minutos de marcação utilizando cromatografia em camada delgada, com 2 sistemas diferentes: Metiletilcetona:acetato de etila 60:40 (v/v) em fita de iTLC-SG para determinação de 99mTcO4- em Rf = 1 e Acetonitrila:água 50:50 (v/v) em fita Whatman 3MM para determinação de 99mTcO2 em Rf = 0. Os resultados foram expressos como média % PRq ± desvio padrão considerando-se análises em duplicata de dois frascos para cada um dos tempos de marcação. 0,74 MBq (200 μCi) de atividade mínima ou 129,5 MBq (3500 μCi) de atividade máxima de marcação em 0,1 mL NaCl 0.9% foram administrados em camundongos Swiss e a radioatividade nos rins, fígado e vesícula, estômago, intestino e carcaça foi medida após 45 minutos. Os valores foram expressos como média % DI (Dose Injetada) ± DP. O estudo de toxicidade aguda foi realizado em um grupo de 10 camundongos machos da linhagem Balb/c, pesando entre 20-30 g, com cerca de dois meses de vida, por um período de 14 dias. Todos os resultados de controle de qualidade atenderam aos critérios especificados. Observou-se que o preparo e a adição dos reagentes, a quantidade de cloreto estanoso e o valor de pH nas etapas intermediárias foram fatores importantes na obtenção de um radiofármaco para marcação com 99mTc, como no caso do MAG3. / Radiopharmaceuticals are pharmaceutical preparations for diagnostic or therapeutic purposes that, when ready for use, contain one or more radionuclides. They are used in Nuclear Medicine for diagnosis and therapy of various diseases. Technetium-99m-mercaptoacetyltriglycine (99mTc-MAG3) was first prepared in 1986 at the University of Utah by Dr. Alan R. Fritzberg and has been used to assess glomerular filtration and renal tubules. The objective of this work was to define the preparation conditions of the formulation to obtain MAG3 in the form of a commercial lyophilized reagent to be labeled with 99mTc. Test lots were initially prepared based on the European and American formulations with final pH 6 and the results were unsatisfactory. The change in pH to 12 resulted in an increased radiochemical purity, however without 99mTc labeling stability in up to 4 hours. Testing with the Cuban formulation at pH 9.5 resulted in radiochemical purity (% PRq) greater than 90% up to 4 hours of labeling. The limit specified for % PRq is 90%. Based on the above results, the components of the IPEN formulation were defined and three batches of the lyophilized product with 100 vials each were evaluated for radiochemical and biological stability up to about 9 months. Four pilot batches produced with 230 freeze-dried vials each are currently in stability studies. The 99mTc labeling activities were 0.74 3,700 MBq (5 - 100 mCi) in 3 mL 0.9% NaCl. The % PRq was determined in up to 240 minutes of labeling using thin layer chromatography with 2 different systems: methyl ethyl ketone:ethyl acetate 60:40 (v/v) on iTLC-SG strip for determination of 99mTcO4- in Rf = 1 and acetonitrile:water 50:50 (v/v) on Whatman 3MM strip for determination of 99mTcO2 in Rf = 0. The results were expressed as mean % PRq ± Standard Deviation (SD) considering duplicate analyzes of two vials for each of the labeling times. 0.74 MBq (200 μCi) of minimal labeling activity or 129.5 MBq (3,500 μCi) of maximum labeling activity in 0.1 mL 0.9% NaCl were administered in Swiss mice and radioactivity in the kidneys, liver and gallbladder, stomach, intestine and carcass was measured after 45 minutes. Values were expressed as mean % ID (Injected Dose) ± SD. The acute toxicity study was performed on a group of 10 male Balb/c mice, weighing between 20-30 g with about two month old, for a period of 14 days. All quality control results met the specified criteria. It was found that the preparation and addition of the reactants, the amount of stannous chloride and the pH value in the intermediate steps were important factors in obtaining a radiopharmaceutical for labeling with 99mTc as in the case of MAG3.

An improved method is introduced for prediction of local tumor control following lung stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC) patients using 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET). A normalized background-corrected tumor maximum Standard Uptake Value (SUVcmax) is introduced using the mean uptake of adjacent aorta (SUVref), instead of the maximum uptake of lung tumor (SUVmax). This method minimizes the variations associated with SUVmax and objectively demonstrates a strong correlation between the low SUVcmax (< 2.5-3.0) and local control of post lung SBRT. The false positive rates of both SUVmax and SUVcmax increase with inclusion of early (<6 months) PET scans, therefore such inclusion is not recommended for assessing local tumor control of post lung SBRT. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2013.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Os conhecimentos fundamentais sobre neoplasias estão aumentando rapidamente, no entanto, poucos avanços estão sendo obtidos na clínica para terapia e diagnóstico de tumores. Por este motivo o desenvolvimento de drogas alternativas é de extrema importância na tentativa de melhorar o prognóstico da doença e aumentar a sobrevida dos pacientes. Peçonhas de serpentes constituem fontes naturais de substâncias bioativas com grande potencial terapêutico. O objetivo deste trabalho foi identificar e caracterizar o efeito antitumoral da peçonha de Crotalus durissus terrificus (PC) e seus polipeptídeos, Crotoxina e Crotamina, sobre linhagens de tumores cerebrais, bem como avaliar seu potencial radiossensibilizador e sua aplicabilidade para detecção de tumores in vivo. Os resultados obtidos demonstraram que PC possui potente efeito antitumoral sobre tumores benigno, adenoma de pituitária (GH3), e maligno, glioblastoma multiforme (RT2), com IC50 de 0,96&#956;g/mL e 2,15&#956;g/mL, respectivamente. Este efeito antitumoral ocorre via apoptose, é ciclo específico e dependente de cálcio extracelular, um importante fator para a atividade fosfolipásica A2 do principal componente da PC, Crotoxina. PC também apresentou um importante efeito radiossensibilizador, tornando os tumores até 66% mais sensíveis à radioterapia. O efeito antitumoral da PC pode ser atribuído, pelo menos parcialmente, aos polipeptídeos Crotoxina e Crotamina, que também induziram apoptose das células de tumores cerebrais. Estes componentes da PC interagiram de maneira específica com tumores sólidos malignos in vitro e foram capazes de detectar foco tumoral in vivo. Apesar da conhecida nefrotoxicidade e neurotoxicidade da PC, o tratamento agudo com a dose antitumoral da PC estabelecida in vitro não foi tóxico para os animais analisados. Estes resultados indicam o potencial biotecnológico da PC como fonte de moléculas moldes para o desenvolvimento de fármacos e radiofármacos para a terapia e/ou diagnóstico do câncer. / The neoplasms basic knowledge is increasing quickly, however, few advances have been reached in clinical therapy and diagnosis of tumours. For this reason, the development of alternative drugs is relevant in the attempt to improve prognosis and to increase the patients survival. Snake venoms are natural sources of bioactive substances with therapeutically potential. The objective of this work was to identify and to characterise the antitumoral effect of Crotalus durissus terrificus venom (PC) and its fractions, Crotoxin and Crotamine, on brain tumours, as well as, to evaluate its radiosensibilising potential and its applicability for tumours detection in vivo. The results demonstrated that PC possess a powerful antitumoral effect for benign (pituitary adenoma) and malignant (glioblastoma multiforme) tumours with IC50 values of 0,96&#956;g/mL and 2,15&#956;g/mL, respectively. This antitumoral effect is mediated by apoptosis induction; it is cell cycle specific and dependent of extracellular calcium, an important factor for Crotoxin phospholipase A2 activity. Besides being a powerful antitumoral agent, PC also presented an important radiosensibilising effect, increasing in 66% the tumour radiotherapy sensitivity. The PC antitumoral effect can be ascribed, at least partially, to the polypeptides Crotoxin and Crotamine that also induced brain tumours apoptosis. These PC polypeptides specifically interacted with malignant tumours in vitro and demonstrated to be capable to detect tumoral focus in vivo. In spite of the PC known nephrotoxicity and neurotoxicity, acute treatment with its antitumoral dose estabilished in vitro was not found to be toxic for the analysed animals. These results indicate the biotechnological potential of PC as source of templates for pharmaceutical and radiopharmaceutical design for cancer therapy and diagnosis.

O câncer tem levado a óbito milhões de pessoas em todo o mundo. Apesar dos conhecimentos a respeito dos mecanismos moleculares desta patologia estarem aumentando rapidamente, poucos avanços estão sendo conseguidos nas clínicas de terapia e diagnósticos de tumores, o que torna de extrema importância o desenvolvimento de novas moléculas para fins terapêuticos e diagnósticos. Toxinas animais possuem uma diversidade de atividades biológicas e farmacológicas e têm se mostrado fonte rica de moléculas com potencial terapêutico. Diversos trabalhos têm sido realizados com toxinas de animais terrestres, mas toxinas de peixes venenosos marinhos são uma fonte potencial e ainda inexplorada de novas moléculas. Neste trabalho a peçonha bruta do peixe-escorpião Scorpaena plumieri (SPB) e uma enzima gelatinolítica (SPGP) purificada a partir desta peçonha, foram avaliadas quanto a sua aplicabilidade na detecção diferencial de tumores. Os resultados in vitro demonstraram que tanto SPB quanto SPGP possuem potente efeito antitumoral sobre células de glioblastoma p-53 selvagem (DL50= 3,90,98&#956;g/mL e 8,00x10-122,94x10-12M, respectivamente) e células de carcinoma ascítico de Ehrlich (DL50=14,052,95&#956;g/mL e 1,22x10-116,56x10-12M, respectivamente), sendo células de glioblastoma p53-mutante mais resistentes, para ambas as substâncias (DL50 > 125&#956;g/mL para SPB e DL50 > 1,39x10-9M para SPGP). As alterações morfológicas observadas nestas linhagens quando tratadas com SPB e SPGP, e os dados da coloração com DAPI, indicam que o efeito antitumoral destas substâncias ocorre via apoptose. Sondas radioativas de SPB ([99mTc]SPB) e SPGP ([131/125I]SPGP) foram sintetizadas com alta atividade específica e alta pureza radioquímica. Estudos de biodistribuição, realizados por injeções via endovenosa caudal, em camundongos implantados nos coxins plantares com tumor de Ehrlich mostraram que a SPB não é captada significativamente pelo tumor. Por outro lado, a SPGP foi significativamente captada pela pata com tumor, em todos os tempos avaliados (p<0,05). A administração intratumoral da [125I]SPGP elevou os níveis desta molécula no tumor e reduziu a captação em outros órgãos. Estudos em animais com edema demonstraram que a SPGP apresenta um tempo de residência maior na região tumoral do que em regiões inflamatórias. Estudos hematológicos e histopatológicos realizados demonstraram que a SPB e SPGP não apresentam toxicidade aguda, mesmo em concentrações dez vezes maiores que as utilizadas nos experimentos de biodistribuição e detecção de tumores. Estes resultados são inéditos e mostram o potencial da SPGP como molde para o desenvolvimento de fármacos e radiofármacos para terapia e diagnóstico de tumores. / Cancer has killed millions of people worldwide. Despite the increasing knowledge about the molecular basis of tumor development, few advances have been reached in clinical therapy and diagnoses, which shows the importance of new drugs development for therapeutic and diagnosis purpose. Venomous creatures have been studied as potential sources of pharmacological agents and physiological tools. A lot of work has been done about biological activity of terrestrial animals, but comparatively less research has been undertaken on venomous marine creature, particularly fish, which means that marine toxins represent a vast and unexplored source of novel molecules with therapeutical potential. In this work, the scorpionfish Scorpaena plumieri crude venom (SPB) and a gelatinolytic protease purified from this venom (SPGP) were evaluated for their applicability for in vivo tumor detection. In vitro results showed that both, SPB and SPGP, possess a powerful antitumor effects on p53-wild-type glioblastoma cells (LD50= 3,90,98&#956;g/mL and 8,00x10-122,94x10-12M, respectively) and Ehrlich ascites carcinoma cells (LD50=14,052,95&#956;g/mL and 1,22x10-116,56x10-12M, respectively). P53- mutant glioblastoma cells were more resistant to both, SPB and SPGP treatment (LD50 > 125&#956;g/mL and LD50 > 1,39x10-9M, respectively). The morphological changes observed in the cell lines treated with SPB and SPGP, and the data of DAPI staining, indicate that the antitumor effect of these substances occurs via apoptosis. Radioactive probes of SPB ([99mTc] SPB) and SPGP ([125I] SPGP) with high specific activity and high radiochemical purity were synthesized. Data of biodistribution studies, performed by intravenous injections in Swiss mice bearing Ehrlich carcinoma cells, showed that SPB has poor uptake in tumor region. On the other hand, SPGP had a substantial uptake in tumor at all analyzed times. Intratumoral administration of [125I]SPGP increased its uptake by the tumoral region and substantially reduced the uptake by other organs. Biodistribution studies in animals with edema confirmed that SPGP presents longer residence time in tumoral region than into inflammation site. Hematologic and histopathologic studies showed that SPB and SPGP did not present acute toxicity, even at concentrations ten times higher than those used in biodistribution studies. These results indicate the potential of SPGP as template for the development of new drugs and radiopharmaceuticals for tumors diagnosis and therapy.