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BACKGROUND: Angiogenesis is a process that many tumors depend on for growth, development, and metastasis. Vascular endothelial growth factor (VEGF) is one of the major players in tumor angiogenesis in several tumor types, including melanoma. VEGF inhibition is achieved by bevacizumab, a humanized monoclonal antibody that binds with high affinity to VEGF and prevents its function. In order to successfully enable in vivo VEGF expression imaging in a murine melanoma model, we previously labeled bevacizumab with [99mTc]Tc. We observed that this was feasible, but it had prolonged blood circulation and delayed tumor uptake. OBJECTIVE: The aim of this study was to develop a radiolabeled Fab bevacizumab fragment, [99mTc]Tc-HYNICFab( bevacizumab), for non-invasive in vivo VEGF expression molecular imaging. METHODS: Flow cytometry was used to examine VEGF presence in the murine melanoma cell line (B16-F10). Bevacizumab was digested with papain for six hours at 37°C to produce Fab(bevacizumab), which was then conjugated to NHS-HYNIC-Tfa for radiolabeling with [99mTc]Tc. Stability and binding affinity assays were also evaluated. Biodistribution and single photon emission computed tomography/computed tomography (SPECT/CT) were performed at 1, 3, and 6 h (n = 4) after injection of [99mTc]Tc-HYNIC-Fab(Bevacizumab) in normal and B16-F10 tumor-bearing C57Bl/6J mice. RESULTS: Using flow cytometry, it was shown that the B16-F10 murine melanoma cell line has intracellular VEGF expression. Papain incubation resulted in the complete digestion of bevacizumab with good purity and homogeneity. The radiolabeling yield of [99mTc]Tc-HYNIC-Fab(bevacizumab) was 85.00 ± 6.06%, with a specific activity of 291.87 ± 18.84 MBq/mg (n=3), showing in vitro stability. Binding assays demonstrated significant intracellular in vitro VEGF expression. Fast blood clearance and high kidney and tumor uptake were observed in biodistribution and SPECT/CT studies. CONCLUSIONS: We present the development and evaluation of [99mTc]Tc-HYNIC-Fab(bevacizumab), a novel molecular VEGF expression imaging agent that may be used for precision medicine in melanoma and potentially in other VEGF-expressing tumors.
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Bevacizumab , Compuestos de Organotecnecio , Factor A de Crecimiento Endotelial Vascular , Animales , Bevacizumab/química , Bevacizumab/farmacología , Ratones , Factor A de Crecimiento Endotelial Vascular/metabolismo , Compuestos de Organotecnecio/química , Imagen Molecular , Radiofármacos/química , Radiofármacos/síntesis química , Ratones Endogámicos C57BL , Melanoma/diagnóstico por imagen , Melanoma/metabolismo , Melanoma/tratamiento farmacológico , Melanoma/patología , Distribución Tisular , Tecnecio/química , Estructura Molecular , Humanos , Línea Celular Tumoral , Tomografía Computarizada de Emisión de Fotón Único , Fragmentos Fab de Inmunoglobulinas/químicaRESUMEN
The development of new radiopharmaceuticals for the detection of hidden infection foci has great relevance for early detection and the selection of the correct treatment, particularly in immunosuppressed patients. In that sense, the labelling of antimicrobial peptides (AMPs) that are capable of binding specifically to the pathogenic microorganism which causes the infection, should provide a sufficiently specific agent, able to distinguish an infection from a sterile inflammation. Defensins are particularly interesting molecules with antimicrobial activity, the EcgDf1 defensin was identified from the genome of a Uruguayan native plant, Erythrina crista-galli, the 'Ceibo' tree. Our group has previously reported a synthetic biologically active short analogue EcgDf21 (ERFTGGHCRGFRRRCFCTKHC) successfully labelled with 99mTc. Herein we present a shorter analogue which also preserves the γ-core domain, as a pharmacophore for a potential infection detection agent. This peptide was derivatized with the bifunctional chelating agent 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) through a lysine linker in the amino-terminal group (NOTA-KGHCRGFRRRC) and radiolabelled with 68Ga ([68Ga]Ga-NOTA-K-EcgDf1(10)). The [68Ga]Ga-NOTA-K-EcgDf1(10) labelling procedure rendered a product with high radiochemical purity and stability in the labelling milieu. The Log P value indicated that the complex has a hydrophilic behaviour, confirmed by the biodistribution profile. The [68Ga]Ga-NOTA-K-EcgDf1(10) complex demonstrated specific binding to cultures of Candida albicans and Aspergillus niger. Its biodistribution showed renal elimination and low accumulation in the rest of the body. It was possible to successfully differentiate sterile inflammation from infection by PET images in nude mice with a target/non-target ratio of 3.3 for C. albicans and 3.7 for A. niger, respectively.
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Defensinas , Radioisótopos de Galio , Tomografía de Emisión de Positrones , Radiofármacos , Animales , Humanos , Ratones , Secuencia de Aminoácidos , Defensinas/química , Radioisótopos de Galio/química , Péptidos/química , Tomografía de Emisión de Positrones/métodos , Radiofármacos/química , Distribución Tisular , Compuestos de Organotecnecio/químicaRESUMEN
BACKGROUND: Gamma cameras with cadmium-zinc telluride (CZT) detectors allowed the quantification of myocardial flow reserve (MBF), which can increase the accuracy of myocardial perfusion scintigraphy (MPS) to detect the cause of chest discomfort. OBJECTIVE: To assess the clinical impact of MBF to detect the cause of chest discomfort. METHODS: 171 patients with chest discomfort who underwent coronary angiography or coronary CT angiography also underwent MPS and MBF in a time interval of <30 days. The acquisitions of dynamic imaging of rest and stress were initiated simultaneously with the 99mTc injection sestamibi (10 and 30mCi, respectively), both lasting eleven minutes, followed by immediately acquiring perfusion images for 5 minutes. The stress was performed with dipyridamole. A global or per coronary territory MBF <2.0 was classified as abnormal. RESULTS: The average age was 65.9±10 years (60% female). The anatomical evaluation showed that 115 (67.3%) patients had coronary obstruction significant, with 69 having abnormal MPs and 91 having abnormal MBF (60.0% vs 79.1%, p<0.01). Among patients without obstruction (56 - 32.7%), 7 had abnormal MPS, and 23 had reduced global MBF. Performing MBF identified the etiology of the chest discomfort in 114 patients while MPS identified it in 76 (66.7% vs 44.4%, p<0.001). CONCLUSION: MBF is a quantifiable physiological measure that increases the clinical impact of MPS in detecting the cause of chest discomfort through greater accuracy for detecting obstructive CAD, and it also makes it possible to identify the presence of the microvascular disease.
FUNDAMENTO: Gama-câmaras com detectores de telureto-cádmio-zinco (CZT) permitiram a quantificação da reserva de fluxo miocárdico (RFM), podendo aumentar a acurácia da cintilografia miocárdica de perfusão (CMP) para detectar a causa do desconforto torácico. OBJETIVO: Avaliar o impacto clínico da RFM para detectar a causa do desconforto torácico. MÉTODOS: 171 pacientes com desconforto torácico que foram submetidos a coronariografia ou angiotomografia de coronárias também realizaram CMP e RFM num intervalo de tempo <30 dias. As aquisições das imagens dinâmicas de repouso e estresse foram iniciadas simultaneamente à injeção de 99mTc sestamibi (10 e 30mCi, respectivamente), ambas com duração de onze minutos, seguidas imediatamente pela aquisição das imagens de perfusão durante 5 minutos. O estresse foi realizado com dipiridamol. Uma RFM global ou por território coronariano <2,0 foi classificada como anormal. RESULTADOS: A idade média foi de 65,9±10 anos (60% do sexo feminino). A avaliação anatômica mostrou que 115 (67,3%) pacientes apresentavam obstrução coronariana significativa, sendo que, 69 apresentavam CMP anormal e 91 apresentavam RFM anormal (60,0% vs. 79,1%, p<0,01). Dentre os pacientes sem obstrução (56 32,7%), 7 tinham CMP anormais e 23 tinham RFM global reduzida. A realização da RFM identificou a etiologia do desconforto torácico em 114 pacientes enquanto a CMP identificou em 76 (66,7% vs. 44,4%, p<0,001). CONCLUSÃO: A RFM é uma medida fisiológica quantificável que aumenta o impacto clínico da CMP na detecção da causa do desconforto torácico através de uma maior acurácia para detecção de DAC obstrutiva e ainda possibilita identificar a presença de doença microvascular.
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Dolor en el Pecho , Angiografía Coronaria , Reserva del Flujo Fraccional Miocárdico , Imagen de Perfusión Miocárdica , Tecnecio Tc 99m Sestamibi , Humanos , Femenino , Masculino , Anciano , Imagen de Perfusión Miocárdica/métodos , Persona de Mediana Edad , Reserva del Flujo Fraccional Miocárdico/fisiología , Dolor en el Pecho/diagnóstico por imagen , Dolor en el Pecho/etiología , Dolor en el Pecho/fisiopatología , Radiofármacos , Reproducibilidad de los Resultados , Telurio , Zinc , Cadmio , Dipiridamol , Angiografía por Tomografía Computarizada/métodos , Valores de ReferenciaRESUMEN
BACKGROUND: Increased thermogenic activity has shown to be a promising target for treating and preventing obesity and type 2 diabetes (T2DM). Little is known about the muscular influence on nonshivering thermogenesis (NST), and it remains unclear whether physical training and potential metabolic improvements could be associated with changes in this type of thermogenic activity. OBJECTIVE: The present study aimed to assess muscular NST activity in overweight and T2DM before and after a combined training period (strength training followed by aerobic exercise). METHODS: Nonshivering cold-induced 18-fluoroxyglucose positron emission computed tomography (18F-FDG PET/CT) was performed before and after 16 weeks of combined training in 12 individuals with overweight and T2DM. The standard uptake value (SUV) of 18F-FDG was evaluated in skeletal muscles, the heart and the aorta. RESULTS: Muscles in the neck region exhibit higher SUV pre- and posttraining. Furthermore, a decrease in glucose uptake by the muscles of the lower and upper extremities and in the aorta was observed after training when adjusted for brown adipose tissue (BAT). These pre-post effects are accompanied by increased cardiac SUV and occur concurrently with heightened energy expenditure and metabolic improvements. CONCLUSIONS: Muscles in the neck region have greater metabolic activity upon exposure to cold. In addition, combined training appears to induce greater NST, favoring the trunk and neck region compared to limbs based on joint work and adaptations between skeletal muscles and BAT.
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Diabetes Mellitus Tipo 2 , Metabolismo Energético , Fluorodesoxiglucosa F18 , Músculo Esquelético , Sobrepeso , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos , Entrenamiento de Fuerza , Termogénesis , Humanos , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/terapia , Masculino , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Fluorodesoxiglucosa F18/administración & dosificación , Femenino , Sobrepeso/fisiopatología , Sobrepeso/terapia , Sobrepeso/metabolismo , Entrenamiento de Fuerza/métodos , Resultado del Tratamiento , Radiofármacos/administración & dosificación , Factores de Tiempo , Adulto , Terapia por Ejercicio/métodos , AncianoRESUMEN
Hemangioblastomas associated with von Hippel-Lindau (VHL) disease are frequently multiple and recur during prolonged follow-up. Currently, no systemic treatment is available for these tumors. Recent studies have shown the expression of somatostatin receptors in these types of hemangioblastomas. Notably, increased somatostatin receptor expression in a tumor, as determined by peptide-receptor radionuclide imaging, is a predictive factor of response to treatment with somatostatin analogs and peptide-receptor radionuclide therapy. The aim of this study was to describe the case of a patient with increased expression of somatostatin receptors in a suprasellar hemangioblastoma associated with VHL disease and conduct a literature review on somatostatin receptor expression in patients with VHL-associated hemangioblastomas. We describe herein the case of a 51-year-old man with VHL disease who had a suprasellar hemangioblastoma detected on magnetic resonance imaging. Peptide-receptor radionuclide imaging using gallium-68-DOTATOC (68Ga-DOTATOC) identified increased expression of somatostatin receptors in the suprasellar hemangioblastoma, along with multiple pancreatic neuroendocrine tumors and bilateral pheochromocytomas. The patient was treated for 1 year with lanreotide, a somatostatin analog. A repeat 68Ga-DOTATOC 1 year after starting lanreotide revealed decreased radiotracer uptake by the hemangioblastoma, consistent with a metabolic response. The presence of somatostatin receptors in hemangioblastomas associated with VHL disease is a novel finding. The decreased expression of these receptors after treatment with a somatostatin analog, as described in the present case, positions the somatostatin receptor as a new target for novel diagnostic, therapeutic, and follow-up opportunities in patients with VHL disease.
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Hemangioblastoma , Receptores de Somatostatina , Enfermedad de von Hippel-Lindau , Humanos , Hemangioblastoma/diagnóstico por imagen , Enfermedad de von Hippel-Lindau/complicaciones , Receptores de Somatostatina/análisis , Receptores de Somatostatina/metabolismo , Masculino , Persona de Mediana Edad , Octreótido/uso terapéutico , Octreótido/análogos & derivados , Neoplasias Cerebelosas/diagnóstico por imagen , Neoplasias Cerebelosas/tratamiento farmacológico , Estudios de Seguimiento , Imagen por Resonancia Magnética , Radiofármacos/uso terapéuticoRESUMEN
The goal of this study was to apply the principles of analytical quality by design (AQbD) to the analytical method for determining the radiochemical purity (PQR) of the radiopharmaceutical sodium iodide 131I oral solution, utilizing thin-layer chromatography (TLC) with a radio-TLC scanner, which also enables the evaluation of product quality. For AQbD, the analytical target profile (ATP), critical quality attributes (CQA), risk management, and the method operable design region (MODR) were defined through response surface methodology to optimize the method using MINITAB® 19 software. This study encompassed the establishment of a control strategy and the validation of the method, including the assessment of selectivity, linearity, precision, robustness, detection limit, quantification limit, range, and the stability of the sample solution. Under the experimental conditions, the method parameters of the TLC scanner were experimentally demonstrated and optimized with an injection volume of 3 µL, a radioactive concentration of 10 mCi/mL, and a carrier volume of 40 µL. Statistical analysis confirmed the method's selectivity for the 131I iodide band Rf of 0.8, a radiochemical impurity IO3- Rf of 0.6, a linearity from 6.0 to 22.0 mCi/mL, and an intermediate precision with a global relative standard deviation (RSD) of 0.624%. The method also exhibited robustness, with a global RSD of 0.101%, a detection limit of 0.09 mCi/mL, and a quantification limit of 0.53 Ci/mL, meeting the prescribed range and displaying stability over time (at 0, 2, and 20 h) with a global RSD of 0.362%, resulting in consistent outcomes. The development of a method based on AQbD facilitated the creation of a design space and an operational space, with comprehensive knowledge of the method's characteristics and limitations. Additionally, throughout all operations, compliance with the acceptance criteria was verified. The method's validity was confirmed under the established conditions, making it suitable for use in the manufacturing process of sodium iodide 131I and application in nuclear medicine services.
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Radioisótopos de Yodo , Radiofármacos , Yoduro de Sodio , Cromatografía en Capa Delgada/métodos , Radiofármacos/química , Radiofármacos/análisis , Radioisótopos de Yodo/análisis , Yoduro de Sodio/química , Administración Oral , Reproducibilidad de los ResultadosRESUMEN
Bone regeneration is crucial for repairing bone tissue following various injuries. Research techniques that enable the study of metabolic changes in bone tissue under different conditions are important for understanding bone repair and remodeling. This study used bone scintigraphy to evaluate osteogenesis secondary to osteotomy in a preclinical model of New Zealand rabbits. For this purpose, we conducted a longitudinal, prospective, case-control study in which scintigraphic variables were measured in both the right forearm (case-operated) and the left forearm (control - non-operated). The study sample consisted of 10 rabbits subjected to osteotomy, followed by a 12-week postoperative evaluation period, divided into six imaging stages at 1, 2, 3, 4, 8, and 12 weeks. We observed that the operated forearm showed significantly higher external radiation than the control side, using the pinhole collimator, denoting an increase in the biodistribution and tropism of the radiopharmaceutical to the operated forearm. Among the three evaluated time points, osteoblastic activity was highest in the second week and presented a significant decline in the 8th and 12th weeks, denoting regeneration and resolution of the surgical injury; the control forearm was also influenced by the inactivity imposed by the operated forearm. This fact was notably evidenced by the reduction in the metabolic activity of osteoblasts in the left forearm. Our study suggested that bone scintigraphy was sensitive enough to semi-quantitatively differentiate the metabolic activity of osteoblasts in the operated forearm in the three temporal landmarks evaluated in the study.
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Radiofármacos , Conejos , Animales , Estudios de Casos y Controles , Estudios Prospectivos , Distribución Tisular , CintigrafíaRESUMEN
Since the end of the Brazilian state monopoly in 2006, allowing private enterprises to act in producing and commercializing short half-life radiopharmaceuticals, the country observed a growth in the laboratories that use 18F-FDG to PET/CT exams. Considering the radiological protection and safety techniques applied to radioisotope-producing facilities or units, this study assembled the current situation of radiological protection showing the received doses of the professionals of four facilities with cyclotrons for 18F-FDG located in south and southeast Brazil in the years 2020 and 2021. The dose values observed are below the dose limits established by national and international regulatory entities but can still be optimized considering differences between the production units.
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Fluorodesoxiglucosa F18 , Tomografía Computarizada por Tomografía de Emisión de Positrones , Brasil , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Ciclotrones , RadiofármacosRESUMEN
Aim: ChiTn, a mouse/human chimeric anti-Tn monoclonal antibody, was radiolabeled with iodine-131 (131I) and technetium-99m (99mTc) to assess its biodistribution and internalization in Tn-expressing (Tn+) and wild-type (Tn-) LL/2 lung cancer cells. Results: Selective accumulation and gradual internalization of ChiTn were observed in Tn+ cells. Biodistribution in mice with both Tn+ or Tn- lung tumors indicated that the uptake of radiolabeled ChiTn within tumors increased over time. Dual-labeling experiments with 99mTc and 131I showed different biodistribution patterns, with 99mTc exhibiting higher values in the liver, spleen, and kidneys, while 131I showed higher uptake in the thyroid and stomach. However, tumor uptake did not significantly differ between Tn+ and Tn- tumors. To improve tumor targeting, Losartan, an antihypertensive drug known to enhance tumor perfusion and drug delivery, was investigated. Biodistribution studies in Losartan-treated mice revealed significantly higher radiolabeled ChiTn uptake in Tn+ tumors. No significant changes were observed in the uptake of the control molecule IgG-HYNIC™99mTc. Conclusions: These findings demonstrate the enhanced tumor targeting of radiolabeled ChiTn in Losartan-treated mice with Tn-expressing lung tumors. They highlight the potential of ChiTn as a theranostic agent for cancer treatment and emphasize the importance of Losartan as an adjunctive treatment to improve tumor perfusion and drug delivery.
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Anticuerpos Monoclonales , Radioisótopos de Yodo , Losartán , Neoplasias Pulmonares , Animales , Ratones , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Losartán/farmacología , Losartán/farmacocinética , Losartán/administración & dosificación , Distribución Tisular , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/farmacocinética , Tecnecio , Radiofármacos/farmacocinética , Radiofármacos/farmacología , Línea Celular Tumoral , Femenino , Proteína Tumoral Controlada Traslacionalmente 1RESUMEN
Despite the successful use of the radiopharmaceutical radium-223 dichloride ([223Ra]RaCl2) for targeted alpha therapy of castration-resistant prostate cancer patients with bone metastases, some short-term side effects, such as diarrhea and vomiting, have been documented, causing patient discomfort. Hence, we prepared a nanosized micellar solution of [223Ra]RaCl2 and evaluated its biodistribution, pharmacokinetics, and induced biochemical changes in healthy mice up to 96 h after intraperitoneal administration as an alternative to overcome the previous limitations. In addition, we evaluated the bone specificity of micellar [223Ra]RaCl2 in patient-derived xenografts in the osteosarcoma model. The biodistribution studies revealed the high bone-targeting properties of the micellar [223Ra]RaCl2. Interestingly, the liver uptake remained significantly low (%ID/g = 0.1-0.02) from 24 to 96 h after administration. In addition, the micellar [223Ra]RaCl2 exhibited a significantly higher uptake in left (%ID/g = 0.85-0.23) and right (%ID/g = 0.76-0.24) kidneys than in small (%ID/g = 0.43-0.06) and large intestines (%ID/g = 0.24-0.09) over time, suggesting its excretion pathway is primarily through the kidneys into the urine, in contrast to the non-micellar [223Ra]RaCl2. The micellar [223Ra]RaCl2 also had low distribution volume (0.055 ± 0.003 L) and longer elimination half-life (28 ± 12 days). This nanosystem was unable to change the enzymatic activities of alanine aminotransferase, aspartate aminotransferase, gamma GT, glucose, and liquiform lipase in the treated mice. Finally, microscopic examination of the animals' osteosarcoma tumors treated with micellar [223Ra]RaCl2 indicated regression of the tumor, with large areas of necrosis. In contrast, in the control group, we observed tumor cellularity and cell anaplasia, mitotic figures and formation of neoplastic extracellular bone matrix, which are typical features of osteosarcoma. Therefore, our findings demonstrated the efficiency and safety of nanosized micellar formulations to minimize the gastrointestinal excretion pathway of the clinical radiopharmaceutical [223Ra]RaCl2, in addition to promoting regression of the osteosarcoma. Further studies must be performed to assess dose-response outcomes and organ/tissue dosimetry for clinical translation.
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Neoplasias Óseas , Osteosarcoma , Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Animales , Ratones , Radiofármacos/farmacocinética , Distribución Tisular , Eliminación Renal , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/radioterapia , Osteosarcoma/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patologíaRESUMEN
Objective.to develop an optimization and training pipeline for a classification model based on principal component analysis and logistic regression using neuroimages from PET with 2-[18F]fluoro-2-deoxy-D-glucose (FDG PET) for the diagnosis of Alzheimer's disease (AD).Approach.as training data, 200 FDG PET neuroimages were used, 100 from the group of patients with AD and 100 from the group of cognitively normal subjects (CN), downloaded from the repository of the Alzheimer's Disease Neuroimaging Initiative (ADNI). Regularization methods L1 and L2 were tested and their respective strength varied by the hyperparameter C. Once the best combination of hyperparameters was determined, it was used to train the final classification model, which was then applied to test data, consisting of 192 FDG PET neuroimages, 100 from subjects with no evidence of AD (nAD) and 92 from the AD group, obtained at the Centro de Diagnóstico por Imagem (CDI).Main results.the best combination of hyperparameters was L1 regularization andC≈ 0.316. The final results on test data were accuracy = 88.54%, recall = 90.22%, precision = 86.46% and AUC = 94.75%, indicating that there was a good generalization to neuroimages outside the training set. Adjusting each principal component by its respective weight, an interpretable image was obtained that represents the regions of greater or lesser probability for AD given high voxel intensities. The resulting image matches what is expected by the pathophysiology of AD.Significance.our classification model was trained on publicly available and robust data and tested, with good results, on clinical routine data. Our study shows that it serves as a powerful and interpretable tool capable of assisting in the diagnosis of AD in the possession of FDG PET neuroimages. The relationship between classification model output scores and AD progression can and should be explored in future studies.
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Enfermedad de Alzheimer , Fluorodesoxiglucosa F18 , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Radiofármacos , Modelos Logísticos , Encéfalo/diagnóstico por imagen , Neuroimagen , Tomografía de Emisión de Positrones/métodosRESUMEN
Radionuclide ventriculography or Multi Gated Acquisition (MUGA) employing [ 99m Tc]Technetium red blood cell (RBC) labeling is considered the gold standard for cardiotoxicity assessments in cancer patients undergoing chemotherapy. This in-vivo RBC labeling technique involves the reduction of [ 99m Tc]Technetium by the stannous chloride present in freeze-dried reagent kits, with the pyrophosphate kit (PYP) being the most employed for this purpose. The literature, however, describes diethylenetriaminepentaacetic acid (DTPA) as an alternative to PYP, although a lack of comparative data from MUGA images between both reagents is noted. A retrospective cross-sectional observational study was conducted at the Brazilian National Cancer Institute Nuclear Medicine Service concerning 80 randomized MUGA images, 20 obtained employing DTPA between 2020 and 2023 and 60 obtained employing PYP between 2017 and 2020, applying the mean count per pixel (ct/pixel) and heart background (C/F) ratios as quality image indicators. Although the heart ct/pixel ratio was statistically lower in the DTPA images compared with PYP ( P â =â 0.02), the C/F ratio was statistically similar when comparing both radiopharmaceuticals ( P â =â 0.697). A semi-quantitative analysis of MUGA images obtained with DTPA and PYP indicates similar image quality, supporting the use of DTPA as an alternative to PYP without compromising diagnostic interpretations.
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Radiofármacos , Tecnecio , Humanos , Estudios Transversales , Estudios Retrospectivos , Ventriculografía con Radionúclidos , Ácido Pentético , EritrocitosRESUMEN
Abstract The goal of this work is to identify new fatty acid-mimetic 99mTc-complexes to be used as myocardial imaging agents that allow studying heart abnormalities in high-risk patients. In this sense, we designed a fatty acid-mimetic substructure including an amide moiety that, among other properties, could improve myocardial residence time. A diamide with a chain length of 15 atoms and porting a 6-hydrazinonicotinyl (HYNIC) chelator, and an analog with a short carbon-chain, were prepared with convergent organic synthetic procedures and radiolabeled with 99mTc using tricine as the sole coligand. The in vivo proofs of concept were performed using healthy mice. The new 99mTc-complexes were obtained with adequate radiochemical purity. The lipophilicities were in agreement with the length of the chains. While both 99mTc-complexes showed uptake in the myocardial muscle, the designed radiopharmaceutical with the longest chain length had preferential target-uptake and target-retention compared to other complexes described in the bibliography. Further studies, involving imaging assays, synthetic modifications, and assay of new coligands for 99mTc-HYNIC complexes, are currently ongoing.
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Animales , Femenino , Ratones , Radiofármacos/efectos adversos , Ácidos Grasos/agonistas , Amidas/efectos adversos , Cardiopatías Congénitas/clasificaciónRESUMEN
BACKGROUND: Glycolytic metabolism in the brain of pediatric patients, imaged with [18F] fluorodeoxyglucose-positron emission tomography (FDG-PET) is incompletely characterized. OBJECTIVE: The purpose of the current study was to characterize [18F]FDG-PET brain uptake in a large sample of pediatric patients with non-central nervous system diseases as an alternative to healthy subjects to evaluate changes at different pediatric ages. MATERIALS AND METHODS: Seven hundred ninety-five [18F]FDG-PET examinations from children < 18 years of age without central nervous system diseases were included. Each brain image was spatially normalized, and the standardized uptake value (SUV) was obtained. The SUV and the SUV relative to different pseudo-references were explored as a function of age. RESULTS: At all evaluated ages, the occipital lobe showed the highest [18F]FDG uptake (0.27 ± 0.04 SUV/year), while the parietal lobe and brainstem had the lowest uptake (0.17 ± 0.02 SUV/year, for both regions). An increase [18F]FDG uptake was found for all brain regions until 12 years old, while no significant uptake differences were found between ages 13 (SUV = 5.39) to 17 years old (SUV = 5.52) (P < 0.0001 for the whole brain). A sex dependence was found in the SUVmean for the whole brain during adolescence (SUV 5.04-5.25 for males, 5.68-5.74 for females, P = 0.0264). Asymmetries in [18F]FDG uptake were found in the temporal and central regions during infancy. CONCLUSIONS: Brain glycolytic metabolism of [18F]FDG, measured through the SUVmean, increased with age until early adolescence (< 13 years old), showing differences across brain regions. Age, sex, and brain region influence [18F]FDG uptake, with significant hemispheric asymmetries for temporal and central regions.
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Fluorodesoxiglucosa F18 , Tomografía de Emisión de Positrones , Masculino , Femenino , Adolescente , Humanos , Niño , Tomografía de Emisión de Positrones/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Voluntarios Sanos , RadiofármacosRESUMEN
Relative biological effectiveness is a radiobiological parameter relevant in radiotherapy planning and useful in evaluating the physiological impact of radiation in different tissues. Targeted radionuclide therapy allows the selective and specific deposition of higher radiation doses in a noninvasive way and without collateral effects through the administration of radiopharmaceuticals. Lu-DOTA-177(hydrazinylnicotinoyl-Lys-(Nal)-NH-CO-NH-Glu) also called Lu-iPSMA177 is a third generation radiopharmaceutical composed by a peptide that recognizes the prostate-specific membrane antigen (PSMA), a membrane protein overexpressed in several types of cancer and that mediates the radiopharmaceutical's recognition of cancer cells. The present study reports radiobiological parameters of Lu-iPSMA177 and demonstrates the superiority of targeted radiopharmaceuticals over external radiotherapy treatment options in terms of their relative biological effectiveness. The relative biological effectiveness value of 1.020±0.003 for the LINAC, estimated by fitting the linear-quadratic model equation to the resulting survival curves, was like those of 1.25±0.04,1.060±0.005and1.00±0.04 obtained by an alternative method in relation to the mean lethal doses at 90, 80 or 60 survival percent respectively. While the relative biological effectiveness values of 5.65±0.13,4.72±0.27and2.87±0.19 estimated for Lu-iPSMA177 were significantly higher than those for the LINAC. The results confirm that the biological effect produced by the deposition of a radiation absorbed dose delivered by the LINAC can be induced with a quarter of that dose using Lu-iPSMA177 due to the energy distribution, dose-rate and energy fluence.
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Radioisótopos , Radiofármacos , Masculino , Humanos , Radiofármacos/uso terapéutico , Efectividad Biológica Relativa , Radioisótopos/uso terapéutico , Lutecio/uso terapéuticoRESUMEN
OBJECTIVE: This study aimed to report the metastatic lesions observed in identified skeletons whose deaths were caused by breast cancer complications to provide information and evidence that can be used in cases of human identification forensics. METHODS: The research was conducted at the Centre for Forensic Anthropology Studies of the Faculty of Odontology of the University of Pernambuco (CEAF/FOP/UPE), Recife, Brazil. The data bank of the CEAF/FOP/UPE was searched for skeletons with the cause of death reported as due to breast cancer, resulting in five cases. The skeletons were arranged in anatomical positions and macroscopically inspected to register, describe and measure the lesions present to establish the macroscopic patterns of bone destruction caused by breast cancer. RESULT: Of the five skeletons, two presented metastatic lesions. In the first, lesions were observed in a disseminated form, affecting almost all bones. The lesions were predominantly osteolytic and ellipsoid-shaped; however, mixed and circular lesions were also found. The second skeleton presented four lesions of mixed characteristics. The finding of bone lesions in the macroscopic analysis of skeletons may reveal a more advanced stage of the neoplasm, as well as its dissemination in areas little rich in hematopoietic tissue, such as the diaphyses of long bones, a situation widely observed in the first reported case. CONCLUSION: Besides providing more excellent knowledge of their macroscopic presentation, bone metastatic lesions may act as an individualizing factor in human identification cases, narrowing the sample of possible victims.
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Neoplasias de la Mama , Antropología Forense , Humanos , Femenino , Neoplasias de la Mama/patología , Huesos/patología , Brasil , RadiofármacosRESUMEN
Current cancer therapies focus on reducing immunosuppression and remodeling the tumor microenvironment to inhibit metastasis, cancer progression, and therapeutic resistance. Programmed death receptor 1 (PD-1) is expressed on immune T cells and is one of the so-called checkpoint proteins that can suppress or stop the immune response. To evade the immune system, cancer cells overexpress a PD-1 inhibitor protein (PD-L1), which binds to the surface of T cells to activate signaling pathways that induce immune suppression. This research aimed to synthesize PD-L1 inhibitory peptides (PD-L1-i) labeled with lutetium-177 (177Lu-DOTA-PD-L1-i) and actinium-225 (225Ac-HEHA-PD-L1-i) and to preclinically evaluate their potential as radiopharmaceuticals for targeted radiotherapy at the tumor microenvironment level. Using PD-L1-i peptide as starting material, conjugation with HEHA-benzene-SCN and DOTA-benzene-SCN was performed to yield DOTA-PD-L1-i and HEHA-PD-L1-I, which were characterized by FT-IR, UV-vis spectroscopy, and HPLC. After labeling the conjugates with 225Ac and 177Lu, cellular uptake in HCC827 cancer cells (PD-L1 positive), conjugate specificity evaluation by immunofluorescence, radiotracer effect on cell viability, biodistribution, biokinetics, and assessment of radiation absorbed dose in mice with in duced lung micrometastases were performed. 225Ac-HEHA-PD-L1-i and 177Lu-DOTA-PD-L1-i, obtained with radiochemical purities of 95 ± 3% and 98.5 ± 0.5%, respectively, showed in vitro and in vivo specific recognition for the PD-L1 protein in lung cancer cells and high uptake in HCC287 lung micrometastases (>30% ID). The biokinetic profiles of 177Lu-DOTA-PD-L1-i and 225Ac-DOTA-PD-L1-i showed rapid blood clearance with renal and hepatobiliary elimination and no accumulation in normal tissues. 225Ac-DOTA-PD-L1-i produced a radiation dose of 5.15 mGy/MBq to lung micrometastases. In the case of 177Lu-DOTA-PD-L1-i, the radiation dose delivered to the lung micrometastases was ten times (43 mGy/MBq) that delivered to the kidneys (4.20 mGy/MBq) and fifty times that delivered to the liver (0.85 mGy/MBq). Therefore, the radiotherapeutic PD-L1-i ligands of 225Ac and 177Lu developed in this research could be combined with immunotherapy to enhance the therapeutic effect in various types of cancer.
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Antígeno B7-H1 , Radiofármacos , Ratones , Animales , Radiofármacos/uso terapéutico , Distribución Tisular , Benceno , Micrometástasis de Neoplasia , Espectroscopía Infrarroja por Transformada de Fourier , Microambiente Tumoral , Lutecio/uso terapéutico , Línea Celular TumoralRESUMEN
BACKGROUND: Tumour hypoxia is associated with increased metastasis, invasion, poor therapy response and prognosis. Most PET radiotracers developed and used for clinical hypoxia imaging belong to the 2-nitroimidazole family. Recently we have developed novel 2-nitroimidazole-derived PET radiotracer [18F]FBNA (N-(4-[18F]fluoro-benzyl)-2-(2-nitro-1H-imidazol-1-yl)-acet-amide), an 18F-labeled analogue of antiparasitic drug benznidazole. The present study aimed to analyze its radio-pharmacological properties and systematically compare its PET imaging profiles with [18F]FMISO and [18F]FAZA in preclinical triple-negative (MDA-MB231) and estrogen receptor-positive (MCF-7) breast cancer models. METHODS: In vitro cellular uptake experiments were carried out in MDA-MB321 and MCF-7 cells under normoxic and hypoxic conditions. Metabolic stability in vivo was determined in BALB/c mice using radio-TLC analysis. Dynamic PET experiments over 3 h post-injection were performed in MDA-MB231 and MCF-7 tumour-bearing mice. Those PET data were used for kinetic modelling analysis utilizing the reversible two-tissue-compartment model. Autoradiography was carried out in tumour tissue slices and compared to HIF-1α immunohistochemistry. Detailed ex vivo biodistribution was accomplished in BALB/c mice, and this biodistribution data were used for dosimetry calculation. RESULTS: Under hypoxic conditions in vitro cellular uptake was elevated in both cell lines, MCF-7 and MDA-MB231, for all three radiotracers. After intravenous injection, [18F]FBNA formed two radiometabolites, resulting in a final fraction of 65 ± 9 % intact [18F]FBNA after 60 min p.i. After 3 h p.i., [18F]FBNA tumour uptake reached SUV values of 0.78 ± 0.01 in MCF-7 and 0.61 ± 0.04 in MDA-MB231 tumours (both n = 3), representing tumour-to-muscle ratios of 2.19 ± 0.04 and 1.98 ± 0.15, respectively. [18F]FMISO resulted in higher tumour uptakes (SUV 1.36 ± 0.04 in MCF-7 and 1.23 ± 0.08 in MDA-MB231 (both n = 4; p < 0.05) than [18F]FAZA (0.66 ± 0.11 in MCF-7 and 0.63 ± 0.14 in MDA-MB231 (both n = 4; n.s.)), representing tumour-to-muscle ratios of 3.24 ± 0.30 and 3.32 ± 0.50 for [18F]FMISO, and 2.92 ± 0.74 and 3.00 ± 0.42 for [18F]FAZA, respectively. While the fraction per time of radiotracer entering the second compartment (k3) was similar within uncertainties for all three radiotracers in MDA-MB231 tumours, it was different in MCF-7 tumours. The ratios k3/(k3 + k2) and K1*k3/(k3 + k2) in MCF-7 tumours were also significantly different, indicating dissimilar fractions of radiotracer bound and trapped intracellularly: K1*k3/(k2 + k3) [18F]FMISO (0.0088 ± 0.001)/min, n = 4; p < 0.001) > [18F]FAZA (0.0052 ± 0.002)/min, n = 4; p < 0.01) > [18F]FBNA (0.003 ± 0.001)/min, n = 3). In contrast, in MDA-MB231 tumours, only K1 was significantly elevated for [18F]FMISO. However, this did not result in significant differences for K1*k3/(k2 + k3) for all three 2-nitroimidazoles in MDA-MB231 tumours. CONCLUSION: Novel 2-nitroimidazole PET radiotracer [18F]FBNA showed uptake into hypoxic breast cancer cells and tumour tissue presumably associated with elevated HIF1-α expression. Systematic comparison of PET imaging performance with [18F]FMISO and [18F]FAZA in different types of preclinical breast cancer models revealed a similar tumour uptake profile for [18F]FBNA with [18F]FAZA and, despite its higher lipophilicity, still a slightly higher muscle tissue clearance compared to [18F]FMISO.