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Background: Intraoperative radiotherapy (IORT) is a novel promising technology that may replace external beam radiation therapy (EBRT) as boost for patients receiving breast-conserving surgery. To better evaluate the efficacy of IORT using low-kilovoltage (low-kV) X-rays as boost, we presented this meta-analysis according to the PRISMA checklist. Methods: Studies reported survival outcomes of intraoperative radiation using low-kilovoltage X-rays system (Intrabeam®, Carl Zeiss Meditec, Dublin, CA, USA) as boost were identified through electronic bibliographic database: PUBMED. The meta-analysis module in Stata (16.0) is used to pool the studies. A Poisson regression model is used to predict a 5-year local recurrence rate. Results: Twelve studies including 3006 cases were included in the final analysis, with a median follow-up of 55 months weighted by sample size. The pooled local recurrence rate is 0.39% per person-year (95% CI: 0.15%-0.71%), with a low degree of heterogeneity (I2 = 0%). The predicted 5-year local recurrence rate was 3.45%. No difference in pooled local recurrence rate was found between non-neoadjuvant patients studies and neoadjuvant patients studies (0.41% per person-year vs. 0.58% per person-year, P = 0.580). Conclusions: This study shows that low-kV IORT is an effective method as boost in breast cancer patients, with a low pooled local recurrence rate and low predicted 5-year local recurrence rate. Besides, no difference in the local recurrence rate was found between non-neoadjuvant patients studies and neoadjuvant patients studies. Low-kV IORT boost may be a promising alternative to EBRT boost in the future, which is being tested in the ongoing TARGIT-B trial.
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Neoplasias de la Mama , Humanos , Femenino , Rayos X , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/cirugía , Lista de Verificación , Mastectomía Segmentaria , Terapia NeoadyuvanteRESUMEN
The purpose of this study was to employ novel tracers PET imaging approach to define the time course and intensity of myocardial repair after apoptosis and to correlate the imaging signal to immunohistochemical staining in myocardial infarction (MI). We designed novel αVß3-targeted and radio-functionalized tracers for detection of apoptosis in H9C2 cells and myocardial tissue. MI rats were imaged with [18F]FDG, [18F]ANP-Cin or [18F]ANP-RGD2 using a small-animal PET/CT device. Rats were sacrificed, and tissue samples from viable and injured myocardial areas were sectioned for TUNEL assay and histology. The uncorrected radiochemical yield of [18F]ANP-Cin and [18F]ANP-RGD2 were 41.3 ± 5.4% and 21.17 ± 4.7%, respectively. Two tracers meet many criteria for cardiac imaging, including high stability, high binding, no toxicity, fast renal clearance and excellent biodistribution in rat models. The uptake of [18F]ANP-Cin was significantly higher on the 1st and 3rd day than the 7th or 28th day after MI induction, a timeframe associated with increased cardiomyocyte apoptosis. Higher uptake of [18F]ANP-Cin was observed in MI rats than in N-acetylcysteine (NAC)-treated rats on the 3rd days. In contrast with [18F]ANP-Cin, no hot-spots was observed with [18F]ANP-RGD2 on the 1st day and more hot-spots was observed from the 3rd day to the 7th day, then less on the 28th days in the high apoptotic site. There was no uptake of [18F]FDG in or around the apoptotic region. On the 7th day the uptake of [18F]ANP-RGD2 was higher in NAC-treated rats than MI rats. [18F]ANP-Cin and [18F]ANP-RGD2 are superior to [18F]FDG for PET/CT imaging for evaluation of cardiomyocyte apoptosis and tissue repair processes in the MI rats.
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Infarto del Miocardio , Tomografía Computarizada por Tomografía de Emisión de Positrones , Animales , Apoptosis , Infarto del Miocardio/diagnóstico por imagen , Miocitos Cardíacos , Tomografía de Emisión de Positrones , Ratas , Distribución TisularRESUMEN
PURPOSE: To evaluate the potential feasibility of Al[18F]F-1,4,7-triazacyclononane-1,4,7-triaceticacid (NOTA)-tripolyethylene glycol (PEG3)-Duramycin (Al[18F]F-NOTA-PEG3-Duramycin) positron emission tomography (PET) for imaging of rat hepatic fibrosis. PROCEDURES: Hepatic fibrosis rat models were injected with thioacetamide (TAA), control rats received saline (n = 12 per group). Rats in the two groups underwent PET imaging using Al[18F]F-NOTA-PEG3-Duramycin and [18F]FDG at multiple time points (2, 4, 6, and 8 weeks after TAA or saline treatment). Between-group differences in the apoptosis rate, fibrotic activity, and liver uptake of Al[18F]F-NOTA-PEG3-Duramycin or [18F]FDG were assessed using Student's t-test. Imaging results were cross-validated using histopathology detection and Pearson's correlation test was used to assess the association relationships between radioactive uptake value and quantified histopathological data. RESULTS: Compared with control group at multiple time points, each TAA group showed a higher radioactive liver uptake of Al[18F]F-NOTA-PEG3-Duramycin (each P < 0.05). Furthermore, the increase in the liver uptake of Al[18F]F-NOTA-PEG3-Duramycin was proportional to the progression of fibrosis (R2 = 0.8846, P < 0.001) and apoptosis rate (R2 = 0.9208, P < 0.001) in the TAA group. Meanwhile, there were also between-group differences in [18F]FDG uptake in each phase (P < 0.05), however, no relationship between [18F]FDG uptake and the fibrotic activity was observed. CONCLUSIONS: Al[18F]F-NOTA-PEG3-Duramycin PET/CT could be applied to monitor the progression of liver fibrosis, whereas [18F]FDG PET/CT could not. Implications of this work for noninvasive diagnosis of liver fibrosis, assessment of fibrotic activity, and evaluation of antifibrotic therapy are expected.
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Tomografía Computarizada por Tomografía de Emisión de Positrones , Animales , Muerte Celular , Humanos , RatasRESUMEN
Comparing MRI and histopathology, this study aims to comprehensively explore the potential application of 18F-trifluoromethylated D-cysteine (S-[18F]CF3-D-CYS) in evaluating glioma by using orthotopic C6 glioma models. Sprague-Dawley (SD) rats (n = 9) were implanted with C6 glioma cells. Tumor growth was monitored every week by multiparameter MRI [including dynamic contrast-enhanced MRI (DCE-MRI)], [18F]FDG, S-[18F]CF3-D-CYS, and [18F]FDOPA PET imaging. Repeated scans of the same rat with the two or three [18F]-labeled radiotracers were investigated. Initial regions of interest were manually delineated on T2WI and set on the same level of PET images, and tumor-to-normal brain uptake ratios (TNRs) were calculated to semiquantitatively assess the tracer accumulation in the tumor. The tumor volume in PET and histopathology was calculated. HE and Ki67 immunohistochemical staining were further performed. The correlations between the uptake of S-[18F]CF3-D-CYS and Ki67 were analyzed. Dynamic S-[18F]CF3-D-CYS PET imaging showed tumor uptake rapidly reached a peak, maintained plateau during 10-30 min after injection, then decreased slowly. Compared with [18F]FDG and [18F]FDOPA PET imaging, S-[18F]CF3-D-CYS PET demonstrated the highest TNRs (P < 0.05). There were no significant differences in the tumor volume measured on S-[18F]CF3-D-CYS PET or HE specimen. Furthermore, our results showed that the uptake of S-[18F]CF3-D-CYS was significantly positively correlated with tumor Ki67, and the poor accumulated S-[18F]CF3-D-CYS was consistent with tumor hemorrhage. There was no significant correlation between the S-[18F]CF3-D-CYS uptakes and the Ktrans values derived from DCE-MRI. In comparison with MRI and histopathology, S-[18F]CF3-D-CYS PET performs well in the diagnosis and evaluation of glioma. S-[18F]CF3-D-CYS PET may serve as a valuable tool in the clinical management of gliomas.
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Purpose: N-(2-[18F]fluoropropionyl)-L-glutamate ([18F]FPGLU) for hepatocellular carcinoma (HCC) imaging has been performed in our previous studies, but its radiosynthesis method and stability in vivo need to be improved. Hence, we evaluated the synthesis and biological properties of a simple [18F]-labeled glutamate analog, [18F]AlF-1,4,7-triazacyclononane-1,4,7-triacetic-acid-2-S-(4-isothiocyanatobenzyl)-l-glutamate ([18F]AlF-NOTA-NSC-GLU), for HCC imaging. Procedures: [18F]AlF-NOTA-NSC-GLU was synthesized via a one-step reaction sequence from NOTA-NSC-GLU. In order to investigate the imaging value of [18F]AlF-NOTA-NSC-GLU in HCC, we conducted positron emission tomography/computed tomography (PET/CT) imaging and competitive binding of [18F]AlF-NOTA-NSC-GLU in human Hep3B tumor-bearing mice. The transport mechanism of [18F]AlF-NOTA-NSC-GLU was determined by competitive inhibition and protein incorporation experiments in vitro. Results: [18F]AlF-NOTA-NSC-GLU was prepared with an overall radiochemical yield of 29.3 ± 5.6% (n = 10) without decay correction within 20 min. In vitro competitive inhibition experiments demonstrated that the Na+-dependent systems X AG - , B0+, ASC, and minor X C - were involved in the uptake of [18F]AlF-NOTA-NSC-GLU, with the Na+-dependent system X AG - possibly playing a more dominant role. Protein incorporation studies of the Hep3B human hepatoma cell line showed almost no protein incorporation. Micro-PET/CT imaging with [18F]AlF-NOTA-NSC-GLU showed good tumor-to-background contrast in Hep3B human hepatoma-bearing mouse models. After [18F]AlF-NOTA-NSC-GLU injection, the tumor-to-liver uptake ratio of [18F]AlF-NOTA-NSC-GLU was 2.06 ± 0.17 at 30 min post-injection. In vivo competitive binding experiments showed that the tumor-to-liver uptake ratio decreased with the addition of inhibitors to block the XAG system. Conclusions: We have successfully synthesized [18F]AlF-NOTA-NSC-GLU as a novel PET tracer with good radiochemical yield and high radiochemical purity. Our findings indicate that [18F]AlF-NOTA-NSC-GLU may be a potential candidate for HCC imaging. Also, a further biological evaluation is underway.
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PURPOSE: This study aimed to evaluate the potential value of 2-[18F]fluoropropionic acid ([18F]FPA) for PET imaging of prostate cancer (PCa) and to explore the relationship between [18F]FPA accumulation and fatty acid synthase (FASN) levels in PCa models. The results of the first [18F]FPA PET study of a PCa patient are reported. PROCEDURES: The LNCaP, PC-3 cell lines with high FASN expression, and DU145 cell lines with low FASN expression were selected for cell culture. A PET imaging comparison of [18F]FDG and [18F]FPA was performed in LNCaP, PC-3, and DU145 tumors. Additionally, in vivo inhibition experiments in those models were conducted with orlistat. In a human PET study, a patient with PCa before surgery was examined with [18F]FPA PET and [18F]FDG PET. RESULTS: The uptake of [18F]FPA in the LNCaP and PC-3 tumors was higher than that of [18F]FDG (P<0.05 and P<0.05), but was lower in DU145 tumors (P<0.05). The accumulation (% ID/g) of [18F]FPA in the LNCaP, PC-3, and DU145 tumors decreased by 27.6, 40.5, and 11.7 %, respectively, after treatment with orlistat. The [18F]FPA showed higher radioactive uptake than [18F]FDG in the first PCa patient. CONCLUSIONS: The [18F]FPA uptake in PCa models may be varies with fatty acid synthase activity and could be reduced after administration of a single FASN inhibitor, albeit the activity that is not measured directly. The [18F]FPA seems to be a potential broad-spectrum PET imaging agent and may serve as a valuable tool in the diagnosis of PCa in humans.
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Propionatos , Neoplasias de la Próstata , Línea Celular Tumoral , Humanos , Masculino , Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/metabolismoRESUMEN
N-(2-18F-fluoropropionyl)-l-glutamate (18F-FPGLU), a new N-substituted 18F-labeling l-glutamate, is a potential amino acid tracer for oncology PET imaging with good tumor-to-background contrast in several tumor-bearing mice. Herein, we evaluated the potential value of 18F-FPGLU for PET imaging of glioma in orthotopic glioma-bearing SD rats. A series of competitive inhibition experiments with various types of inhibitors were conducted with C6 cells to investigate the transport mechanism of 18F-FPGLU in glioma. Establishment of orthotopic rat C6 glioma-bearing SD rats models was confirmed by MRI. Then PET imaging of 18F-FPGLU was performed on the orthotopic C6 glioma-bearing SD rats and compared with that of 18F-FDG. After the rats sacrificed, the whole brain was collected and immunofluorescence staining of glial fibrillary acidic protein (GFAP) and matrix metalloproteinase 2 (MMP2) were processed. Na+-dependent system XAG- and Na+-independent system XC- are the mainly transporters of 18F-FPGLU in C6 cells. N-methyl-d-aspartate (NMDA) receptor, which is associated with the invasiveness and proliferation of glioma cells, is also involved in the uptake of 18F-FPGLU. High uptake and retention of 18F-FPGLU was observerd in orthotopic glioma with good visualization and the tumor/background ratio reached 2.35 at 60 min post-injection, which was significantly higher than that of 18F-FDG (1.72) in small-animal PET images. High expression of MMP-2 and GFAP was observed in the immunofluorescence staining of glioma xerography slices. 18F-FPGLU seems to be a better potential PET tracer than 18F-FDG for brain glioma imaging with good visualization and ability to assess the tumor activity.
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Encéfalo/diagnóstico por imagen , Radioisótopos de Flúor/química , Glioma/diagnóstico por imagen , Glutamatos/química , Tomografía de Emisión de Positrones/métodos , Radiofármacos/química , Animales , Línea Celular Tumoral , Técnica del Anticuerpo Fluorescente , Glutamatos/farmacocinética , Xenoinjertos , Imagen por Resonancia Magnética/métodos , Ratas , Ratas Sprague-DawleyRESUMEN
PURPOSE: Externalization of phosphatidylethanolamine (PE) in dying cells makes the phospholipid an attractive target for apoptosis imaging. However, no ideal PE-targeted positron emission tomography (PET) radiotracer was developed. The goal of the study was to develop a novel PE-targeted radiopharmaceutical to imaging apoptosis. PROCEDURE: In this study, we have radiolabeled PE-binding polypeptide duramycin with fluorine-18 for PET imaging of apoptosis. Al[18F]F-NOTA-PEG3-duramycin was synthesized via chelation reaction of NOTA-PEG3-duramycin with Al[18F]F. PE-binding capacity of Al[18F]F-NOTA-PEG3-duramycin was determined in a competitive radiometric PE-binding assay. The pharmacokinetic profile was evaluated in Kunming mice. The apoptosis imaging capacity of Al[18F]F-NOTA-PEG3-duramycin was evaluated using in vitro cell uptake assay with camptothecin-treated Jurkat cells, along with in vivo PET imaging using erlotinib-treated nude mice. RESULTS: The total synthesis procedure lasted for 30 min, with a decay-uncorrected radiochemical yield of 21.3 ± 2.6 % (n = 10). Compared with the control cells, the binding of Al[18F]F-NOTA-PEG3-duramycin with camptothecin-induced apoptotic cells resulted in a tripling increase. A competitive radiometric PE-binding assay strongly confirmed the binding of Al[18F]F-NOTA-PEG3-duramycin to PE. The biodistribution study showed rapid blood clearance, prominent kidney retention, and low liver uptake. In the in vivo PET/CT imaging, Al[18F]F-NOTA-PEG3-duramycin demonstrated 2-fold increase in erlotinib-treated HCC827 tumors in nude mice. CONCLUSION: Considering the facile preparation and improved biological properties, Al[18F]F-NOTA-PEG3-duramycin seems to be a promising PET tracer candidate for imaging apoptosis in the monitoring of cancer treatment.
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Apoptosis , Radioisótopos de Flúor/química , Sondas Moleculares/química , Fosfatidiletanolaminas/metabolismo , Tomografía Computarizada por Tomografía de Emisión de Positrones , Bibliotecas de Moléculas Pequeñas/química , Coloración y Etiquetado , Animales , Bacteriocinas/farmacología , Camptotecina/farmacología , Línea Celular Tumoral , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Compuestos Organometálicos/química , Péptidos/farmacología , Distribución TisularRESUMEN
Although 11C-labelled sulfur-containing amino acids (SAAs) including L-methyl-[11C]methionine and S-[11C]-methyl-L-cysteine, are attractive tracers for glioma positron emission tomography (PET) imaging, their applications are limited by the short half-life of the radionuclide 11C (t1/2 = 20.4 min). However, development of 18F-labelled SAAs (18F, t1/2 = 109.8 min) without significant structural changes or relying on prosthetic groups remains to be a great challenge due to the absence of adequate space for chemical modification. Methods: We herein present 18F-trifluoromethylated D- and L-cysteines which were designed by replacing the methyl group with 18F-trifluoromethyl group using a structure-based bioisosterism strategy. These two enantiomers were synthesized stereoselectively from serine-derived cyclic sulfamidates via a nucleophilic 18F-trifluoromethylthiolation reaction followed by a deprotection reaction. Furthermore, we conducted preliminary in vitro and in vivo studies to investigate the feasibility of using 18F-trifluoromethylated cysteines as PET tracers for glioma imaging. Results: The two-step radiosynthesis provided the desired products in excellent enantiopurity (ee > 99%) with 14% ± 3% of radiochemical yield. In vitro cell study demonstrated that both enantiomers were taken up efficiently by C6 tumor cells and were mainly transported by systems L and ASC. Among them, the D-enantiomer exhibited relatively good stability and high tumor-specific accumulation in the animal studies. Conclusion: Our findings indicate that 18F-trifluoromethylated D-cysteine, a new SAA tracer, may be a potential candidate for glioma imaging. Taken together, our study represents a first step toward developing 18F-trifluoromethylated cysteines as structure-mimetic tracers for PET tumor imaging.
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Cisteína/aislamiento & purificación , Glioma/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Trazadores Radiactivos , Animales , Cisteína/administración & dosificación , Cisteína/análogos & derivados , Ratones , Trasplante de Neoplasias , Trasplante HeterólogoRESUMEN
PURPOSE: 2-[18F]Fluoropropionic acid (RS-[18F]FPA) has shown potential value as a short-chain fatty acid positron emission tomography (PET) tracer for the detection of liver cancer. However, RS-[18F]FPA is a mixture of 2-R-[18F]fluoropropionic acid (R-[18F]FPA) and 2-S-[18F]fluoropropionic acid (S-[18F]FPA). The aim of this study is to validate the feasibility of R-[18F]FPA in preclinical PET imaging of liver cancer and to compare the use of R-[18F]FPA with that of RS-[18F]FPA and S-[18F]FPA. PROCEDURES: A comparative study of R-[18F]FPA, RS-[18F]FPA, S-[18F]FPA, and [18F]FDG micro-PET imaging was performed in HepG2 and SK-Hep-1 tumor-bearing mice. A comparison of R-[18F]FPA uptake with that of S-[18F]FPA by HepG2 and SK-Hep-1 cells was made at different time points. Additionally, in vivo blocking experiments in HepG2 and SK-Hep-1 tumor models were conducted with orlistat and 3-nitropropionic acid (3-NP). In vitro blocking experiments with orlistat or 3-NP were performed with HepG2 and SK-Hep-1 cells. RESULTS: The radioactivity uptake values of R-[18F]FPA were comparable to those of RS-[18F]FPA but were higher than those of S-[18F]FPA and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) in HepG2 tumors. The radioactivity uptake values of R-[18F]FPA in large HepG2 tumors were lower than those of [18F]FDG (P < 0.05), while R-[18F]FPA PET was significantly superior to [18F]FDG PET in detecting small tumors (both SK-Hep-1 and HepG2 tumors). The in vivo PET imaging experiments showed that R-[18F]FPA uptake in HepG2 tumor-bearing mice was blocked by 19.3 % and 31.8 % after treatment with orlistat and 3-NP, respectively. The radioactivity uptake values of R-[18F]FPA in SK-Hep-1 tumor-bearing mice was blocked by 39.5 % with orlistat. CONCLUSION: R-[18F]FPA seems to be more potential than S-[18F]FPA as an optically pure PET probe, with effective compensation for the deficiencies of [18F]FDG, particularly in PET imaging of small liver cancer. The uptake mechanism of [18F]FPA in liver cancer may be related to fatty acid synthesis and the tricarboxylic acid cycle. However, compared with the racemic RS-[18F]FPA, the possible advantages of R-enantiomer R-[18F]FPA still needs further research.
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Fluorocarburos/química , Neoplasias Hepáticas/diagnóstico por imagen , Tomografía de Emisión de Positrones , Radiofármacos/química , Animales , Línea Celular Tumoral , Ciclo del Ácido Cítrico , Ácido Graso Sintasas/metabolismo , Humanos , Neoplasias Hepáticas/patología , Ratones Endogámicos BALB C , Ratones Desnudos , Distribución Tisular , Tomografía Computarizada por Rayos XRESUMEN
OBJECTIVE: To evaluate the preclinical value of 18F-fluoropropionic acid (18F-FPA) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) for imaging HCCs. METHODS: The 18F-FPA and 18F-FDG uptake patterns in 3 HCC cell lines (Hep3B, HepG2, and SK-Hep1) were assessed in vitro and in vivo. The 18F-FPA uptake mechanism was investigated using inhibition experiments with orlistat and 5-tetradecyloxy-2-furoic acid. The 18F-FPA PET imaging was performed in different tumor animal models and compared with 18F-FDG. We also evaluated the expressions of glucose transporter-1 (GLUT1), fatty acid synthase (FASN), and matrix metalloproteinase-2 (MMP2) in these cell lines. RESULTS: In vitro experiments showed that the radiotracer uptake patterns were complementary in the HCC cell lines. Orlistat and 5-tetradecyloxy-2-furoic acid decreased the uptake of 18F-FPA. The tumor-to-liver ratio of 18F-FPA was superior to that of 18F-FDG in the SK-Hep1 and HepG2 tumors ( P < .05). However, in the Hep3B tumors, the tumor-to-liver normalized uptake of 18F-FDG was higher than 18F-FPA ( P < .01). FASN was highly expressed in cell lines with high 18F-FPA uptake, whereas GLUT1 was highly expressed in cell lines with high 18F-FDG uptake. The 18F-FPA uptake correlated with FASN ( r = 0.89, P = .014) and MMP2 ( r = 0.77, P = .002) expressions. CONCLUSIONS: PET imaging with 18F-FPA combined with 18F-FDG can be an alternative for detecting HCC.
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Carcinoma Hepatocelular/diagnóstico por imagen , Acido Graso Sintasa Tipo I/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Neoplasias Hepáticas/diagnóstico por imagen , Metaloproteinasa 2 de la Matriz/metabolismo , Radiofármacos/farmacocinética , Animales , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Fluorodesoxiglucosa F18/administración & dosificación , Fluorodesoxiglucosa F18/farmacocinética , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Ratones , Trasplante de Neoplasias , Orlistat/administración & dosificación , Orlistat/farmacología , Tomografía de Emisión de Positrones , Propionatos/administración & dosificación , Propionatos/farmacocinética , Radiofármacos/administración & dosificación , Regulación hacia ArribaRESUMEN
PURPOSE: The purpose of this study was to assess the potential utility of small-molecule apoptotic radiotracer, 2-(5-[18F]fluoropentyl)-2-methyl malonic acid ([18F]ML-10), for positron emission tomography (PET)/computed tomography (CT) monitoring the progression of pulmonary fibrosis in a rat model. PROCEDURES: Male Sprague-Dawley rats were used to establish a rat model of pulmonary fibrosis by means of bleomycin (BLM) administration; control rats received saline (n = 12 per group). PET/CT with [18F]ML-10 and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) was performed in two groups at different stages of pulmonary fibrosis. The fibrotic response and the cell apoptosis were assessed with histologic examination. Differences in the apoptosis rate, fibrotic activity, and the lung uptake of [18F]ML-10 and [18F]FDG between two groups were determined with Student t test. RESULTS: Compared with control group, BLM group showed a higher lung uptake of [18F]ML-10 at all imaging time points (all P < 0.001). During the fibrotic phase of this disease model (days 21 and 28), the lung uptake of [18F]ML-10 was higher than that of [18F]FDG in the BLM group (all P < 0.001). Moreover, accumulation of [18F]ML-10 in the lung tissues increased in proportion to the apoptosis rate (R2 = 0.9863, P < 0.0001) and fibrotic activity (R2 = 0.9631, P < 0.0001) of rat pulmonary fibrosis. Conversely, no correlation between [18F]FDG uptake and fibrotic activity was found. CONCLUSIONS: [18F]ML-10 PET/CT enabled monitoring the progression of rat pulmonary fibrosis, whereas [18F]FDG PET/CT could not. Implications for noninvasive diagnosis of pulmonary fibrosis, assessment of fibrotic activity, and evaluation of antifibrotic therapy are expected.
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Apoptosis , Tomografía de Emisión de Positrones , Fibrosis Pulmonar/diagnóstico por imagen , Fibrosis Pulmonar/patología , Radiofármacos/química , Animales , Bleomicina , Colágeno/metabolismo , Fluorodesoxiglucosa F18/química , Pulmón/diagnóstico por imagen , Pulmón/patología , Masculino , Ácido Metilmalónico/análogos & derivados , Ácido Metilmalónico/química , Tomografía Computarizada por Tomografía de Emisión de Positrones , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: To investigate the value of 2-(3-[18F]fluoropropyl)-2-methyl-malonic acid ([18F]ML-8) positron emission tomography (PET) imaging of rat pulmonary fibrosis. METHODS: Male Sprague-Dawley rats were divided into 2 groups, including pulmonary fibrosis model group and control group. The rat model was established by an intratracheal instillation of bleomycin (BLM). Control rats were treated with saline. Positron emission tomography/computed tomography (CT) with [18F]ML-8 or 18F-fluorodeoxyglucose ([18F]FDG) was performed on 2 groups. After PET/CT imaging, lung tissues were collected for histologic examination. Data were analyzed and comparisons between 2 groups were performed using Student t test. RESULTS: Bleomycin-treated rats showed a higher lung uptake of [18F]ML-8 than control rats ( P < .05). In BLM-treated rats, the lung to muscle relative uptake ratio of [18F]ML-8 was also higher than that of [18F]FDG ( P < .05). Pathological examination showed overproliferation of fibroblasts and deposition of collagen in lungs from BLM-treated rats. Compared to control rats, BLM-treated rats had higher lung hydroxyproline content ( P < .05). Immunofluorescence staining indicated more apoptotic cells in BLM-treated rats than those in control rats. Moreover, the apoptosis rate of lung tissues obtained from BLM-treated rats was higher than that from control rats ( P < .05). CONCLUSIONS: 2-(3-[18F]fluoropropyl)-2-methyl-malonic acid PET/CT could be used for noninvasive diagnosis of pulmonary fibrosis in a rat model.
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Apoptosis , Ácido Metilmalónico/análogos & derivados , Tomografía de Emisión de Positrones , Fibrosis Pulmonar/diagnóstico por imagen , Fibrosis Pulmonar/patología , Animales , Fluorodesoxiglucosa F18/química , Pulmón/diagnóstico por imagen , Pulmón/patología , Masculino , Ácido Metilmalónico/química , Tomografía Computarizada por Tomografía de Emisión de Positrones , Ratas Sprague-DawleyRESUMEN
OBJECTIVES: As acid-base imbalance is involved in many pathological processes, the capability to image tissue pH alterations in the clinic could offer new ways to detect disease and respond to treatment. In this study, the authors show that tissue pH can be imaged in vivo with 11C-labeled bicarbonate (H11CO3-) buffer and positron emission tomography (PET). METHODS: H11CO3- was produced by on-column NaOH adsorption. Biodistribution of H11CO3- in normal mice was determined. In addition, uptake studies and inhibition experiments of H11CO3- in the S180 fibrosarcoma-bearing mice and the inflammatory mice were investigated with PET imaging. The tumor and inflammatory interstitial pH was measured by a needle pH microelectrode. RESULTS: PET imaging demonstrated the high uptake of H11CO3- in mice tumor tissues and inflammatory tissues, which showed that the average tumor or inflammatory interstitial pH was significantly lower than the surrounding tissue. Administration of sodium bicarbonate in the drinking water increased the measured tumor pH, while the uptake of H11CO3- in mice model tissues had no change. Similarly, administration with ammonium chloride (NH4Cl) decreased the pH, whereas the unchanged uptake of H11CO3- in mice model tissues was also found. However, after administration of acetazolamide, the low uptake of H11CO3- in mice model tissues was observed. CONCLUSIONS: H11CO3- solution is an endogenous bicarbonate buffer tracer that can be injected into patients without toxicity. H11CO3- PET can be used clinically to image pathological processes that are associated with acid-base imbalance, such as cancer and inflammation.
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Bicarbonatos/farmacocinética , Radioisótopos de Carbono/farmacocinética , Tomografía de Emisión de Positrones/métodos , Acetazolamida/farmacología , Animales , Bicarbonatos/administración & dosificación , Bicarbonatos/química , Radioisótopos de Carbono/administración & dosificación , Radioisótopos de Carbono/química , Inhibidores de Anhidrasa Carbónica/farmacología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Fibrosarcoma/diagnóstico por imagen , Fibrosarcoma/patología , Humanos , Concentración de Iones de Hidrógeno , Inflamación/diagnóstico por imagen , Inflamación/patología , Ratones , Distribución Tisular/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
N-(2-[18 F]Fluoropropionyl)-l-glutamic acid ([18 F]FPGLU) is a potential amino acid tracer for tumor imaging with positron emission tomography. However, due to the complicated multistep synthesis, the routine production of [18 F]FPGLU presents many challenging laboratory requirements. To simplify the synthesis process of this interesting radiopharmaceutical, an efficient automated synthesis of [18 F]FPGLU was performed on a modified commercial fluorodeoxyglucose synthesizer via a 2-step on-column hydrolysis procedure, including 18 F-fluorination and on-column hydrolysis reaction. [18 F]FPGLU was synthesized in 12 ± 2% (n = 10, uncorrected) radiochemical yield based on [18 F]fluoride using the tosylated precursor 2. The radiochemical purity was ≥98%, and the overall synthesis time was 35 minutes. To further optimize the radiosynthesis conditions of [18 F]FPGLU, a brominated precursor 3 was also used for the preparation of [18 F]FPGLU, and the improved radiochemical yield was up to 20 ± 3% (n = 10, uncorrected) in 35 minutes. Moreover, all these results were achieved using the similar on-column hydrolysis procedure on the modified fluorodeoxyglucose synthesis module.
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Técnicas de Química Sintética/métodos , Fluorodesoxiglucosa F18/síntesis química , Glutamatos/síntesis química , Neoplasias/diagnóstico por imagen , Tomografía de Emisión de Positrones , Automatización , Fluorodesoxiglucosa F18/química , Glutamatos/química , Hidrólisis , Cinética , Trazadores RadiactivosRESUMEN
INTRODUCTION: Several 11C and 18F labeled 3,4-dihydroxy-l-phenylalanine (l-DOPA) analogues have been used for neurologic and oncologic diseases, especially for brain tumors and neuroendocrine tumors PET imaging. However, 18F-labeled N-substituted l-DOPA analogues have not been reported so far. In the current study, radiosynthesis and biological evaluation of a new 18F-labeled l-DOPA analogue, N-(2-[18F]fluoropropionyl)-3,4-dihydroxy-l-phenylalanine ([18F]FPDOPA) for tumor PET imaging are performed. METHODS: The synthesis of [18F]FPDOPA was via a two-step reaction sequence from 4-nitrophenyl-2-[18F]fluoropropionate ([18F]NFP). The biodistribution of [18F]FPDOPA was determined in normal Kunming mice. In vitro competitive inhibition and protein incorporation experiments were performed with SPC-A-1 lung adenocarcinoma cell lines. PET/CT studies of [18F]FPDOPA were conducted in C6 rat glioma and SPC-A-1 human lung adenocarcinoma and H460 human large cell lung cancer-bearing nude mice. RESULTS: [18F]FPDOPA was prepared with a decay-corrected radiochemical yield of 28±5% and a specific activity of 50±15GBq/µmol (n=10) within 125min. In vitro cell experiments showed that [18F]FPDOPA uptake in SPC-A-1 cells was primarily transported through Na+-independent system L, with Na+-dependent system B0,+ and system ASC partly involved in it. Biodistribution data in mice showed that renal-bladder route was the main excretory system of [18F]FPDOPA. PET imaging demonstrated intense accumulation of [18F]FPDOPA in several tumor xenografts, with (8.50±0.40)%ID/g in C6 glioma, (6.30±0.12)%ID/g in SPC-A-1 lung adenocarcinoma, and (6.50±0.10)%ID/g in H460 large cell lung cancer, respectively. CONCLUSION: A novel N-substituted 18F-labeled L-DOPA analogue [18F]FPDOPA is synthesized and evaluated in vitro and in vivo. The results support that [18F]FPDOPA seems to be a potential PET tracer for tumor imaging, especially be a better potential PET tracer than [18F]fluoro-2-deoxy-d-glucose ([18F]FDG) for brain tumor imaging.
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Neoplasias/diagnóstico por imagen , Fenilalanina/análogos & derivados , Fenilalanina/síntesis química , Fenilalanina/farmacocinética , Tomografía de Emisión de Positrones , Animales , Línea Celular Tumoral , Técnicas de Química Sintética , Estabilidad de Medicamentos , Humanos , Ratones , Neoplasias/metabolismo , Fenilalanina/química , Trazadores Radiactivos , Radioquímica , Ratas , Distribución TisularRESUMEN
BACKGROUND: Phosphatidylserine (PS)-targeting positron emission tomography (PET) imaging with labeled small-molecule tracer is a crucial non-invasive molecule imaging method of apoptosis. In this study, semi-automatic radiosynthesis and biodistribution of N-(2-18F-fluoropropionyl)-bis(zinc(II)-dipicolylamine) (18F-FP-DPAZn2), as a potential small-molecule tracer for PET imaging of cell death in Alzheimer's disease (AD) model, were performed. METHODS: 18F-FP-DPAZn2 was synthesized on the modified PET-MF-2V-IT-I synthesizer. Biodistribution was determined in normal mice and PET images of AD model were obtained on a micro PET-CT scanner. RESULTS: With the modified synthesizer, the total decay-corrected radiochemical yield of 18F-FP-DPAZn2 was 35 ± 6% (n = 5) from 18F- within 105 ± 10 min. Biodistribution results showed that kidney has the highest uptake of 18F-FP-DPAZn2. The uptake of radioactivity in brain kept at a relatively low level during the whole observed time. In vivo 18F-FP-DPAZn2 PET images demonstrated more accumulation of radioactivity in the brain of AD model mice than that in the brain of normal mice. CONCLUSIONS: The semi-automatic synthetic method provides a slightly higher radiochemical yield and shorter whole synthesis time of 18F-FP-DPAZn2 than the manual operation method. This improved method can give enough radioactivity and high radiochemical purity of 18F-FP-DPAZn2 for in vivo PET imaging. The results show that 18F-FP-DPAZn2 seems to be a potential cell death tracer for AD imaging.
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Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Radioisótopos de Flúor/farmacocinética , Marcaje Isotópico/métodos , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/farmacocinética , Ácidos Picolínicos/síntesis química , Ácidos Picolínicos/farmacocinética , Animales , Encéfalo/diagnóstico por imagen , Composición de Medicamentos/métodos , Radioisótopos de Flúor/química , Tasa de Depuración Metabólica , Ratones , Imagen Molecular/métodos , Especificidad de Órganos , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Robótica/métodos , Distribución TisularRESUMEN
INTRODUCTION: We have reported that N-(2-18F-fluoropropionyl)-L-glutamate (18F-FPGLU) showed good tumor-to-background contrast and 18F-FPGLU was prepared via complex multi-step reaction sequence; here, it is synthesized by a facile two-step reaction sequence. The objectives of this study are to synthesize 18F-FPGLU via a two-step reaction sequence and to evaluate the value of 18F-FPGLU in nude mice bearing human hepatocellular carcinoma SMCC-7721 (HCC SMCC-7721). METHODS: 18F-FPGLU was synthetized from the precursor (2S)-dimethyl 2-(2-bromopropanamido)pentanedioate via the two-step on-column hydrolysis using a modified commercial FDG synthesizer. To investigate the transport mechanism of 18F-FPGLU, we conducted a series of competitive inhibition experiments on HCC SMCC-7721 cells in the absence or presence of Na+ and various types of inhibitors. Small-animal PET-CT imaging was performed on tumor-bearing nude mice using 18F-FPGLU and 2-18F-2-deoxy-D-glucose (18F-FDG). RESULTS: The radiochemical yield of 18F-FPGLU was up to 15±5% (EOS, n=10) in 35min with the two-step procedure and the radiochemical purity was higher than 95% with a specific activity of 30-40GBq/µmol. In vitro cell experiments show that 18F-FPGLU is primarily transported through the Na+-dependent system XAG- and Na+-independent system XC-. PET imaging in a tumor model indicates that 18F-FPGLU may be superior to 18F-FDG for hepatocellular carcinoma (HCC) imaging. CONCLUSION: An optimized route to prepare 18F-FPGLU was developed and 18F-FPGLU was synthetized from the precursor ((2S)-dimethyl 2-(2-bromopropanamido)pentanedioate) via the two-step on-column hydrolysis. 18F-FPGLU was a potential novel PET tracer for HCC imaging.
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Carcinoma Hepatocelular/diagnóstico por imagen , Radioisótopos de Flúor , Ácido Glutámico/química , Neoplasias Hepáticas/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Animales , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Transformación Celular Neoplásica , Técnicas de Química Sintética , Ácido Glutámico/síntesis química , Ácido Glutámico/farmacocinética , Humanos , Marcaje Isotópico , Cinética , Neoplasias Hepáticas/patología , Ratones , Ratones Desnudos , Trazadores Radiactivos , Radioquímica , Distribución TisularRESUMEN
[18F]ML-10 (2-(5-[18F]fluoro-pentyl)-2-methylmalonic acid) is a small molecule positron emission tomography (PET) probe for apoptosis imaging. Automated synthesis of [18F]ML-10 was developed by using two different purification methods through a direct saponification procedure on a modified commercial [18F]Fluoro-2-Deoxyglucose ([18F]FDG) synthesizer. C18 purification method 1: The final [18F]ML-10 solution containing ethanol was obtained with radiochemical yields of 60±5% (n=5) at the end of bombardment (EOB) and radiochemical purity of 98% in 35min. Al2O3 and SCX purification method 2: To avoid possible side effects of a conventional ethanol-containing formulation, an new ethanol-free solution of [18F]ML-10 was also developed, the radiochemical yields was 50±5% (n=5, EOB) within 45min and the radiochemical purity was 98%.
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Radioisótopos de Flúor/química , Ácido Metilmalónico/análogos & derivados , Radiofármacos/síntesis química , Animales , Apoptosis , Técnicas de Química Sintética/instrumentación , Diseño de Equipo , Fluorodesoxiglucosa F18/síntesis química , Fluorodesoxiglucosa F18/química , Humanos , Ácido Metilmalónico/síntesis química , Ácido Metilmalónico/química , Tomografía de Emisión de Positrones , Radiofármacos/química , Tecnología Radiológica/instrumentaciónRESUMEN
In this study, radiosynthesis and biological evaluation of a new [18F]labeled glutamine analogue, N-(2-[18F]fluoropropionyl)-L-glutamine ([18F]FPGLN) for tumor PET imaging are performed. [18F]FPGLN was synthesized via a two-step reaction sequence from 4-nitrophenyl-2-[18F]fluoropropionate ([18F]NFP) with a decay-corrected yield of 30 ± 5% (n=10) and a specific activity of 48 ± 10 GBq/µmol after 125 ± 5 min of radiosynthesis. The biodistribution of [18F]FPGLN was determined in normal Kunming mice and high uptake of [18F]FPGLN was observed within the kidneys and quickly excreted through the urinary bladder. In vitro cell experiments showed that [18F]FPGLN was primarily transported by Na+-dependent system XAG- and was not incorporated into proteins. [18F]FPGLN displayed better stability in vitro than that in vivo. PET/CT studies revealed that intense accumulation of [18F]FPGLN were shown in human SPC-A-1 lung adenocarcinoma and PC-3 prostate cancer xenografts. The results support that [18F]FPGLN seems to be a possible PET tracer for tumor imaging.