Em pacientes portadores de insuficiência coronariana com prognóstico desfavorável pela presença de disfunção ventricular significativa, a pesquisa de viabilidade miocárdica traz contribuições ao predizer a possibilidade de recuperação contrátil após revascularização. Os segmentos miocárdicos com disfunção contrátil por hipoperfusão podem melhorar o desempenho contrátil restabelecido o aporte sanguíneo local, indicando que a revascularização miocárdica, quando bem indicada, é capaz de melhorar a sobrevida deste grupo de pacientes. Realizou-se pesquisa de tese de doutoramento do Departamento de Radiologia da Universidade de São Paulo na unidade de medicina nuclear da Nuclear Medcenter/Hospital SOCOR em Belo Horizonte, Minas Gerais. O objetivo do estudo foi verificar se a cintilografia de perfusão miocárdica com duplo-isótopo (99mTcsestamibi/ cloreto de tálio-201) como método radioisotópico para identificação do músculo viável, tem sua especificidade aumentada com a inclusão de informações sobre reserva contrátil miocárdica obtidas simultaneamente através do gatedSPECT (imagens tomográficas do coração sincronizadas ao eletrocardiograma) na vigência de baixas doses de dobutamina de forma semelhante ao ecocardiograma. Estudou-se 54 pacientes com infarto do miocárdio prévio, encaminhados ao serviço de medicina nuclear para realização de pesquisa de viabilidade miocárdica. Foram excluídos do estudo os pacientes que no seguimento não foram revascularizados ou que não realizaram controle cintilográfico pós-cirúrgico, uma vez que considerouse como critério de viabilidade a melhora da contratilidade miocárdica após a revascularização. Avaliou-se os parâmetros de viabilidade (integridade celular e reserva contrátil) e o desempenho contrátil pós-cirúrgico de 260 segmentos miocárdicos de treze pacientes revascularizados. Os pacientes estudados foram submetidos a cintilografia de perfusão miocárdica duoisotópica em protocolo de dois dias com imagens tomográficas do coração obtidas em gamma-camera de duas cabeças, modelo Varicam (Elscint) e processadas em estação de trabalho eNTEGRA(GE). As imagens de estresse foram adquiridas em sincronia com o ECG (gated SPECT) em condições basais e na vigência de baixa dose de dobutamina (10 a 15g/Kg/min) 45 minutos após a administração endovenosa do 99mTcsestamibi no pico do exercício isotônico (esforço) ou da ação de agentes farmacológicos (estresse farmacológico) e nas etapas de repouso e redistribuição do cloreto de tálio-201, 20 minutos e quatro a seis horas após a administração endovenosa do radioisótopo em condições basais. Os pacientes operados foram submetidos a um segundo estudo cintilográfico de perfusão miocárdica com gated SPECT, no período mínimo de três meses após o procedimento, para avaliação da performance contrátil pós-cirúrgica. Para análise dos achados cintilográficos, dividiu-se o coração em 20 segmentos que receberam diferentes escores, permitindo a quantificação da perfusão e função miocárdica pelo Cedars Sinai Quantitative Pefusion SPECT QPS/QGS(GE),. Analisou-se o padrão perfusional nas etapas de estresse, repouso e redistribuição e de função (análise do espessamento sistólico, motilidade parietal, valores de fração de ejeção e volumes cardíacos do ventrículo esquerdo) em condições basais e sob estímulo inotrópico. No tratamento estatístico a análise do espessamento sistólico foi o parâmetro considerado significativo para avaliação da reserva contrátil miocárdica pelo método. Houve incremento na especificidade da pesquisa de viabilidade miocárdica pelo método radioisotópico realizado, demonstrando valores de especificidade superiores aos encontrados na literatura. As contribuições do método se mostraram efetivas / In patients with coronariopathy in the setting of ventricular dysfunction having an unpromising prognostic, the myocardial viability must be assessed thus, bringing contribution as it can predict the myocardial dysfunction recovery after revascularization. The myocardial segments with contractile dysfunction as a consequence of hypoperfusion can improve wall motion after perfusion recovery, demonstrating that myocardial revascularization, whenever suggested, can improve survival to this group of patients. This research is a PHD thesis from Radiology Department of São Paulo University and was performed at a nuclear medicine unit - Nuclear Medcenter/SOCOR hospital - in Belo Horizonte, Minas Gerais. The aim of the study was to check if dual isotope perfusion myocardial gated SPECT (99mTc-sestamibi/thallium-201) as a nuclear medicine procedure to the identification of viable myocardium, can improve the method specificity with addition of contractile reserve information obtained simultaneously by gated SPECT with low dose of dobutamine, similar to the echocardiogram. 54 patients with myocardial stroke, referred to the nuclear medicine unit to seek myocardial viability have been studied. Patients that do not have been submitted to revascularization or that did not undergo the post surgery control were excluded, as the parameter considered for viability was the wall motion recovery after revascularization. 260 myocardial segments in 13 patients had their viability parameters (cellular integrity and contractile reserve) as the contractile performance after surgery evaluated. The images were acquired by a Varicam (Elscint) double head gamma camera and processed by eNTEGRA (GE) workstation. The gated SPECT stress images were performed in baseline conditions and with low-dose dobutamine (10 a 15g/Kg/min) 45 minutes after intravenous injection of 99mTc-sestamibi.on the peak of isotonic exercise or pharmacologic stress. The rest and redistribution images were acquired , 20 minutes and 4 or 6 hours after intravenous injection of thallium-201 at rest. The revascularizated patients were also submitted to a second gated SPECT study at least 3 months after surgery for evaluation of the contractile performance. In order to analyze the scintigraphic findings, the heart was divided into 20 segments that received different scores for quantification of myocardial perfusion and function by Cedars Sinai Quantitative Perfusion SPECT QPS/QGS(GE),. The perfusion pattern of stress, rest and redistribution and the parameters of function (wall thickening and motion, ejection fraction and cardiac volumes analysis) at baseline conditions and by inotropic effect. By the statistics analysis wall thickening was considered significant to evaluate the myocardial contractile reserve by this method. There was improvement in the specificity of the radioisotopic research showing specificity values larger than those found in literature. These method contributions were effective

INTRODUÇÃO: O limite de tempo de isquemia renal sem causar um dano permanente à função ainda é um questionamento pertinente na prática cirúrgica urológica. Algumas cirurgias requerem um campo cirúrgico menos sangrante, necessitando de uma interrupção temporária do fluxo sanguíneo para o parênquima renal através de clampeamento do pedículo. Este estudo objetivou avaliar qual técnica de clampeamento em isquemia isotérmica é superior, em termos de preservação da função renal. MÉTODOS: Neste estudo, foram utilizados 28 coelhos da raça New Zealand distribuídos em quatro grupos de forma randomizada e submetidos à laparotomia com interrupção do fluxo sanguíneo renal esquerdo, conforme grupo: grupo 1 - Controle, sem isquemia (4 animais), grupo 2 - Isquemia seletiva (8 animais), grupo 3 - Isquemia não-seletiva (8 animais) e grupo 4 - Isquemia não-seletiva intermitente (8 animais). Os animais foram submetidos à análises cintilográficas da função renal com mercaptoacetiltriglicina (MAG3) e dosagens séricas de creatinina no pré-operatório, no primeiro, terceiro e sétimo dias pós-operatórios. Após 15 dias da cirurgia, os animais foram sacrificados e os rins submetidos à análise histológica. RESULTADOS: A análise cintilográfica da função renal mostrou que os três grupos submetidos à isquemia apresentaram um agravo semelhante, nas primeiras 24 horas; não havendo diferença estatística entre eles no tocante a perda de função renal do rim esquerdo (p= 0,165), neste período. No exame do terceiro dia pós-operatório, houve diferença estatística (p= 0,006) entre os grupos não-seletivo (3) e o intermitente (4), mostrando uma superioridade do fator desclampeamento na proteção à função renal. No sétimo dia pós-operatório, o grupo do clampeamento seletivo (2) mostrou-se superior (p< 0,001) ao grupo não-seletivo (3), mas não apresentou diferença estatística em relação ao grupo intermitente (4). Este último, por sua vez, também apresentou-se superior ao grupo 3, com diferença estatística (p< 0,001). Após sete dias não foi observada diferença estatística entre os grupos 2 e 4. A histologia e a creatinina não mostraram diferença estatisticamente significante entre os grupos isquêmicos. Do ponto de vista funcional, a isquemia seletiva e a intermitente foram superiores em relação a não-seletiva. CONCLUSÃO: O modelo utilizado neste estudo mostrou uma superioridade da isquemia isotérmica seletiva e da intermitente em relação a não-seletiva na proteção da função renal. Não houve diferença entre o clampeamento seletivo e o intermitente não-seletivo na função do rim / INTRODUCTION: The time limit of renal ischemia with no permanent damage to renal function still remains as a pertinent question in urologic surgical practice. Several procedures require a bloodless surgical field most of time needing an interruption of blood flow to the renal parenchyma and they can require hilum control and clamping. This study assessed which normothermic clamping technique is superior in order to preserve kidney function. METHODS: In this project, 28 New Zealand rabbits were distributed in four groups by randomization and submitted to laparotomy and blood flow interruption of left kidney: Group 1 - Control, no ischemia (four animals), Group 2 Selective ischemia (eight animals), Group 3 Nonselective ischemia (eight animals) e Group 4 intermittent nonselective ischemia (eight animals). The animals were submitted to renal scintigraphy with mercaptoacetiltriglicin (MAG3) and serum creatinine analysis preoperatively and at days 1, 3 and 7 after left hilum clamping. The animals were submitted to nephrectomy and immediately sacrificed and the kidneys subjected to blinded evaluation by a nephropathologist. RESULTS: Renal scintigraphy showed equal damage in the three groups in first 24 hours, with no statistical difference in loss of left kidney function (p= 0,165) in this period. At third day examination, there was statistical difference (p= 0,006) between the nonselective group (3) and intermittent one (4), demonstrating a superiority of declamping factor in renal function protection. At seventh postoperative day, selective group (2) proved to be better (p< 0,001) than nonselective one (3), however there was not statistical difference between group 2 and the intermittent group (4). The intermittent clamping group was also superior to group 3 (p< 0,001). Histopathology and serum creatinine did not demonstrate statistical difference among groups. Functionally, selective and intermittent warm ischemia techniques are better than nonselective one. CONCLUSION: The model used in this study presented a superiority of selective clamping and intermittent arteriovenous clamping in shielding the renal function. No difference occurred between selective clamping and intermittent nonselective one

A doença arterial coronária (DAC) é uma das principais causas de morte no mundo. A detecção precoce é importante para prevenir este tipo de ocorrência. O método considerado padrão ouro para avaliar obstruções parciais críticas é a cinecoronariografia, uma técnica invasiva, trabalhosa e cara. Existem métodos não invasivos que podem ser utilizados para estabelecer este diagnóstico. A base do diagnóstico não invasivo da DAC tem sido a análise seqüencial dos fatores de risco e dos resultados do teste ergométrico e da cintilografia de perfusão do miocárdio. Muitos pesquisadores demonstraram que a utilização diagnóstica apropriada da cintilografia de perfusão do miocárdio e da cinecoronariografia é naqueles pacientes que têm probabilidade intermediária e alta para DAC, respectivamente. Apesar desta informação ser útil, ela é utilizada de forma limitada na prática clínica, devido à dificuldade em classificar apropriadamente os pacientes. Desde os artigos pioneiros de Lotfi A. Zadeh, a lógica fuzzy tem sido aplicada em diversas áreas. Ela é especialmente útil nas aplicações médicas, uma vez que as informações utilizadas no processo de decisão são incertas. Neste trabalho, foram desenvolvidos e testados modelos baseados na teoria de conjuntos fuzzy, para selecionar os pacientes que devem ser submetidos a cintilografia de perfusão do miocárdio e a cinecoronariografia. Utilizou-se grupo de 1053 pacientes para desenvolver os modelos e outro de 1045 para testá-los. Comparou-se o desempenho dos modelos com o de médicos especialistas utilizando-se curvas ROC e observou-se que os modelos fuzzy têm desempenho igual ou superior a estes especialistas na seleção dos pacientes que devem ser submetidos a cintilografia e cinecoronariografia, podendo, portanto, ser de grande auxílio ao médico na realização desta tarefa. / Coronary artery disease (CAD) is a worldwide leading cause of death. Early detection is important to prevent such sort of outcome. The gold standard method for evaluating critical partial occlusions is coronary arteriography, a catheterization technique which is invasive, time consuming, and costly. There are noninvasive approaches for early detection of CAD. The basis for the noninvasive diagnosis of CAD has been laid in a sequential analysis of the risk factors, and the results of treadmill electrocardiography and myocardial perfusion scintigraphy. Many investigators have demonstrated that appropriate diagnostic applications of myocardial perfusion scintigraphy and coronary arteriography are in patients who have an intermediate and a high likelihood of disease, respectively. Although this information is useful, it is only partially utilized in the clinical practice due to the difficulty to properly classify the patients. Since the seminal article by Lotfi A. Zadeh fuzzy logic has been applied in numerous areas. It is especially suited to medical applications, since much of the information required for decision-making is uncertain. In this paper, we proposed and tested models to select patients that have to undergo myocardial perfusion scintigraphy and coronary arteriography based on fuzzy set theory. It was used a group of 1053 patients to develop the models and another one of 1045 patients to test them. It was utilized ROC curves to compare the performance of the models with the ones of experts’ physicians and it was observed that the fuzzy models have a performance equal or superior to the experts in the selection of the patients that should perform scintigraphy and coronary arteriography, therefore, they could be a useful tool to assist the general practitioner in this task.

Um grande problema em atletas com fraturas por estresse é o tempo necessário para sua recuperação completa. Nenhum método de imagem tem se mostrado eficaz em apresentar dados objetivos com relação ao tempo de recuperação dos atletas em casos de fraturas por estresse. Dois grupos foram incluídos no nosso estudo: grupo I consistente de 21 atletas com suspeita clínica de fratura de estresse (13 masculinos, idade média de 31,62 &#61617; 9,39) e grupo II consistente de 10 atletas sem sinais clínicos de fraturas de estresse (grupo controle) (seis masculinos, idade média 29,80 &#61617; 3,94). Todos os indivíduos do grupo I tiveram seguimento mínimo de seis meses e foram submetidos ao mesmo protocolo de reabilitação. Todos os atletas foram submetidos à ressonância magnética e cintilografia óssea com intervalo, entre os exames, inferior a sete dias. Um índice quantitativo foi obtido utilizando a técnica de ROI, comparando o lado afetado com o contralateral não afetado. Esta análise quantitativa foi comparada à análise semiquantitativa da ressonância magnética. Ambos os métodos mostraram 100% de sensibilidade; entretanto, sinais inespecíficos foram encontrados em 40% dos atletas assintomáticos na ressonância magnética e na cintilografia óssea. A média de captação de MDP-Tc99m na perna sintomática foi estatisticamente diferente no grupo I (2,54 &#61617; 0,77) em comparação ao grupo II (1,05 &#61617; 0,11) (p < 0,001). Um índice de 1,30 foi considerado ponto crítico onde 99% dos atletas apresentarão diagnóstico de fratura de estresse. Uma equação de regressão foi obtida, associando o tempo de recuperação necessário para o atleta e o índice calculado. Na presente amostragem de pacientes, o índice obtido por meio da cintilografia óssea nos permite obter um método objetivo para estimar o apropriado tempo de recuperação após um diagnóstico de fratura por estresse da tíbia. Entretanto, mais estudos prospectivos, com maior amostragem, são necessários para comprovar nosso achado. / A major problem in athletes with stress fractures is the length of resting time required for complete recovery. No imaging tool has been capable of offering objective data regarding the appropriate recovery time in athletes with stress fractures. Two groups of athletes were included in our study: Group I consisted of 21 athletes with clinical suspicion of tibial stress fracture (13 male; mean age + SD: 31.62 + 9.39) and, Group II consisted of 10 athletes without clinical signs of stress fracture (control group) (6 male; mean age + SD: 29.80 + 3.94). All individuals of Group I had minimum 6 months of follow up and the symptoms were recorded according to the same rehabilitation protocol. All athletes underwent to bone scintigraphy and MRI, with a mean interval between them no longer than 7 days. A quantitative index was obtained using ROI technique, comparing the affected to the non affected leg. This quantitative analysis was compared to a semi quantitative evaluation of MRI findings). Both methods showed 100% sensitivity; however, non specific signs were found in 40% of asymptomatic athletes either by MRI or by bone scan. The mean uptake of MDP-Tc99m in affected limbs were statistically different in Group I (2.54 + 0.77) in comparison to Group II (1.05 + 0.11) (p<0.001). An index of 1.30 was considered a critical point where 99% of athletes will present the clinical diagnosis of tibial stress fracture. A regression equation was obtained associating the time of recovery required for each athlete with the uptake index calculated. In the present sample of athletes the uptake index obtained through bone scintigraphy allowed us to obtain an objective method to estimate the appropriate recovering time after the tibial stress fracture diagnosis. However, more prospective studies using larger samples are needed to prove that assumption.

Introdução: A quantificação da isquemia miocárdica é um dado de grande auxílio na tomada de decisões clínicas ou intervencionistas no tratamento da doença arterial coronária (DAC) avançada. Dentre os métodos disponíveis para esta finalidade, se destacam a cintilografia de perfusão miocárdica (CPM) e a ressonância magnética cardíaca (RMC), que além de fornecerem informações quanto à alteração de motilidade entre o estresse e o repouso, são capazes de analisar a perfusão miocárdica. Neste estudo, investigamos a correlação e a concordância entre esses dois métodos em pacientes com DAC sintomática e avançada. Métodos e Resultados: Cinquenta e três pacientes com DAC avançada (padrão obstrutivo triarterial) não elegíveis para revascularização completa devido à extensão e caráter difuso das lesões foram submetidos à RMC e à CPM. A maioria (57%) apresentava sintomas limitantes (angina CCS 3 ou 4). Na quantificação da carga isquêmica, o percentual de miocárdio isquêmico total (%Mioisquêmico) foi significativamente maior na RMC do que na CPM (25,3±13,7% vs. 20,5±13,5%, respectivamente; P = 0,02). A RMC identificou baixa carga isquêmica em apenas 15% dos pacientes, enquanto pela CPM 53% dos pacientes foram assim classificados. Foram encontradas correlações fracas entre os métodos para o %Miofixo, no %Mioestresse e %Mioisquêmico (coeficiente de Spearman variando de 0,06 a 0,54), assim como uma fraca concordância (kappa de 0,11 e bias elavado de 9,3 para %Mioisquêmico). De um total de 159 territórios coronarianos, 18 (11%) apresentaram grandes discordâncias (%Mioisquêmico pela CPM < 10% e > 20% pela RMC) em regiões do ventrículo esquerdo com alta probabilidade pré-teste de possuírem isquemia importante (miocárdio viável em território irrigado por artéria coronária ocluída cronicamente). Conclusão: A quantificação da carga isquêmica estresse-induzida avaliada pela CPM e pela RMC possui fraca correlação e concordância em pacientes com DAC avançada e complexa, com a RMC demonstrando uma maior carga isquêmica do ventrículo esquerdo, principalmente nas regiões com infarto prévio / Introduction: The quantification of myocardial ischemia is a key element in the decision-making process in patients with advanced coronary artery disease (CAD). Single-photon emission computed tomography (SPECT) and cardiovascular magnetic resonance (CMR) are non-invasive tools for myocardial perfusion assessment. We investigated the correlation and agreement between these two methods in patients with symptomatic and complex CAD. Methods and Results: Fifty-three patients with advanced CAD (multivessel obstructive disease) not eligible for complete revascularization due the extension and diffuseness of the disease underwent both CMR and SPECT. The majority (57%) presented limiting symptoms (angina CCS 3 or 4). The quantification of the ischemic burden revealed that the mean percentage of total ischemic myocardium (%Myoischemic) was significantly higher as assessed by CMR compared with by SPECT (25.3±13.7% vs. 20.5±13.5%, respectively; P = 0.02). There were no significant correlations between CMR and SPECT regarding %Myostress (r = 0.23, p = 0.09), fixed (r = 0.20, p = 0.14), or ischemic (r = 0.11, p = 0.44). While SPECT classified 28 patients (53%) as having low ischemic burden (%Myoischemic < 10%), CMR classified only 8 patients (15%) in this category. Poor correlations between the two methods were found for %Myostress, %Myoischemic, and %Myofixed (Spearman\'s rho ranging from 0.06 to 0.54), depicting also slight agreement (kappa of 0.11 and bias as high as 9.3% for %Myoischemic). On a per-segment-based analysis, 18 coronary territories (11%) of the total 159, presented highly disagreements (%Myoischemic by SPECT < 10% and > 20% by CMR) in LV regions likely to have severe ischemia (viable myocardium supplied by chronically occluded vessels. Conclusion: The quantification of inducible myocardial ischemia by SPECT and CMR disagrees in patients with advanced and complex CAD, with CMR displaying greater left ventricular ischemic burden, particularly in patients with a previous myocardial infarction

<p>Liquid chromatography – mass spectrometry (LC-MS) methods were developed for the analysis of positron emission tomography (PET) radiotracers in biological matrices. Additionally, radiotracer chemistry was explored as an analytical tool for supporting LC-MS method development and imaging molecular interactions in miniaturised chemical analysis systems.</p><p>Conventional radiodetection methods can offer high sensitivity in the analysis of radiotracers in biological matrices, although with the short half-life of PET tracers, this mass sensitivity decreases rapidly with time. This limits the time frame for analysis, and may compromise the precision and accuracy of the later measurements. Performing LC-MS analysis of the dominant stable isotope form of the tracer removes such time restrictions.</p><p>An LC-MS/MS method was developed for determination of the tracer flumazenil in human plasma, with high inter-assay precision (RSD < 7%) and accuracy (95 – 104%). The method was applied in a multiple scan PET study where the plasma concentration spanned from 0.07 to 0.21 nM. The method removed the time restrictions associated with radiodetection methods and thus provided the opportunity of analysing a greater number of samples than would have been possible with radioanalysis.</p><p>Furthermore, an LC-MS/MS method was developed that provided an efficient metabolic screening tool of potential PET tracers, whereby the substrates could be collected directly from 11C-labelling batches. This permitted repeated incubation experiments without the need of repeated labelling syntheses. A para-methoxy-benzamide analogue of the radiotracer WAY-100635 was thus identified as a potential tracer with improved metabolic stability. Additionally, a capillary LC-MS method was developed with rapid (0.75 min) and efficient (> 99%) on-line high flow-rate extraction for determination of metabolic stability of PET radiotracers.</p><p>Finally, the concept of radionuclide imaging of miniaturised chemical analysis systems was demonstrated with the direct study of interactions within capillary extraction columns and microchannels moulded in a plastic CD and poly(dimethylsiloxane).</p>

Liquid chromatography – mass spectrometry (LC-MS) methods were developed for the analysis of positron emission tomography (PET) radiotracers in biological matrices. Additionally, radiotracer chemistry was explored as an analytical tool for supporting LC-MS method development and imaging molecular interactions in miniaturised chemical analysis systems. Conventional radiodetection methods can offer high sensitivity in the analysis of radiotracers in biological matrices, although with the short half-life of PET tracers, this mass sensitivity decreases rapidly with time. This limits the time frame for analysis, and may compromise the precision and accuracy of the later measurements. Performing LC-MS analysis of the dominant stable isotope form of the tracer removes such time restrictions. An LC-MS/MS method was developed for determination of the tracer flumazenil in human plasma, with high inter-assay precision (RSD &lt; 7%) and accuracy (95 – 104%). The method was applied in a multiple scan PET study where the plasma concentration spanned from 0.07 to 0.21 nM. The method removed the time restrictions associated with radiodetection methods and thus provided the opportunity of analysing a greater number of samples than would have been possible with radioanalysis. Furthermore, an LC-MS/MS method was developed that provided an efficient metabolic screening tool of potential PET tracers, whereby the substrates could be collected directly from 11C-labelling batches. This permitted repeated incubation experiments without the need of repeated labelling syntheses. A para-methoxy-benzamide analogue of the radiotracer WAY-100635 was thus identified as a potential tracer with improved metabolic stability. Additionally, a capillary LC-MS method was developed with rapid (0.75 min) and efficient (&gt; 99%) on-line high flow-rate extraction for determination of metabolic stability of PET radiotracers. Finally, the concept of radionuclide imaging of miniaturised chemical analysis systems was demonstrated with the direct study of interactions within capillary extraction columns and microchannels moulded in a plastic CD and poly(dimethylsiloxane).

Radionuclide molecular imaging is an emerging multidisciplinary technique that is used in modern medicine to visualise diseases at cellular and molecular levels. This thesis is based on five papers (I-V) and focuses on the development of site-specific radiolabelled recombinant anti-HER2 Affibody molecules and preclinical evaluations in vitro and in vivo of the labelled conjugates. This work is part of a preclinical development of an Affibody molecule-based tracer for molecular imaging of HER2 expressing tumours. Papers I and II report the evaluation of the Affibody molecule ZHER2:2395-C, site-specifically labelled with the radiometals 111In (for SPECT) and 57Co (as a surrogate for 55Co, suitable for PET applications) using a thiol reactive DOTA derivative as a chelator. Both conjugates demonstrated very suitable biodistribution properties, enabling high contrast imaging just a few hours after injection. Papers III and IV report the development and optimization of a technique for site-specific labelling of ZHER2:2395-C with 99mTc using an N3S chelating peptide sequence. 99mTc-ZHER2:2395-C demonstrated high and specific tumour uptake and rapid clearance of non-bound tracer from the blood, resulting in high tumour-to-non-tumour ratios shortly after injection, enabling high contrast imaging. In addition, in the study described in paper IV, freeze-dried kits previously developed for 99mTc-labelling were optimised, resulting in the development of a kit in which all the reagents and protein needed for labelling of ZHER2:2395-C with 99mTc were contained in a single vial. Paper V reports the evaluation of an anti-HER2 Affibody molecule, ABY-025, with a fundamentally re-engineered scaffold. Despite the profound re-engineering, the biodistribution pattern of 111In-ABY-025 was very similar to that of two variants of the parental molecule. It seems reasonable to believe that these results will also be applicable to Affibody molecules towards other targets. Hopefully, this work will also be helpful in the development of other small proteinaceous tracers.

Thesis (D.Tech.: Radiography)-Dept. of Radiography, Durban Institute of Technology, 2006 xxiii, 166 leaves / The purpose of this study was to evaluate 99mTc- methoxyisobutylisonitrile (MIBI) imaging, in terms of sensitivity and specificity, for non invasively detecting extracutaneous involvement of Kaposi’s sarcoma (KS) and for differentiating pulmonary infection from malignancy in acquired immunodeficiency syndrome (AIDS) patients before and after treatment. Current investigations are invasive.

The rapid discovery of novel therapeutic agents, targeting the specific mechanism of cancer progression, invasion and angiogenesis, necessitates the development and validation of efficient techniques to assess the therapeutic efficacy of these drugs in vivo. Recently the development of dedicated PET scanners for the imaging of small animals, such as the microPET system (CTI Concorde R4), has allowed for the high-resolution functional and molecular imaging of murine and rodent models of disease. This study, investigates the ability of microPET imaging, using the 18F labelled 2-fluoro-2-deoxyglucose (FDG) PET tracer, to detect the therapeutic efficacy of novel targeted therapies in a rat model of glioma. This technique potentially allows for the rapid and high-throughput assessment of tumour response and evaluation of efficacy of such therapeutic agents in vivo at the pre-clinical stage and will, consequently, facilitate the translation of these novel drugs from the discovery to the clinical phases. / La découverte accélérée de nouvelles molécules thérapeutiques qui ciblent lesmécanismes de progression du cancer tels que l'invasion et l'angiogenèse, nécessite lamise au point et la validation de techniques efficaces qui permettent d'évaluer l'efficacitéthérapeutique de ces agents in vivo. Le développement récent des scanners detomographie à émission de positron (TEP) dédiés à l'imagerie de petits animaux(microPET, CT! Concorde R4), permet aujourd'hui d'obtenir une image fonctionnelle etmoléculaire de haute résolution des modèles rongeurs. Cette étude s'intéresse au potentieldu 18F-2-fluoro-2-deoxyglucose (FDG) en utilisant l'imagerie microPET dansl'évaluation de l'efficacité de nouveaux agents thérapeutiques dans un modèle de gliomechez le. rat. Cette technique pourrait éventuellement mener à une évaluation rapide et àgrande échelle de la réponse tumorale, ainsi que la mesure de l'efficacité d'agentsthérapeutiques in vivo au stade d'étude préclinique. Globalement, cette étude a pour butde faciliter la transition entre la découverte de nouvelles molécules thérapeutiques et leursapplications cliniques.