Hans-Jürgen Wester

Technische Universität München, München, Bavaria, Germany

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Publications (138)632.04 Total impact

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    ABSTRACT: Neuroendocrine tumours are frequently located in the upper abdomen and especially in the pancreas. Imaging of the abdomen with somatostatin analogs such as (68)Ga-DOTA-Phe(1)-Tyr(3)-octreotide (DOTATOC) is a standard approach for imaging neuroendocrine cancer, but is still challenging due to physiological and technical considerations in this area. Therefore, the aim of this study was to further investigate the origin of (68)Ga-DOTATOC findings in the pancreas. Forty-three consecutive patients with neuroendocrine tumours were examined by (68)Ga-DOTATOC positron emission tomography (PET)/CT for staging or restaging. As imaging of the upper abdomen is frequently affected by breathing artefacts, PET and CT data were analysed for misalignment and rearranged if necessary. Any noticeable uptake in the pancreas was described. Tracer uptake in the head of the pancreas and the liver was measured by means of maximum and average standard uptake value (SUV(max), SUV(av)). The reference standards (malignant versus benign) for correlation with PET findings were clinical and radiological follow-up (mean follow-up time 14 months) (n = 37) or histological confirmation (n = 6). In 23 of 43 studies (54%) misalignment between PET and CT data was found with a mean value of 1.4 cm. Visual assessment demonstrated that 20 of 43 scans (46.6%) showed no uptake in the head of the pancreas. Of 43 scans, 23 (53.4%) showed noticeable uptake with focal pattern in the head of the pancreas in 10 scans and irregular pattern in 13 scans. Follow-up indicated malignant pancreatic lesions in three patients. The pancreatic head to liver SUV(av) ratios in these patients ranged from 1.62 to 6.85, whereas in cases of uptake without known malignancy ratios ranged from 0.56 to 1.19. Considering SUV(max), the ratio ranged from 3.24 to 9.1 and from 0.84 to 1.47, respectively. No statistically significant difference was noted between uptake in the head of the pancreas and the liver in patients without malignant pancreatic tumours (p > 0.05). (68)Ga-DOTATOC uptake in the head of the pancreas is a common finding in patients undergoing (68)Ga-DOTATOC PET/CT. However, this finding most likely represents a physiological condition, especially if the uptake in the pancreatic head is similar to the uptake in the liver (uptake ratio head to liver SUV(av) < 1.4). Therefore, quantification is recommended to avoid false-positive diagnosis. Misalignment due to respiratory motion must always be taken into account.
    European Journal of Nuclear Medicine 07/2011; 38(11):2005-13. · 4.53 Impact Factor
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    ChemMedChem 07/2011; 6(10):1789-91. · 2.84 Impact Factor
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    ABSTRACT: Cross-sectional imaging studies suggest that patterns of hypometabolism (measured by [(18)F] fluorodeoxyglucose positron emission tomography [FDG-PET]) and amyloid deposition (measured by [(11)C] Pittsburgh Compound B [PiB]- PET) in Alzheimer's disease (AD) show some overlap with each other. This indicates that neuronal dysfunction might spread within the anatomical pattern of amyloid deposition. The aim of this study was to examine longitudinal regional patterns of amyloid deposition and hypometabolism in the same population of mild AD subjects and to establish their regional relationship to each other. Twenty patients with mild AD underwent baseline (BL) and follow-up (FU) examination with [(18)F] FDG-PET and [(11)C] PiB-PET. Voxel-by-voxel statistical group comparison (SPM5) was performed between patient BL- and FU-PET data as well as between patients and 15 PiB-negative elderly control subjects, who had undergone identical imaging procedures. To obtain objective measures of regional overlap, Dice similarity coefficients (DSC) between the imaging findings were calculated. Compared with elderly control subjects, AD patients showed typical patterns of BL hypometabolism and BL amyloid deposition, with a similarity of 40% (DSC). Amyloid deposition was more extended than hypometabolism at BL and showed only minor changes over time, whereas significant expansion of hypometabolism was observed, almost exclusively within areas already affected by BL amyloid deposition. Thus, increased similarity of FU hypometabolism with BL amyloid deposition was found (DSC: 47%). Longitudinal regional expansion of cerebral hypometabolism, as a measure of neuronal dysfunction in AD, seems to follow the anatomical pattern of amyloid deposition with temporal delay. This indicates that amyloid-based disruption of neuronal integrity might contribute to the regional expansion of neuronal dysfunction.
    Biological psychiatry 06/2011; 71(9):792-7. · 8.93 Impact Factor
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    ABSTRACT: L-[methyl-(11)C]methionine (MET)-positron emission tomography (PET) has a high sensitivity and specificity for imaging of gliomas and metastatic brain tumors. The short half-life of (11)C (20 minutes) limits the use of MET-PET to institutions with onsite cyclotron. O-(2-[(18)F]fluoroethyl)-L-tyrosine (FET) is labeled with (18)F (half-life, 120 minutes) and could be used much more broadly. This study compares the uptake of FET and MET in gliomas and metastases, as well as treatment-induced changes. Furthermore, it evaluates the gross tumor volume (GTV) of gliomas defined on PET and magnetic resonance imaging (MRI). We examined 42 patients with pretreated gliomas (29 patients) or brain metastases (13 patients) prospectively by FET- and MET-PET on the same day. Uptake of FET and MET was quantified by standardized uptake values. Imaging contrast was assessed by calculating lesion-to-gray matter ratios. Tumor extension was quantified by contouring GTV in 17 patients with brain gliomas. Gross tumor volume on PET was compared with GTV on MRI. Sensitivity and specificity of MET- and FET-PET for differentiation of viable tumor from benign changes were evaluated by comparing the PET result with histology or clinical follow-up. There was a strong linear correlation between standardized uptake values calculated for both tracers in cortex and lesions: r = 0.78 (p = 0.001) and r = 0.84 (p < 0.001), respectively. Image contrast was similar for MET- and FET-PET (lesion-to-gray matter ratios of 2.36 ± 1.01 and 2.33 ± 0.77, respectively). Mean GTV in 17 glioma patients was not significantly different on MET- and FET-PET. Both MET- and FET-PET delineated tumor tissue outside of MRI changes. Both tracers provided differentiated tumor tissue and treatment-related changes with a sensitivity of 91% at a specificity of 100%. O-(2-[(18)F]fluoroethyl)-L-tyrosine-PET and MET-PET provide comparable diagnostic information on gliomas and brain metastases. Like MET-PET, FET-PET can be used for differentiation of residual or recurrent tumor from treatment-related changes/pseudoprogression, as well as for delineation of gliomas.
    International journal of radiation oncology, biology, physics 05/2011; 81(4):1049-58. · 4.59 Impact Factor
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    ABSTRACT: Metabolic imaging of gastric cancer is limited due to the 30% of primary tumors that are not (18)F-fluorodeoxyglucose (FDG) avid. In contrast, the proliferation marker (18)F-fluorothymidine (FLT) has been shown to visualize also non-FDG-avid gastric tumors. In this study we tested whether FLT-positron emission tomography (PET) can improve the predictive potential of molecular imaging for assessing response to neoadjuvant therapy in gastric cancer compared with FDG-PET. 45 patients with gastric cancer underwent FDG- and FLT-PET before and 2 weeks after initiation of chemotherapy. FDG/FLT-PET findings and Ki67 immunohistochemistry were correlated with clinical and histopathological response and survival. 14 patients had non-FDG-avid tumors, whereas all tumors could be visualized by FLT-PET. No significant association of clinical or histopathological response with any of the analyzed metabolic parameters [initial standardized uptake value (SUV), SUV after 2 weeks, change of SUV for FDG/FLT] was found. Univariate Cox regression analysis for Ki67 and metabolic parameters revealed significant prognostic impact for survival only for FLT SUV(mean) day 14 (p=0.048) and Ki67 (p=0.006). Multivariate Cox regression analysis (including clinical response, Lauren type, ypN category, and FLT SUV(mean) day 14) revealed Lauren type and FLT SUV(mean) day 14 as the only significant prognostic factors (p=0.006, p=0.002). FLT uptake 2 weeks after initiation of therapy was shown to be the only imaging parameter with significant prognostic impact. Neither FLT-PET nor FDG-PET were correlated with histopathological or clinical response. However, these data must be interpreted with caution due to the single-center trial study design, relatively short follow-up, poor response rates, and unfavorable prognosis.
    Annals of Surgical Oncology 05/2011; 18(12):3316-23. · 4.12 Impact Factor
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    ABSTRACT: R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)-like chemotherapy is the standard therapy in aggressive B-cell lymphoma. (18)F-FDG PET has high prognostic implications at treatment completion but is limited as an early predictor. Here, we present the results of a prospective study correlating the initial uptake of the in vivo proliferation marker 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) with the clinical outcome of patients with aggressive non-Hodgkin lymphoma treated with R-CHOP. Sixty-six eligible patients were evaluated prospectively with (18)F-FLT PET before R-CHOP. PET was performed 45 min after injection of 300-370 MBq of (18)F-FLT. Mean and maximum standardized uptake values (SUVs) were calculated on a lesion-by-lesion basis. Response was assessed at the end of therapy. International Prognostic Index (IPI) scores and clinical parameters (Ann Arbor stage, lactate dehydrogenase, performance status, extranodal disease) were determined in all patients. Response was assessed according to revised response criteria after the end of therapy. After treatment, patients were followed in intervals from 4 wk to 6 mo (mean follow-up, 23.1 mo [range, 1-63 mo]), and progression-free and overall survival were determined. All lymphoma lesions identified by a reference method ((18)F-FDG PET/CT or multislice CT of the trunk) showed increased focal tracer uptake (mean (18)F-FLT SUV, 7.3 ± 2.5). Response assessment revealed progressive disease in 4, partial response in 3, and complete response (CR) in the remaining 55 patients. The IPI score was predictive for achieving CR (P = 0.034). Importantly, initial mean SUV was also significantly higher in patients who showed progressive disease and partial response than in patients who achieved CR (P = 0.049). In addition, we found a significant correlation between IPI score and initial (18)F-FLT uptake. Taken together, high (18)F-FLT uptake is a negative predictor of response to R-CHOP treatment in aggressive B-cell non-Hodgkin lymphoma and correlates with the IPI score. Thus, (18)F-FLT PET may represent a useful tool for implementing risk-adapted treatment in these patients.
    Journal of Nuclear Medicine 05/2011; 52(5):690-6. · 5.77 Impact Factor
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    ABSTRACT: (11)C-Choline-positron emission tomography (PET)/computed tomography (CT) is increasingly used in patients with prostate cancer. Another promising technique for assessment of tumor biology is diffusion-weighted MR imaging (DWI). The aim of the study was to compare the functional parameters standardized uptake value (SUV) in PET and apparent diffusion coefficient (ADC) value in DWI of lymph nodes in prostate cancer patients. Fourteen patients with prostate cancer underwent DWI at 1.5T and (11)C-Choline-PET/CT. ADC values and SUVs of all lymph nodes larger than 5 mm (n = 55) were compared by using linear regression analysis. Performance of DWI and (11)C-Choline PET was assessed by receiver operator characteristic curve analysis using histopathology or clinical follow-up as standard of reference. ADC values and SUV showed a moderate but highly significant inverse correlation (r = -0.5144, p < 0.0001). In lymph nodes with low ADC values, the dispersion of SUV was more pronounced. Moreover, a highly significant difference was observed for mean ADC values and SUV in lymph nodes considered as benign or malignant by follow-up/histopathology (ADC 1.60 ± 0.24 vs. 1.09 ± 0.23 × 10(-3) mm(2)/s; SUV 1.82 ± 0.57 vs. 4.68 ± 03.12; p < 0.0001, respectively). These pilot data propose the ADC value in DWI as a new potential imaging biomarker which might provide additional information on tumor pathophysiology compared to the SUV in (11)C-Choline PET/CT.
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 04/2011; 13(2):352-61. · 2.47 Impact Factor
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    ABSTRACT: We report a novel series of (11)C-labeled imidazo[2,1-b]benzothiazoles (IBTs) as tracers for imaging of cerebral β-amyloid (Aβ) deposits in patients with Alzheimer's disease (AD) by means of positron emission tomography (PET). From a series of 11 compounds, candidates were identified to have a high binding affinity for Aβ. Selected compounds were prepared as O- or N-[(11)C]methyl derivatives and shown to have a high initial brain uptake in wild-type mice (range 1.9-9.2% I.D./g at 5 min). 2-(p-[(11)C]Methylaminophenyl)-7-methoxyimidazo[2,1-b] benzothiazole ([(11)C]5) was identified as a lead based on the combined favorable properties of high initial brain uptake, rapid clearance from normal brain, and high in vitro affinity for Aβ(1-40) (K(i) = 3.5 nM) and Aβ(1-42) (5.8 nM), which were superior to the Pittsburgh compound B (1a). In an APP/PS1 mouse model of AD (Tg), we demonstrate a specific uptake of [(11)C]5 in Aβ-containing telencephalic brain regions by means of small-animal PET that was confirmed by regional brain biodistribution, ex vivo autoradiography, and immunohistochemistry. Analysis of brain sections of Tg mice receiving a single bolus injection of [(11)C]5 and [(3)H]1a together revealed that the tracers bind to Aβ plaques in the brain of Tg mice in a comparable pattern. Taken together, these data suggest that IBTs represent useful PET imaging agents for high-sensitivity detection of Aβ plaques.
    Journal of Medicinal Chemistry 02/2011; 54(4):949-56. · 5.61 Impact Factor
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    ABSTRACT: Rats affected by the MENX multitumor syndrome develop pheochromocytoma (100%). Pheochromocytomas are uncommon tumors and animal models are scarce, hence the interest in MENX rats to identify and preclinically evaluate novel targeted therapies. A prerequisite for such studies is a sensitive and noninvasive detection of MENXassociated pheochromocytoma. We performed positron emission tomography (PET) to determine whether rat pheochromocytomas are detected by tracers used in clinical practice, such as 68Ga-DOTATOC (somatostatin analogue) or 11C-Hydroxyephedrine (HED), a norepinephrine analogue. We analyzed four affected and three unaffected rats. The PET scan findings were correlated to histopathology and immunophenotype of the tumors, their proliferative index, and the expression of genes coding for somatostatin receptors or the norepinephrine transporter. We observed that mean 68Ga-DOTATOC standard uptake value (SUV) in adrenals of affected animals was 23.3 ± 3.9, significantly higher than in control rats (15.4 ± 7.9; P = .03 ). The increase in mean tumor-to-liver ratio of 11C-HED in the MENX-affected animals (1.6 ± 0.5) compared to controls (0.7 ± 0.1) was even more significant ( P = .0016 ). In a unique animal model, functional imaging depicting two pathways important in pheochromocytoma biology discriminated affected animals from controls, thus providing the basis for future preclinical work with MENX rats.
    International Journal of Molecular Imaging. 01/2011; 2011.
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    ABSTRACT: PET imaging of integrin αvβ3 expression has been studied intensely by the academia and recently also by the industry. Imaging of integrin αvβ3 expression is of great potential value, as the integrin αvβ3 is a key player in tumor metastasis and angiogenesis. Therefore PET imaging of this target might be a suitable in-vivo biomarker of angiogenesis and metastatic potential of tumors. In this manuscript, the various strategies for PET imaging of the integrin αvβ3 will be summarized, including monomeric and multimeric radiolabelled RGD peptides and nanoparticles. While most experiments have been performed using preclinical tumor models, more and more clinical results on PET imaging of αvβ3 expression are available and will be discussed in detail. However, while a multitude of radiotracer strategies have been successfully evaluated for PET imaging of αvβ3, the ultimate clinical value of this new imaging biomarker still has to be evaluated in large clinical trials.
    Theranostics 01/2011; 1:48-57. · 7.81 Impact Factor
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    ABSTRACT: Rats affected by the MENX multitumor syndrome develop pheochromocytoma (100%). Pheochromocytomas are uncommon tumors and animal models are scarce, hence the interest in MENX rats to identify and preclinically evaluate novel targeted therapies. A prerequisite for such studies is a sensitive and noninvasive detection of MENXassociated pheochromocytoma. We performed positron emission tomography (PET) to determine whether rat pheochromocytomas are detected by tracers used in clinical practice, such as 68Ga-DOTATOC (somatostatin analogue) or (11)C-Hydroxyephedrine (HED), a norepinephrine analogue. We analyzed four affected and three unaffected rats. The PET scan findings were correlated to histopathology and immunophenotype of the tumors, their proliferative index, and the expression of genes coding for somatostatin receptors or the norepinephrine transporter. We observed that mean 68Ga-DOTATOC standard uptake value (SUV) in adrenals of affected animals was 23.3 ± 3.9, significantly higher than in control rats (15.4 ± 7.9; P = .03). The increase in mean tumor-to-liver ratio of (11)C-HED in the MENX-affected animals (1.6 ± 0.5) compared to controls (0.7 ± 0.1) was even more significant (P = .0016). In a unique animal model, functional imaging depicting two pathways important in pheochromocytoma biology discriminated affected animals from controls, thus providing the basis for future preclinical work with MENX rats.
    International journal of molecular imaging. 01/2011; 2011:175352.
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    ABSTRACT: The synthesis, radiolabeling, and initial evaluation of new silicon-fluoride acceptor (SiFA) derivatized octreotate derivatives is reported. So far, the main drawback of the SiFA technology for the synthesis of PET-radiotracers is the high lipophilicity of the resulting radiopharmaceutical. Consequently, we synthesized new SiFA-octreotate analogues derivatized with Fmoc-NH-PEG-COOH, Fmoc-Asn(Ac₃AcNH-β-Glc)-OH, and SiFA-aldehyde (SIFA-A). The substances could be labeled in high yields (38 ± 4%) and specific activities between 29 and 56 GBq/μmol in short synthesis times of less than 30 min (e.o.b.). The in vitro evaluation of the synthesized conjugates displayed a sst2 receptor affinity (IC₅₀ = 3.3 ± 0.3 nM) comparable to that of somatostatin-28. As a measure of lipophilicity of the conjugates, the log P(ow) was determined and found to be 0.96 for SiFA-Asn(AcNH-β-Glc)-PEG-Tyr³-octreotate and 1.23 for SiFA-Asn(AcNH-β-Glc)-Tyr³-octreotate, which is considerably lower than for SiFA-Tyr³-octreotate (log P(ow) = 1.59). The initial in vivo evaluation of [¹⁸F]SiFA-Asn(AcNH-β-Glc)-PEG-Tyr³-octreotate revealed a significant uptake of radiotracer in the tumor tissue of AR42J tumor-bearing nude mice of 7.7% ID/g tissue weight. These results show that the high lipophilicity of the SiFA moiety can be compensated by applying hydrophilic moieties. Using this approach, a tumor-affine SiFA-containing peptide could successfully be used for receptor imaging for the first time in this proof of concept study.
    Bioconjugate Chemistry 11/2010; 21(12):2289-96. · 4.58 Impact Factor
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    ABSTRACT: Both dynamic contrast-enhanced (DCE) MRI and PET provide quantitative information on tumor biology in living organisms. However, imaging biomarkers often neglect tissue heterogeneity by focusing on distributional summary statistics. We analyzed the spatial relationship of α(v)β(3) expression, glucose metabolism, and perfusion by PET and DCE MRI, focusing on tumor heterogeneity. Thirteen patients with primary or metastasized cancer (non-small cell lung cancer, n = 9; others, n = 4) were examined with DCE MRI and with PET using (18)F-galacto-RGD and (18)F-FDG. Twenty-three different regions of interest were defined by cluster analysis based on the heterogeneity of tracer uptake. In these regions, the initial area under the gadopentetate dimeglumine concentration-time curve (IAUGC), as well as the regional blood volume (rBV) and regional blood flow (rBF), were estimated from DCE MRI and correlated with standardized uptake values from PET. Regions with simultaneously high uptake of (18)F-galacto-RGD and (18)F-FDG showed higher functional MRI data (IAUGC, 0.35 ± 0.04 mM·s; rBF, 70.2 ± 12.7 mL/min/100 g; rBV, 23.3 ± 2.7 mL/100 g) than did areas with low uptake of both tracers (IAUGC, 0.15 ± 0.04 mM·s [P < 0.01]; rBF, 28.3 ± 10.8 mL/min/100 g; rBV, 9.9 ± 1.9 mL/100 g [P < 0.01]). There was a weak to moderate correlation between the functional MRI parameters and (18)F-galacto-RGD (r = 0.30-0.62) and also (18)F-FDG (r = 0.44-0.52); these correlations were significant (P < 0.05), except for (18)F-galacto-RGD versus rBF (P = 0.17). These data show that multiparametric assessment of tumor heterogeneity is feasible by combining PET and MRI. Perfusion is highest in tumor areas with simultaneously high α(v)β(3) expression and high glucose metabolism and restricted in areas with both low α(v)β(3) expression and low glucose metabolism. The current limitations resulting from imaging with separate scanners might be overcome by future hybrid PET/MRI scanners.
    Journal of Nuclear Medicine 10/2010; 51(11):1691-8. · 5.77 Impact Factor
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    ABSTRACT: [(11)C]Choline has been established as a PET tracer for imaging prostate cancer. The aim of this study was to determine whether [(11)C]choline can be used for monitoring the effects of therapy in a prostate cancer mouse xenograft model. The androgen-independent human prostate cancer cell line PC-3 was implanted subcutaneously into the flanks of 13 NMRI (nu/nu) mice. All mice were injected 4-6 weeks after xenograft implantation with 37 MBq [(11)C]choline via a tail vein. Dynamic imaging was performed for 60 min with a small-animal PET/CT scanner (Siemens Medical Solutions). Six mice were subsequently injected intravenously with docetaxel twice (days 1 and 5) at a dose of 3 mg/kg body weight. Seven mice were treated with PBS as a control. [(11)C]Choline imaging was performed prior to and 1, 2 and 3 weeks after treatment. To determine choline uptake the images were analysed in terms of tumour-to-muscle (T/M) ratios. Every week the size of the implanted tumour was determined with a sliding calliper. The PC-3 tumours could be visualized by [(11)C]choline PET. Before treatment the T/M(mean) ratio was 1.6+/-0.5 in the control group and 1.8+/-0.4 in the docetaxel-treated group (p=0.65). There was a reduction in the mean [(11)C]choline uptake after docetaxel treatment as early as 1 week after initiation of therapy (T/M ratio 1.8+/-0.4 before treatment, 0.9+/-0.3 after 1 week, 1.1+/-0.3 after 2 weeks and 0.8+/-0.2 after 3 weeks). There were no decrease in [(11)C]choline uptake in the control group following treatment (T/M ratio 1.6+/-0.5 before treatment, 1.7+/-0.4 after 1 week, 1.8+/-0.7 after 2 weeks and 1.7+/-0.4 after 3 weeks). For analysis of the dynamic data, a generalized estimation equation model revealed a significant decrease in the T/M(dyn) ratios 1 week after docetaxel treatment, and the ratio remained at that level through week 3 (mean change -0.93+/-0.24, p<0.001, after 1 week; -0.78+/-0.21, p<0.001, after 2 weeks; -1.08+/-0.26, p<0.001, after 3 weeks). In the control group there was no significant decrease in the T/M(dyn) ratios (mean change 0.085+/-0.39, p=0.83, after 1 week; 0.31+/-0.48, p=0.52, after 2 weeks; 0.11+/-0.30, p=0.72, after 3 weeks). Metabolic changes occurred 1 week after therapy and preceded morphological changes of tumour size during therapy. Our results demonstrate that [(11)C]choline has the potential for use in the early monitoring of the therapeutic effect of docetaxel in a prostate cancer xenograft animal model. The results also indicate that PET with radioactively labelled choline derivatives might be a useful tool for monitoring responses to taxane-based chemotherapy in patients with advanced prostate cancer.
    European Journal of Nuclear Medicine 10/2010; 37(10):1861-8. · 4.53 Impact Factor
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    ABSTRACT: The invention relates to the provision of compds., methods for producing them, and their use for imaging and quantification of aggregates of amyloid peptides in vivo. In a preferred aspect of the invention, a tracer is administered to humans and displays enrichment in the areas that are contg. amyloid plaques. Tracers of the invention can be used for in vivo visualization and quantification of aggregates of amyloid peptides in patients affected diseases characterized in the generation of aggregates of amyloid peptides, for example familial or sporadic Alzheimer's disease and type II diabetes. Tracers of the invention can be used for monitoring effects of amyloid-modulating therapies of patients affected with diseases characterized in the generation of aggregates of amyloid peptides, for example familial or sporadic Alzheimer's disease and type II diabetes. [on SciFinder(R)]
    Year: 01/2010
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    Ambros J. Beer, Hans-Jürgen Wester, Markus Schwaiger
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    ABSTRACT: Molecular imaging attempts to visualize biologic processes in order to improve diagnosis and to direct therapy. Angiogenesis is an important process in oncogenesis, inflammation, and wound healing. Most recently, new drugs have been introduced to stop tumor growth in patients with cancer. Angiogenesis is a complex process closely linked to tissue hypoxia and proliferation. Besides growth factors such as vascular endothelial growth factor (VEGF), the expression of integrins has been selected as a potential target for imaging. The integrin ανβ3 is overexpressed on activated endothelial cells in the process of angiogenesis. Cyclic arginine-glycine-aspartate (RGD) peptides specific for the integrin ανβ3, such as the positron emission tomography (PET) tracer [18F] galacto-RGD, have been successfully used for imaging angiogenesis. However, tracer uptake is also observed in tumor cells and inflammatory cells. Future studies have to address the specificity of the tracer approach. Using multimodal probes and combining functional and molecular imaging studies might help to further define the prognostic and diagnostic value of this exciting new imaging approach.
    12/2009: pages 105-115;
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    ABSTRACT: In vivo imaging of α(v)β(3) has important diagnostic and therapeutic applications. (18)F-Galacto-arginine-glycine-aspartic acid (RGD) has been developed for positron emission tomography (PET) imaging of integrin α(v)β(3) expression and is now being tested on humans. Dimerization and multimerization of cyclic RGD peptides have been reported to improve the integrin α(v)β(3)-binding affinity due to the polyvalency effect. Here, we compared a number of new dimeric RGD peptide tracers with the clinically used (18)F-galacto-RGD. RGD monomers and dimers were coupled with galacto or PEG(3) linkers, and labeled with (18)F using 4-nitrophenyl 2-(18)F-fluoropropionate ((18)F-NFP) or N-succinimidyl 4-(18)F-fluorobenzoate as a prosthetic group. The newly developed tracers were evaluated by cell-based receptor-binding assay, biodistribution, and small-animal PET studies in a subcutaneous U87MG glioblastoma xenograft model. Starting with (18)F-F(-), the total reaction time for (18)F-FP-SRGD2 and (18)F-FP-PRGD2 is about 120 min. The decay-corrected radiochemical yields for (18)F-FP-SRGD2 and (18)F-FP-PRGD2 are 52 ± 9% and 80 ± 7% calculated from (18)F-NFP. Noninvasive small-animal PET and direct tissue sampling experiments demonstrated that the dimeric RGD peptides had significantly higher tumor uptake as compared to (18)F-galacto-RGD. Dimeric RGD peptide tracers with relatively high tumor integrin-specific accumulation and favorable in vivo kinetics may have the potential to be translated into clinic for integrin α(v)β(3) imaging.
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 12/2009; 12(5):530-8. · 2.47 Impact Factor
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    ABSTRACT: We determined the ability of PET with the thymidine analog 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) to detect hepatocellular carcinoma (HCC). In this pilot study, (18)F-FLT PET was performed in 18 untreated patients with clinically suspected HCC. Routine diagnostic procedures included ultrasound, MRI, or contrast-enhanced spiral CT of the upper gastrointestinal tract in all patients. At 45-60 min after the intravenous injection of approximately 270-340 MBq of (18)F-FLT, emission and transmission scanning was performed with a high-resolution PET scanner. Tracer uptake in the tumor and surrounding liver tissue was evaluated semiquantitatively by calculation of mean and maximum standardized uptake values (SUVs). Results were correlated with those of the conventional imaging methods. A total of 13 of 18 tumors (sensitivity, 72%; 95% confidence interval [CI], 47%-90%) showed focal (18)F-FLT uptake higher than surrounding liver activity and were detectable as hot lesions. Five tumors were characterized as photopenic lesions or contained a mixture of hot and cold lesions exhibiting a comparable or lower (18)F-FLT uptake than the surrounding liver tissue. When all lesions were considered, the mean (18)F-FLT SUV was 7.8 (range, 2.5-11.1), and the maximum (18)F-FLT SUV was 9.3 (range, 2.9-14.3). Histology and clinical follow-up revealed HCC in 16 patients and cholangiocarcinoma in 2 patients. In the subgroup of HCC, the sensitivity for tumor detection was 69% (11/16; 95% CI, 41%-89%). Correlation analysis demonstrated a significant positive relationship between the proliferation marker MIB-1 and the mean SUV (r = 0.66, P = 0.02). Survival analysis (Cox proportional hazards regression) for initial (18)F-FLT uptake (mean and maximum SUVs) revealed increased hazard ratios (mean SUV, 1.20; maximum SUV, 1.12), but because of the small number of events, these results were not statistically significant. In this pilot study, HCC tumors showed a mixed uptake pattern for the in vivo proliferation marker (18)F-FLT. A total of 69% of the HCC lesions showed (18)F-FLT uptake higher than that of the surrounding liver tissue, whereas the remaining lesions were photopenic or contained a mixture of hot and cold lesions. High initial (18)F-FLT uptake seems to be associated with reduced overall survival and could be an important prognostic factor if this tendency can be confirmed in a larger prospective trial.
    Journal of Nuclear Medicine 09/2009; 50(9):1441-7. · 5.77 Impact Factor
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    ABSTRACT: Antagonist radiotracers have shown only a low sensitivity for detecting competition from high-efficacy agonists at opioid receptors (ORs) in vivo. We report that [(11)C]PEO binds with high affinity to mu and kappa-opioid receptors, is a full agonist, and concentrates in brain regions of rats with a high density of the mu-OR after intravenous injection. Blocking studies with mu and kappa-OR selective compounds demonstrated that the binding of [(11)C]PEO is saturable and selective to the mu-OR in rat brain.
    Journal of Medicinal Chemistry 09/2009; 52(18):5586-9. · 5.61 Impact Factor
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    ABSTRACT: The alpha(v)beta(3)- and alpha(5)beta(1)-integrins play a key role in angiogenesis, the formation of new vessels in tissues that lack them. By serving as receptors for a variety of extracellular matrix proteins containing an arginine-glycine-aspartic acid (RGD) sequence, these integrins mediate migration of endothelial cells into the basement membrane and regulate their growth, survival, and differentiation. Besides being involved in angiogenesis, the alpha(v)beta(3)-integrin is also presented on tumor cells of various origin, where it is involved in the processes that govern metastasis. Because the alpha(v)beta(3)-integrin is an attractive target for cancer treatment, high-affinity ligands containing the RGD sequence, for example, cyclic pentapeptides, have been developed. They inhibit angiogenesis, induce endothelial apoptosis, decrease tumor growth, and reduce invasiveness and spread of metastasis. This development finally resulted in cyclo(RGDf(NMe)V) (cilengitide), which is a drug for the treatment of glioblastoma (currently in phase III clinical trials). With the growing focus on individualized medicine, clinicians would like to be able to assess the severity of the disease and monitor therapy for each patient. Such measurements would be based on a noninvasive visualization and quantification the alpha(v)beta(3)-integrin expression levels before, during, and after antiangiogenic therapy. A wide spectrum of in vivo imaging probes for the nuclear imaging modalities positron emission tomography (PET) and single-photon emission computed tomography (SPECT), for optical imaging, and for magnetic resonance imaging (MRI) have been developed with these goals in mind. In this Account, we describe the synthesis and preclinical and clinical assessments of dedicated targeting probes. These molecules ideally accumulate selectively and in high concentrations in alpha(v)beta(3)-integrin-expressing tissues, have low uptake and retention in nontarget tissues, and are highly stable against in vivo degradation. [(123)I]cyclo(RGDyV) was the first radiolabeled "imaging analogue" of cilengitide that we evaluated preclinically in detail. Subsequent studies focused on cyclo(RGDfK) and cyclo(RGDyK), which allowed conjugation with various signaling moieties, such as prosthetic groups, bifunctional chelators (DTPA, DOTA, NOTA, TETA, and TE2A for labeling with (111)In or (177)Lu for SPECT and (86)Y, (68)Ga, or (64)Cu for PET), or fluorescent dyes (Cy5.5, cypate). Furthermore, pharmacokinetic modifiers such as carbohydrates, charged amino acids, or PEG analogues were coupled to the peptide core without significantly affecting the binding affinity. Finally, dimers, tetramers, octamers, and polymers and decorated quantum dots with several dozens of peptide units were constructed and investigated. Some of these multimers demonstrated significantly improved affinity (avidity) and targeting efficiency in vivo. Besides peptidic alpha(v)beta(3)-integrin ligands, researchers have investigated radiolabeled antibodies such as Abegrin and used molecular modeling to design small peptidomimetics with improved activity, in vivo stability, and subtype selectivity (e.g., (111)In-TA138). Furthermore, there is an increasing interest in nanoparticles such as nanotubes, quantum dots, or paramagnetic particles coated with cyclic RGD analogues as targeting agents. [(18)F]Galacto-RGD, a glycosylated cyclo(RGDfK) analogue, was the first such substance applied in patients and has been successfully assessed in more than 100 patients so far. Because of modification with carbohydrates, rapid renal excretion, and inherently low background activity in most regions of the body, imaging of alpha(v)beta(3) expression with high tumor/background ratios and high specificity is possible. Other (18)F-labeled RGD analogues recently developed by Siemens and GE Healthcare have entered clinical trials.
    Accounts of Chemical Research 07/2009; 42(7):969-80. · 20.83 Impact Factor

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  • 2002–2014
    • Technische Universität München
      • • Section of Radiochemistry and Pharmaceutical Radiochemistry
      • • Nuklearmedizinische Klinik und Poliklinik
      München, Bavaria, Germany
  • 2013
    • Vienna General Hospital
      Wien, Vienna, Austria
    • Carl Gustav Carus-Institut
      Pforzheim, Baden-Württemberg, Germany
  • 2009–2013
    • ABX Advanced Biochemical Compounds Gmbh
      Radeberg, Saxony, Germany
  • 2004–2012
    • Deutsches Herzzentrum München
      München, Bavaria, Germany
  • 2006
    • Medical Research Council (UK)
      Londinium, England, United Kingdom
    • Medizinische Universität Innsbruck
      Innsbruck, Tyrol, Austria