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Resumen En el linfoma Hodgkin, la tomografía por emisión de positrones (PET-TC) forma parte de los nuevos algoritmos diagnósticos y de valoración de respuesta al tratamiento como método eficaz para evaluar supervivencia y pronóstico de la enfermedad, ya sea a través del PET-TC interino con 2-[18F]fluoro- 2-desoxi-D-glucosa, ([18F]FDG), como también del PET-TC al final de la terapéutica. Sin embargo, la [18F]FDG presenta una baja especificidad en linfoma no Hodgkin de grandes células B. Ante la aprobación en nuestro país del radiotrazador 3´-desoxi-3´-[18F]fluorotimidina, [18F]FLT, indicador de proliferación celular de fase S, éste resultaría un prometedor radiofármaco de uso diagnóstico frente a [18F]FDG. Por lo tanto, el objetivo de este estudio fue valorar la utilización de [18F]FLT mediante un modelo animal en primates no humanos Sapajus cay. Se obtuvieron imágenes de cuerpo entero para evaluar la biodistribución y realizar un cálculo dosimétrico en la médula ósea, dado que este es un órgano crítico por la permanencia del radiofármaco. Para órganos de inte rés, se trazaron curvas de actividad en función del tiempo y se calculó la actividad acumulada normalizada. La dosis media absorbida en la médula ósea se determinó aplicando el esquema conocido como Medical Internal Radiation Dosimetry (MIRD). La dosis media obtenida en el modelo animal por unidad de actividad administrada fue de 8.7 μGy/MBq. Este resultado se extrapoló a un modelo humano adulto resultando en 32 μGy/MBq, de lo que se desprende que PET-TC con [18F]FLT es una herramienta segura para uso diagnóstico y de seguimiento en pacientes con enfermedad oncológica linfoproliferativa u otros tumores sólidos.
Abstract Positron emission tomography-computed tomography (PET-CT) is part of the new diagnostic and therapeutic algorithms for Hodgkin lymphoma. PET-CT is a valuable tool for the assessment of treatment response and prognosis, both by means of interim PET-CT with 2-[ 18F]fluoro-2-deoxy-D-glucose ([18F]FDG) as well as end of treatment (EOT) PET-CT. Given the low specificity of [ 18F]FDG for the diffuse large B cell lymphoma (DLBCL), there is an emerging need for a more specific radiopharmaceutical agent. The recent approval of the radiotracer 3´-deoxy-[18F]-3´-flourothymidine ([18F]FLT), a phase-S mitosis cell proliferation marker, for clinical application in our country, shows as a promising radiopharmaceutical for diagnostic use with incremental value over [18F]FDG. In this study, non-human primates (Sapajus cay) were studied. PET-CT study was performed after the injection of [18F]FLT. Whole-body images were obtained to evaluate the biodistribution and to calculate the dosimetry of bone marrow, as this is a critic organ to this radiotracer. Time-activity curves were traced, normalized activity uptake of the organs of interest were calculated, and mean absorbed dose was also calculated using the established Medical Internal Radiation Dosimetry (MIRD) scheme. The mean dose obtained in the animal model per unit of activity administered was 8.7 μGy/MBq. This result was extrapolated to an adult human model resulting in 32 μGy/MBq, thereby suggesting that [18F]FLT is a secure diagnostic tool to be used on the tracing of patients with DLBCL.
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Objective To evaluate the capability of 18 F-FLT uptake and investigate the early radiation response of human colorectal cancer cells HCT116 exposed to 6 MV X-rays.Methods 3.7 kBq 18F-FLT was added to HCT116 cells with different cell numbers (1.0 × 105-1.5 × 106) and cultured with different times (36,60,84 h).The 18F-FLT uptake rate was measured with a γ-counter after exposed to different does of 6 MV X-rays (0,2,4,6,8 Gy) after 24,48,and 72 h of irradiation.Then the cell uptake inhibition rate,cell proliferation,and cell cycle phase were measured.Results The uptake rate of 18F-FLT in HCT116 was (18.97 ± 1.16)％.The 18F-FLT uptake inhibition rates at 24 h after different does of irradiation (2,4,6,8 Gy) were (32.10±0.02)％,(54.46 ±0.04)％,(62.74 ±0.04)％,and (65.81 ±4.81)％,respectively,which was positively correlated with radiation dose.Conclusions The 18F-FLT uptake rate of human colorectal cancer HCT116 cells could be used to evaluate the early radiation response.
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PURPOSE: Several radioisotope-labeled thymidine derivatives such as [11C]thymidine was developed to demonstrate cell proliferation in tumor. But it is difficult to track metabolism with [11C]thymidine due to rapid in vivo degradation and its short physical half-life. 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT) was reported to have the longer half life of fluorine-18 and the lack of metabolic degradation in vivo. Here, we described the synthesis of the 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT) and compared with [18F]FET and [18F]FDG in cultured 9L cell and obtained the biodistribution and PET image in 9L tumor bearing rats. MATERIAL AND METHOD: For the synthesis of [18F]FLT, 3-N-tert-butoxycarbonyl-(5'-O-(4,4'-dimethoxytriphenylmethyl)-2'-deoxy-3'-O-(4-nitrobenzenesulfonyl)-beta-D-threopentofuranosyl)thymine was used as a FLT precursor, on which the tert-butyloxycarbonyl group was introduced to protect N3-position and nitrobenzenesulfonyl group. Radiolabeling of nosyl substitued precursor with 18F was performed in acetonitrile at 120 degrees C and deproteced with 0.5 N HCl. The cell uptake was measured in cultured 9L glioma cell. The biodistribution was evaluated in 9L tumor bearing rats after intravenous injection at 10 min, 30 min, 60 min and 120 min and obtained PET image 60 minutes after injection. RESULTS: The radiochemical yield was about 20-30% and radiochemical purity was more than 95% after HPLC purification. Cellular uptake of [18F]FLT was increased as time elapsed. At 120 min post-injection, the ratios of tumor/blood, tumor/muscle and tumor/brain were 1.61+/-0.34, 1.70+/-0.30 and 9.33+/-2.22, respectively. The 9L tumor was well visualized at 60 min post injection in PET image. CONCLUSION: The uptake of [18F]FLT in tumor was higher than in normal brain and PET image of [18F]FLT was acceptable. These results suggest the possibility of [18F]FLT as an imaging agent for brain tumor.
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Animals , Rats , Brain , Brain Neoplasms , Cell Proliferation , Chromatography, High Pressure Liquid , Glioma , Half-Life , Injections, Intravenous , Metabolism , ThymidineABSTRACT
Objective To investigate the biodistribution and positron emission tomography (PET) imaging of 3′-deoxy-3′-~ 18 F-fluorothymidine (~ 18 F-FLT) in a murine model of pulmonary carcinoma, and to evaluate the use of ~ 18 F-FLT as a new PET tracer for diagnosis of pulmonary malignant tumor. Methods 40 T739 mice bearing the pulmonary adenocarcinoma were randomly divided into five groups according to different tracers and time after their injection (n=8/group). The biodistribution of mice for ~ 18 F-FLT was measured with well-gamma detector at 30min, 60min, 90min, 120min after injection via the tail veins. The biodistribution of mice for ~ 18 F-FDG was examined at 60min after injection as controls. In addition, the PET imaging of mice was performed using two tracers. Results In the biodistribution study of ~ 18 F-FLT, considerable radioactive uptake in tumor was observed, and high radioactivity was showed in the kidney and spleen. The T/NT ratios of tumor/blood, tumor/muscle and tumor/lung was all above 2.0. The tumor PET images with ~ 18 F-FLT were clear, as well. Conclusions The uptake of ~ 18 F-FLT in pulmonary adenocarcinoma is higher than that in normal tissues, thus the pulmonary neoplasm could be identified accurately with PET imaging. Our preliminary study of ~ 18 F-FLT in lung carcinoma xenografts is satisfactory, and it provides a basis for further clinical study.