In radionuclide therapy it is still common to administer standard activities or to scale administered activity with blunt parameters such as body weight or surface area. This is not ideal because, due to considerable variation in kinetics, large safety margins have to be applied to avoid radiation damage to healthy organs, which causes under-treatment of many patients. To base the administered activity on individual dosimetry, as in other therapy modalities using ionizing radiation, will essentially solve this problem. However, dosimetry in radionuclide therapy is resource-demanding and debilitating for the patient because it involves a number of measurements to determine the kinetics of the therapy radionuclide and needs to be optimized for clinical feasibility. First, the ability to measure radioactivity distributions of radionuclides for therapy was investigated. SPECT measurements of 177Lu, which was later used clinically, showed good spatial resolution and a reasonable quantitative accuracy. A new method to calculate absorbed dose to solid risk organs and tumours was developed and applied in the clinic. Kinetic data were obtained by repeated SPECT measurements. Radiation concentration determined in small volumes of interest could then be multiplied by a constant to obtain absorbed dose because it was shown that cross-fire was negligible in organs with high activity concentration. The new dosimetry method, compared to other methods, was found to give better results with less effort. In addition, a method to calculate absorbed dose to bone marrow was developed and clinically implemented. In 200 patients, individual kinetics and absorbed dose were studied and variations were found to be large. Kidney was the dose-limiting organ in almost all patients (98.5%). Keeping the kidney dose < 23Gy, about half of the patients could receive 5, or up to 10 treatments instead of the stipulated 4.

Tumores carcinoides (neoplasias bem diferenciadas) são tumores neuroendócrinos que podem surgir em diferentes locais anatômicos. Na população a prevalência dos tumores carcinoides é de aproximadamente 10 casos para um milhão de habitantes e sua incidência é maior na quinta e sexta década de vida. Este trabalho propõe um modelo cinético baseado na teoria da análise compartimental em humanos com tumores carcinoides que se submeterão ao tratamento com o radiofármaco [177Lu-DOTA0,Tyr3]Octreotato. Imagens cintilográficas dinâmicas planares, obtidas imediatamente à injeção de 370 MBq (10 mCi) do radiofármaco, foram obtidas com o tomógrafo SPECT (Single Photon Emission Computed Tomography). Por meio da seleção de regiões de interesse (ROI) os resultados foram digitalizados e aplicados ao modelo cinético aqui proposto. A primeira fase do estudo (atividade de 370 MBq) teve como objetivo conhecer os parâmetros cinéticos e subsequentemente, o paciente foi submetido ao protocolo de tratamento radioterápico, a critério médico, aos quatro ciclos de 7,4 GBq (200 mCi) do radiofármaco. Desta forma, foi possível estimar previamente as constantes cinéticas ki,j da biodistribuição do 177Lu-DOTATATO no corpo, sendo ki,j a fração de transferência do i-ésimo compartimento (tecido ou órgão) para o j-ésimo compartimento a partir das ROI demarcadoras dos órgãos de maior captação, a saber: fígado, rins, região vascularizada e tumores carcinoides. A partir das constantes cinéticas ki,j a estimativa de dose absorvida em 26 órgãos foi estimada pelo método MIRD. Os resultados dosimétricos foram compatíveis com outras metodologias descritas na literatura. Para um paciente adulto de 73,6 kg, em termos médios seus rins (sem os protetores renais) recebem a maior intensidade de dose (2,39 mGy/MBq) seguido do fígado (0,70 mGy/MBq). Observou-se que tumores com aproximadamente 100g recebem dose da ordem de 0,52 mGy/MBq independentemente da posição a que se encontram no corpo. Este achado se deve à predominância do dano devido às partículas beta quando comparado à radiação gama que possui pouco rendimento de emissão no processo de decaimento do 177Lu. Portanto, os parâmetros cinéticos que promovem a captação do 177Lu nas células são os principais responsáveis pela composição da dose no tumor e demais órgãos. / Carcinoid tumors (well differentiated neoplasms) are neuroendocrine tumors that may arise in different anatomical locations. The population prevalence of carcinoid tumors is approximately 10 cases per one million inhabitants. Its incidence is higher in the fifth and sixth decade of life. This paper proposes a kinetic model in humans with carcinoid tumors who will underwent treatment with the radiopharmaceutical [177Lu-DOTA0,Tyr3 ]OCTREOTATE based on the theory of compartmental analysis. Dynamic planar scintigraphic images acquired immediately upon injection of 370 MBq (10 mCi) of the radiopharmaceutical were obtained with the SPECT (Single Photon Emission Computed Tomography) tomography. Samples from regions of interest (ROI) were used for the kinetic study applying the kinetic proposed model. The first phase of the study (activity 370 MBq) was aimed to evaluate the kinetic parameters. Subsequently, the patient underwent the [177Lu-DOTA0,Tyr3 ]OCTREOTATE radiotherapy protocol, under the physician\'s prescription (up to four cycles of 7.4 GBq (200 mCi)). Thus, it was possible to previously estimate the kinetic constants ki,j relative to biodistribution of [177Lu-DOTA0,Tyr3 ]OCTREOTATE in the body. The ki,j is the transfer fraction from the ith compartment (a tissue or an organ) to the jth compartment. Only few organs showed significant ROI radioactivity count level, among them: the liver, kidney, blood and carcinoid tumors. The MIRD method and the kinetic constants ki,j were used to estimate the absorbed dose in 26 body organs. The absorbed dose D(mGy/MBq) was comparable to other methods described in the literature. For an adult patient of 73.6 kg, on average, the kidneys (without amino acid protectors) showed the highest dose (2.39 mGy/MBq) followed by liver (0.70 mGy / MBq) and tumor (0.52 mGy/MBq) with a tissue size of approximately 100 g. It was observed that tumors receive the same absorbed dose D(mGy/MBq) regardless their position in the body. This finding is due to the predominance of the tissue radiation damage of beta particles compared to gamma radiation that has little yield emission in the 177Lu decay scheme. Therefore, the kinetic parameters ki,j that promote the uptake of 177Lu in cells are primarily responsible for the absorbed D dose in the tumor and other organs.

Tumores carcinoides (neoplasias bem diferenciadas) são tumores neuroendócrinos que podem surgir em diferentes locais anatômicos. Na população a prevalência dos tumores carcinoides é de aproximadamente 10 casos para um milhão de habitantes e sua incidência é maior na quinta e sexta década de vida. Este trabalho propõe um modelo cinético baseado na teoria da análise compartimental em humanos com tumores carcinoides que se submeterão ao tratamento com o radiofármaco [177Lu-DOTA0,Tyr3]Octreotato. Imagens cintilográficas dinâmicas planares, obtidas imediatamente à injeção de 370 MBq (10 mCi) do radiofármaco, foram obtidas com o tomógrafo SPECT (Single Photon Emission Computed Tomography). Por meio da seleção de regiões de interesse (ROI) os resultados foram digitalizados e aplicados ao modelo cinético aqui proposto. A primeira fase do estudo (atividade de 370 MBq) teve como objetivo conhecer os parâmetros cinéticos e subsequentemente, o paciente foi submetido ao protocolo de tratamento radioterápico, a critério médico, aos quatro ciclos de 7,4 GBq (200 mCi) do radiofármaco. Desta forma, foi possível estimar previamente as constantes cinéticas ki,j da biodistribuição do 177Lu-DOTATATO no corpo, sendo ki,j a fração de transferência do i-ésimo compartimento (tecido ou órgão) para o j-ésimo compartimento a partir das ROI demarcadoras dos órgãos de maior captação, a saber: fígado, rins, região vascularizada e tumores carcinoides. A partir das constantes cinéticas ki,j a estimativa de dose absorvida em 26 órgãos foi estimada pelo método MIRD. Os resultados dosimétricos foram compatíveis com outras metodologias descritas na literatura. Para um paciente adulto de 73,6 kg, em termos médios seus rins (sem os protetores renais) recebem a maior intensidade de dose (2,39 mGy/MBq) seguido do fígado (0,70 mGy/MBq). Observou-se que tumores com aproximadamente 100g recebem dose da ordem de 0,52 mGy/MBq independentemente da posição a que se encontram no corpo. Este achado se deve à predominância do dano devido às partículas beta quando comparado à radiação gama que possui pouco rendimento de emissão no processo de decaimento do 177Lu. Portanto, os parâmetros cinéticos que promovem a captação do 177Lu nas células são os principais responsáveis pela composição da dose no tumor e demais órgãos. / Carcinoid tumors (well differentiated neoplasms) are neuroendocrine tumors that may arise in different anatomical locations. The population prevalence of carcinoid tumors is approximately 10 cases per one million inhabitants. Its incidence is higher in the fifth and sixth decade of life. This paper proposes a kinetic model in humans with carcinoid tumors who will underwent treatment with the radiopharmaceutical [177Lu-DOTA0,Tyr3 ]OCTREOTATE based on the theory of compartmental analysis. Dynamic planar scintigraphic images acquired immediately upon injection of 370 MBq (10 mCi) of the radiopharmaceutical were obtained with the SPECT (Single Photon Emission Computed Tomography) tomography. Samples from regions of interest (ROI) were used for the kinetic study applying the kinetic proposed model. The first phase of the study (activity 370 MBq) was aimed to evaluate the kinetic parameters. Subsequently, the patient underwent the [177Lu-DOTA0,Tyr3 ]OCTREOTATE radiotherapy protocol, under the physician\'s prescription (up to four cycles of 7.4 GBq (200 mCi)). Thus, it was possible to previously estimate the kinetic constants ki,j relative to biodistribution of [177Lu-DOTA0,Tyr3 ]OCTREOTATE in the body. The ki,j is the transfer fraction from the ith compartment (a tissue or an organ) to the jth compartment. Only few organs showed significant ROI radioactivity count level, among them: the liver, kidney, blood and carcinoid tumors. The MIRD method and the kinetic constants ki,j were used to estimate the absorbed dose in 26 body organs. The absorbed dose D(mGy/MBq) was comparable to other methods described in the literature. For an adult patient of 73.6 kg, on average, the kidneys (without amino acid protectors) showed the highest dose (2.39 mGy/MBq) followed by liver (0.70 mGy / MBq) and tumor (0.52 mGy/MBq) with a tissue size of approximately 100 g. It was observed that tumors receive the same absorbed dose D(mGy/MBq) regardless their position in the body. This finding is due to the predominance of the tissue radiation damage of beta particles compared to gamma radiation that has little yield emission in the 177Lu decay scheme. Therefore, the kinetic parameters ki,j that promote the uptake of 177Lu in cells are primarily responsible for the absorbed D dose in the tumor and other organs.

Este trabalho teve por objetivo propor uma racionalização da síntese, da análise e da purificação do radiofármaco 177Lu3+-DOTATATO para uso diagnóstico e terapêutico em tumores neuroendócrinos, bem como avaliar a biodistribuição deste radiofármaco em modelo animal. A reação de complexação para a síntese do radiofármaco foi realizada em tampão acetato de amônio 0,5 M, pH 7,0, à 95 oC, com tempo de reação de 30 minutos. Obteve-se pureza radioquímica > 95%, de acordo com a análise por cromatografia em ITLC-SG, utilizando-se como fase móvel, tampão citrato de sódio 0,1 M, pH 5,0. A razão molar-limite 177Lu3+: DOTATATO utilizada na síntese do radiofármaco 177Lu3+-DOTATATO foi dependente da atividade específica e da procedência do radioisótopo, sendo de 1:3,5 (370 MBq : 2,6 mg) para radioisótopo oriundo do Oak Ridge National Laboratory/EUA e de 1:16 (370 MBq : 11,8 mg) para o radioisótopo oriundo do Nuclear Analytical and Medical Services/Holanda, considerando para ambos, um decaimento de cinco dias a partir da data de produção do radioisótopo. Esta racionalização da síntese do radiofármaco 177Lu3+-DOTATATO permite uma grande economia nos custos de produção. O estudo químico da síntese do radiofármaco também evidenciou a interferência do 177Hf4+, produto de decaimento do 177Lu3+, como competidor do 177Lu3+ pelo DOTATATO. A preparação radiofarmacêutica mostrou-se estável durante 24 horas, a uma atividade de 2775 MBq, com adição de 0,6 mg/mL de ácido gentísico, mantida em gelo seco. Nos estudos de biodistribuição em camundongos Swiss e Nude demonstrou-se a especificidade do radiofármaco pelos tecidos receptor-específicos para somatostatina como pâncreas, estômago, pulmão, adrenais, rins e de células tumorais AR42J. Palavras chave: síntese, complexação, radiofármaco, 177Lu-DOTATATO, tumor neuroendócrino. / The aim of this work was to propose rationalization in the synthesis, analysis and purification of radiopharmaceutical 177Lu3+-DOTATATO for diagnostic and therapeutic use in neuroendocrine tumors, as well as for evaluating biodistribution of this radiopharmaceutical in an animal-model. The complexation reaction for the synthesis of radiopharmaceutical was carried out in ammonium acetate buffer 0.5 M, pH 7.0, for 30 minutes at 95 oC. The radiochemical purity was > 95%, according to analysis by chromatography in ITLC-SG, when using the sodium citrate buffer 0,1 M, pH 5.0, as the mobile phase. The molar-limit ratio 177Lu3+: DOTATATO, used in the synthesis of radiopharmaceutical 177Lu3+-DOTATATO, in ammonium acetate buffer 0.5 M, pH 7.0, for 30 minutes at 95 oC, was dependent on the specific activity and origin of the radioisotope, this being 1:3.5 (370 MBq : 2.6 mg) for that from the Oak Ridge National Laboratory/U.S.A., and 1:16 (370 MBq : 11.8 mg) for that from Nuclear Analytical and Medical Services/Holland, when considering a decay of five days from the production date of the radioisotopes. This rationalization in the synthesis of radiopharmaceutical 177Lu3+-DOTATATO permits high economy in production costs. Chemical studies on the synthesis of radiopharmaceuticals also placed in evidence the interference of 177Hf4+, the decay product of 177Lu3+, as the 177Lu3+ competitor for DOTATATO. Radiopharmaceutical preparation proved to be stable during 24 hours, at an activity rate of 2775 MBq, with the addition of 0.6 mg/mL of gentisic acid and when kept in dry ice. In biodistribution studies on Swiss and Nude mice, the specificity of radiopharmaceutical for somatostatin positive-receptor tissues, such as the pancreas, stomach, lungs, adrenal glands, kidneys and the cell tumor AR42J was demonstrated. Key words: synthesis, complexation, radiopharmaceutical, 177Lu3+-DOTATATO, neuroendocrine tumors

Este trabalho teve por objetivo propor uma racionalização da síntese, da análise e da purificação do radiofármaco 177Lu3+-DOTATATO para uso diagnóstico e terapêutico em tumores neuroendócrinos, bem como avaliar a biodistribuição deste radiofármaco em modelo animal. A reação de complexação para a síntese do radiofármaco foi realizada em tampão acetato de amônio 0,5 M, pH 7,0, à 95 oC, com tempo de reação de 30 minutos. Obteve-se pureza radioquímica > 95%, de acordo com a análise por cromatografia em ITLC-SG, utilizando-se como fase móvel, tampão citrato de sódio 0,1 M, pH 5,0. A razão molar-limite 177Lu3+: DOTATATO utilizada na síntese do radiofármaco 177Lu3+-DOTATATO foi dependente da atividade específica e da procedência do radioisótopo, sendo de 1:3,5 (370 MBq : 2,6 mg) para radioisótopo oriundo do Oak Ridge National Laboratory/EUA e de 1:16 (370 MBq : 11,8 mg) para o radioisótopo oriundo do Nuclear Analytical and Medical Services/Holanda, considerando para ambos, um decaimento de cinco dias a partir da data de produção do radioisótopo. Esta racionalização da síntese do radiofármaco 177Lu3+-DOTATATO permite uma grande economia nos custos de produção. O estudo químico da síntese do radiofármaco também evidenciou a interferência do 177Hf4+, produto de decaimento do 177Lu3+, como competidor do 177Lu3+ pelo DOTATATO. A preparação radiofarmacêutica mostrou-se estável durante 24 horas, a uma atividade de 2775 MBq, com adição de 0,6 mg/mL de ácido gentísico, mantida em gelo seco. Nos estudos de biodistribuição em camundongos Swiss e Nude demonstrou-se a especificidade do radiofármaco pelos tecidos receptor-específicos para somatostatina como pâncreas, estômago, pulmão, adrenais, rins e de células tumorais AR42J. Palavras chave: síntese, complexação, radiofármaco, 177Lu-DOTATATO, tumor neuroendócrino. / The aim of this work was to propose rationalization in the synthesis, analysis and purification of radiopharmaceutical 177Lu3+-DOTATATO for diagnostic and therapeutic use in neuroendocrine tumors, as well as for evaluating biodistribution of this radiopharmaceutical in an animal-model. The complexation reaction for the synthesis of radiopharmaceutical was carried out in ammonium acetate buffer 0.5 M, pH 7.0, for 30 minutes at 95 oC. The radiochemical purity was > 95%, according to analysis by chromatography in ITLC-SG, when using the sodium citrate buffer 0,1 M, pH 5.0, as the mobile phase. The molar-limit ratio 177Lu3+: DOTATATO, used in the synthesis of radiopharmaceutical 177Lu3+-DOTATATO, in ammonium acetate buffer 0.5 M, pH 7.0, for 30 minutes at 95 oC, was dependent on the specific activity and origin of the radioisotope, this being 1:3.5 (370 MBq : 2.6 mg) for that from the Oak Ridge National Laboratory/U.S.A., and 1:16 (370 MBq : 11.8 mg) for that from Nuclear Analytical and Medical Services/Holland, when considering a decay of five days from the production date of the radioisotopes. This rationalization in the synthesis of radiopharmaceutical 177Lu3+-DOTATATO permits high economy in production costs. Chemical studies on the synthesis of radiopharmaceuticals also placed in evidence the interference of 177Hf4+, the decay product of 177Lu3+, as the 177Lu3+ competitor for DOTATATO. Radiopharmaceutical preparation proved to be stable during 24 hours, at an activity rate of 2775 MBq, with the addition of 0.6 mg/mL of gentisic acid and when kept in dry ice. In biodistribution studies on Swiss and Nude mice, the specificity of radiopharmaceutical for somatostatin positive-receptor tissues, such as the pancreas, stomach, lungs, adrenal glands, kidneys and the cell tumor AR42J was demonstrated. Key words: synthesis, complexation, radiopharmaceutical, 177Lu3+-DOTATATO, neuroendocrine tumors

Radiolabeled somatostatin analogues based on octreotide have proven useful in the management of somatostatin receptor subtype 2 (sstr2)-positive tumours in clinical trials. The aim was to compare the potency and evaluate the combination of 111In- and 177Lu-DOTATOC with a double-deleted version of vaccinia virus (ddVV), an oncolytic virus for inhibiting the growth of sstr2-expressing human embryonic kidney (HEK-293) cells or MC-38 murine colon cancer cells grown as monolayers or as spheroids. Cytotoxicity studies were carried out using ddVV, 111In-DOTATOC and 177Lu-DOTATOC, individually or in combination on MC-38 spheroids, HEK-293 cells and spheroids. HEK-293 cell growth in spheroids was reduced to 17.2 ± 4.9% and 26.5 ± 6.3 % with 111In-DOTATOC and 177Lu-DOTATOC alone and 13.1 ± 7.1% and 0% in combination, respectively. MC-38 spheroids showed greater toxicity in combination treatment. Combination of ddVV with 111In- or 177Lu-DOTATOC is only advantageous in monolayer culture. No advantage was observed in spheroid models.

Radiolabeled somatostatin analogues based on octreotide have proven useful in the management of somatostatin receptor subtype 2 (sstr2)-positive tumours in clinical trials. The aim was to compare the potency and evaluate the combination of 111In- and 177Lu-DOTATOC with a double-deleted version of vaccinia virus (ddVV), an oncolytic virus for inhibiting the growth of sstr2-expressing human embryonic kidney (HEK-293) cells or MC-38 murine colon cancer cells grown as monolayers or as spheroids. Cytotoxicity studies were carried out using ddVV, 111In-DOTATOC and 177Lu-DOTATOC, individually or in combination on MC-38 spheroids, HEK-293 cells and spheroids. HEK-293 cell growth in spheroids was reduced to 17.2 ± 4.9% and 26.5 ± 6.3 % with 111In-DOTATOC and 177Lu-DOTATOC alone and 13.1 ± 7.1% and 0% in combination, respectively. MC-38 spheroids showed greater toxicity in combination treatment. Combination of ddVV with 111In- or 177Lu-DOTATOC is only advantageous in monolayer culture. No advantage was observed in spheroid models.