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    Keywords: BLOOD ; IN-VIVO ; MODEL ; IMAGES ; liver ; TISSUE ; ACCUMULATION ; COMPLEX ; LIGAND ; COMPLEXES ; REPERFUSION ; RAT ; blood flow ; KINETICS ; ISCHEMIA ; myocardium ; BAT ligands ; BMS-181321 ; HYPOXIC TISSUE MARKER ; ischaemia ; nitroimidazole ; RAT-HEART ; TC-99M-MIBI ; technetium ; TECHNETIUM-99M-NITROIMIDAZOLE BMS181321
    Abstract: Myocardial perfusion single-photon emission tomography (SPET) performed with cationic technetium-99m complexes indicates ischaemic areas as cold lesions. By contrast, nitroimidazole derivatives labelled with fluorine-18 or Tc-99m have recently shown promising results for hot spot imaging of ischaemic myocardium. This study evaluates (TcO)-Tc-99m(BAT-NI), a new Tc-99m complex comprising the nitroimidazole ligand, 2,10- dimercapto-2,10-dimethyl-4,8-diaza-6-[4-(2-nitroimidazolyl)- butyl]undecane, in a low-flow in vivo model of myocardial ischaemia in thoracotomised rats. To elucidate the influence of the 2-nitroimidazole group on ischaemia-induced uptake, comparisons with ligand derivatives were performed where (a) the 2-nitro group was deleted [(TcO)-Tc-99m(BAT-I)], (b) the 2- nitroimidazole functionality was replaced by a Br atom [(TcO)- Tc-99m(BAT-Br)] and (c) the (TcO)-Tc-99m(BAT) moiety was replaced by an iodine-125 iodophenoxybutyl ligand ((IP)-I-125- NI). The radiolabelled compounds were i.v. injected 15 min after reducing resting myocardial blood flow by 50-60% and the uptake of radioactivity was assessed 90 min post injection. Autoradiography of left ventricular short-axis slices showed median uptake ratios of ischaemic/non-ischaemic myocardium (I/N) of 3.4, 4.5 and 3.4 for (TcO)-Tc-99m(BAT-NI), 99mTcO(BAT- I) and (TcO)-Tc-99m(BAT-Br), respectively. In contrast, (IP)-I- 125-NI was not preferentially taken up by ischaemic myocardium. Accumulation of (TcO)-Tc-99m(BAT-NI) in ischaemic heart regions was comparable to that in the liver. Biodistribution studies showed a median uptake of 0.65% ID/g of (TcO)-Tc-99m(BAT-NI) in ischaemic tissue and an IN of 3.3. On planar images of the thorax and upper abdomen the ischaemic hearts were visualised faintly; the median heart to lung count ratio for (TcO)-Tc- 99m(BAT-NI) was 1.7, and the median heart to liver count ratio was 1.0. We conclude that uptake of (TcO)-Tc-99m(BAT-NI) in ischaemic myocardium does not depend on the nitroimidazole moiety but is intrinsic to the BAT complex. Clinical use of the (TcO)-Tc-99m(BAT)-labelled tracers seems unlikely owing to their low uptake and their low ischaemic tissue contrast on planar images in vivo
    Type of Publication: Journal article published
    PubMed ID: 12574972
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    Keywords: EXPRESSION ; DIAGNOSIS ; F-18 FDG ; data analysis ; correlation ; [F-18]FDG ; BINDING, BLOOD ; GA-68-DOTATO
    Abstract: Purpose: The purpose of this study was to evaluate and compare, by means of dynamic PET, the pharmacokinetics of Ga-68-DOTATOC, a tracer which reflects the expression of somatostatin receptors (SSTRs), and of [F-18]FDG, a marker of tumour viability, in patients with metastatic neuroendocrine tumours (NETs) in whom Y-90-DOTATOC therapy was planned. Materials and methods: Fifteen patients (63 lesions) with confirmed metastatic NETs were enrolled in this study. Dynamic [F-18]FDG and Ga-68-DOTATOC PET scans were performed on two different days in the same week. The data analysis was based on qualitative and quantitative analysis using a two-tissue compartment model with a blood compartment and a non-compartment model based on the fractal dimension (FD). Multivariate analysis was used for evaluation of the kinetic data. Results: Enhanced [F-18]FDG uptake was observed in 43/63 lesions. Ga-68-DOTATOC showed pathologically enhanced uptake in all evaluated patients and in 57/63 lesions. Discordant scintigraphic results for [F-18]FDG and Ga-68-DOTATOC were observed in 6/15 patients. Global SUV was defined as the SUV measured in the last frame (55-60 min p.i.) of the dynamic series, for each tracer. The median global SUV uptake was 7.9 for Ga-68-DOTATOC and 4.6 for [F-18]FDG. The selection of patients for Y-90-DOTATOC therapy was based on the uptake of Ga-68-DOTATOC. Multiple linear regression analysis was applied to determine the effect of each kinetic parameter (K-1-k(4), V-B) on the global SUV of both tracers. The highest positive t-ratio was found for K (1) (receptor binding), followed by k (3) (cellular internalisation) and V-B (fractional blood volume), when using the global Ga-68-DOTATOC uptake (SUV) as a target variable. Analysis of the [F-18]FDG data revealed the highest positive t-ratio for V-B, followed by k(3) (phosphorylation) and K-1 (influx). The comparison of global SUV, K-1-k(4) and the FD for [F-18]FDG and Ga-68-DOTATOC did not show any statistically significant correlation. The only parameter that demonstrated a significant linear correlation between the tracers was V-B. Conclusion: Ga-68-DOTATOC is a promising tool for evaluation of the expression of SSTR2 in NETs. The combination of [F-18]FDG and Ga-68-DOTATOC dynamic PET studies provides different information regarding the biological properties of lesions in patients with metastatic NETs in whom Y-90-DOTATOC therapy is planned. While the global Ga-68-DOTATOC uptake is influenced mostly by K-1, the global [F-18]FDG uptake is mostly influenced by V (B). Only patients with enhanced Ga-68-DOTATOC uptake (SUV 〉 5.0) were referred to Y-90-DOTATOC therapy
    Type of Publication: Journal article published
    PubMed ID: 16763820
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    Keywords: RECEPTOR ; ANGIOGENESIS ; APOPTOSIS ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; INHIBITOR ; proliferation ; ANGIOSTATIN ; BLOOD ; CELL ; CELL-PROLIFERATION ; Germany ; human ; IN-VIVO ; PERFUSION ; VIVO ; imaging ; VOLUME ; HEPATOCELLULAR-CARCINOMA ; NEW-YORK ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; METABOLISM ; cell line ; gene therapy ; LINES ; NUCLEAR-MEDICINE ; TRANSDUCTION ; RAT ; RATS ; tumour ; CELL-LINES ; signal transduction ; SIGNAL ; gene expression ; ARRAYS ; STRESS ; SIGNAL-TRANSDUCTION ; CELL-LINE ; chemotherapy ; LINE ; HEPATOMA ; EXCHANGE ; positron emission tomography ; POSITRON-EMISSION-TOMOGRAPHY ; tomography ; SQUAMOUS-CELL CARCINOMA ; RT-PCR ; GLUCOSE ; PET ; cell lines ; nuclear medicine ; TNF-ALPHA ; INCREASED EXPRESSION ; INHIBITORS ; HUMAN BREAST-CANCER ; radiology ; MATRIX ; TUMOR-GROWTH ; ARRAY ; TRANSPORTER ; cell proliferation ; methods ; HIGH-THROUGHPUT ; NUCLEAR ; USA ; uptake ; vascular endothelial growth factor ; FDG-PET ; in vivo ; ENDOTHELIAL-CELL ; FDG ; EMISSION-TOMOGRAPHY ; gene profiling ; gene array ; MEDICINE ; EMISSION ; emission tomography ; positron ; ENDOTHELIAL GROWTH ; HSV THYMIDINE KINASE ; MORRIS HEPATOMA
    Abstract: Purpose Human troponin I (TROP), the soluble receptor for vascular endothelial growth factor (sFLT) and angiostatin (ASTAT) are potent inhibitors of endothelial cell proliferation, angiogenesis and tumour growth in vivo. Transfer of these genes into tumours may induce changes not only in perfusion, but also more general ones such as changes in metabolism. The aim of this study was to assess these reactions using FDG-PET and high-throughput methods such as gene profiling. Methods We established Morris hepatoma (MH3924A) cell lines expressing TROP, sFLT or ASTAT and quantified F-18-fluorodeoxyglucose ((18)FDG) uptake by dynamic positron emission tomography (PET) after tumour inoculation in ACI rats. Furthermore, expression of glucose transporter-1 and -3 (GLUT-1 and GLUT-3) as well as hexokinase-1 and -2 were investigated by RT-PCR and immunohistomorphometry. In addition, gene array analyses were performed. Results (18)FDG uptake, vascular fraction and distribution volume were significantly higher in all genetically modified tumours. Immunohistomorphometry showed an increased percentage of hexokinase-1 and -2 as well as GLUT-1 and -3 immunoreactive (ir) cells. Using gene arrays and comparing all three groups of genetically modified tumours, we found upregulated expression of 36 genes related to apoptosis, signal transduction, stress or metabolism. Conclusion TROP-, sFLT- or ASTAT-expressing MH3924A tumours show enhanced influx of (18)FDG, which seems to be caused by several factors: enhanced exchange of nutrients between blood and tumour, increased amounts of glucose transporters and hexokinases, and increased expression of genes related to apoptosis, matrix and stress, which induce an increased demand for glucose
    Type of Publication: Journal article published
    PubMed ID: 17701172
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    Keywords: ACID, AGENT, AMBIENT-TEMPERATURE, antibodies, antibody, BIODISTRIBUTION, biological, BIOLOGICAL-ACTI
    Abstract: Purpose The success of Ga-68-labeled peptides for positron emission tomography of neuroendocrine tumors is mainly depending on the complex chemistry of this radioisotope. 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), the chelator of choice has however limitations if its application is expanded to heat-sensitive proteins. Recombinant antibodies like single chain Fv or diabodies belong to this class of proteins. They are suited to provide imaging contrast despite the short-lived Ga-68 because of their rapid blood clearances and nanomolar affinities. The heterobifunctional agent N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC) was chosen as an alternative ligand because this agent is complexing [Ga-68]Ga3+ much faster than DOTA at ambient temperatures. Materials and methods A versatile technology for HBED-CC conjugation of proteins and Ga-68-labeling has been developed. This included HBED-CC-tetrafluorophenol (TFP) ester synthesis, coupling to the antibody at various pH and complexation reactions performed in 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer under different conditions. Results The synthesis of the monoreactive 2,3,5,6-tetrafluorophenolate of HBED-CC at a carboxyl group not participating in complex formation used [Fe(HBED-CC)](-) for ester formation. The removal of Fe3+ from purified (HBED-CC)TFP ester was achieved with RP18 cartridge technology. The conjugation chemistry was performed with mAb425 which binds to the epidermal growth factor receptor (EGFR). This protein was used for optimizing purposes only. The influence of complexation parameters like temperature, pH, reaction time, and HBED-CC/antibody ratio on the biological activity of this model antibody was investigated. Furthermore, the outcome of this labeling procedure on the biological activity of a recombinant diabody (50 kDa) was studied. Conclusion It is known that small HBED-CC/antibody ratios are prerequisites for minimal interference of labels with antigen-binding domains. Here, the coupling of about one HBED-CC per antibody proved to be sufficient for efficient Ga-68 labeling, pointing to the successful application of Ga-68 for molecular imaging with small recombinant proteins
    Type of Publication: Journal article published
    PubMed ID: 18509635
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    Abstract: PURPOSE: Dysregulation of histone acetylation associated with an up-regulation of histone deacetylase (HDAC) activity is common in malignant tumours. Therefore, HDAC inhibitors were developed whose effects on proliferation and apoptosis have been shown in different tumour entities. Since non-iodide-concentrating thyroid carcinomas represent a therapeutic problem, this study addressed the effects of the HDAC inhibitor MS-275 on thyroid carcinoma cells. METHODS: After the antiproliferative effect of MS-275 had been proven in different human and rat thyroid carcinoma cell lines, FRO82-2, SW1736 and FTC133 cells were further investigated with respect to changes in apoptosis, cell cycle and metabolism by the annexin V/propidium iodide assay, FACS analysis and uptake experiments employing 3-O-methyl-D: -((3)H)glucose, fluoro-2-deoxy-D: -glucose(2) [5,6-(3)H] and (14)C-aminoisobutyric acid (AIB). The induction of iodide transport and gene expression were investigated in (125)iodide uptake experiments and real-time polymerase chain reaction (PCR). RESULTS: MS-275 induced a concentration- and time-dependent inhibition of proliferation in the thyroid carcinoma cell lines with varying IC(50) values. In FRO82-2, SW1736 and FTC133 cells characterized by low, moderate and high sensitivity an up-regulation of p21(CIP/WAF1) expression and G(1) and/or G(2) phase arrest were observed upon MS-275 exposure corresponding to the sensitivity of individual cell lines. In addition, high MS-275 concentrations increased the apoptotic cell fraction of FTC133 and SW1736 cells, whereas resistance to apoptosis and simultaneous up-regulation of Bcl-2 gene expression were observed in FRO82-2 cells. MS-275 treatment also mediated a concentration-dependent decrease of (3)H-FDG uptake and an increased 3-O-methyl-D: -((3)H)glucose uptake in all thyroid carcinoma cell lines after 24 h, an increased uptake of both tracers in FTC133 cells after 48 h, and restored the functional activity of the sodium-iodide symporter in SW1736 and FTC133 cells up to 20- and 45-fold. CONCLUSION: MS-275 exerts dose-dependent antiproliferative effects including growth arrest, differentiation and apoptosis in some thyroid carcinoma cell lines and might, therefore, be considered for the treatment of anaplastic and non-iodide-concentrating thyroid carcinomas.
    Type of Publication: Journal article published
    PubMed ID: 20680269
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    Keywords: PERFUSION ; CT ; LUNG-CANCER ; DISEASE ; DIFFERENTIATION ; chemotherapy ; PET ; KINETICS ; LIVER METASTASES ; F-18-FDG ; IMATINIB MESYLATE ; GIST ; FDG UPTAKE ; Dynamic (18)F-FDG PET ; Gastrointestinal stromal tumours ; Molecular targeted therapy ; Parametric images
    Abstract: PURPOSE: (18)F-Fluorodeoxyglucose positron emission tomography (FDG PET) may underestimate viable tumour tissue in patients with gastrointestinal stromal tumours (GIST) treated with molecular targeted agents. The aim of the present study was to investigate the value of parametric images generated after dynamic data acquisition for the detection of active liver metastases. METHODS: The analysis included 65 dynamic FDG PET studies in 34 patients with liver metastases from GIST who were treated with imatinib or sunitinib. Parametric images of intercept and slope were calculated by dedicated software using a voxel-based linear regression of time-activity data. Intercept images represent the tracer's distribution volume and the slope its overall metabolic turnover. All images were assessed visually and semi-quantitatively. Liver disease status was established 12 months after each PET study. Dichotomous variables of visual interpretation and various quantitative parameters were entered in a statistical model of linear discriminant analysis. RESULTS: Visual analysis of slope images was more sensitive than the standard 1-h FDG uptake evaluation (70.6 vs 51.0%, p = 0.016) in detecting cases with liver disease progression (n = 51). Specificity did not differ. Combination of all variables in the discriminant analysis model correctly classified 87.7% of cases as progressive or non-progressive disease. Sensitivity was raised to 88.2%. CONCLUSION: Parametric images of intercept and slope add a new dimension to the interpretation of FDG PET studies, by isolating visually and quantifying the perfusion and phosphorylation-dependent part of tracer uptake. In treated GIST patients, integration of this information with the 1-h uptake data achieves better characterization of hepatic lesions with respect to disease activity.
    Type of Publication: Journal article published
    PubMed ID: 21400009
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