Hans-Jürgen Wester

Technische Universität München, München, Bavaria, Germany

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Publications (281)1204.74 Total impact

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    ABSTRACT: IBTs (imidazo[2,1-b]benzothiazoles) are a promising novel class of amyloid PET radiopharmaceuticals for diagnosis of neurodegenerative disorders like Alzheimer's disease (AD). Their good in vivo imaging properties have previously been shown in preclinical studies. Among IBTs, fluorinated [18F]FIBT was selected for further characterization and advancement towards use in humans. [18F]FIBT characteristics were analyzed in relation to Pittsburgh compound B (PiB) as reference ligand. [18F]FIBT and [3H]PiB were co-injected to an APP/PS1 mouse for ex vivo dual-label autoradiographic correlation. Acute dose toxicity of FIBT was examined in two groups of healthy mice. Preexisting in vivo stability and biodistribution studies in mice were complemented with analogous studies in rats. [18F]FIBT was titrated against post-mortem human AD brain homogenate in a saturation binding assay previously performed with [3H]PiB. Binding of [18F]FIBT to human AD brain was further analyzed by in vitro incubation of human AD brain sections in comparison to [11C]PiB and standard immunohistochemistry. Finally, [18F]FIBT was administered to two human subjects for a dynamic 90-min PET/MR brain investigation. Ex vivo autoradiography confirmed good uptake of [18F]FIBT to mouse brain and its excellent correlation to [3H]PiB binding. No toxicity of FIBT could be found in mice at a concentration of 33.3 nmol/kg. As in mice, [18F]FIBT was showing high in vivo stability in rats and comparable regional brain biodistribution dynamics to [3H]PiB. Radioligand saturation binding confirmed at least one high-affinity binding component of [18F]FIBT around 1 nM. Good binding of FIBT relative to PiB was further confirmed in binding assays and autoradiography using post-mortem AD brain. First use of [18F]FIBT in humans successfully yielded clinical [18F]FIBT PET/MR images with very good contrast. In summary, [18F]FIBT has been characterized to be a new lead compound with improved binding characteristics and pharmacokinetics on its own as well as in comparison to PiB. A pilot human PET investigation provided high-quality images with a plausible tracer distribution pattern. Detailed clinical investigations are needed to confirm these first results and to explore the specific qualities of [18F]FIBT PET for dementia imaging in relation to established ligands.
    No preview · Article · Dec 2014 · ACS Chemical Neuroscience
  • Johannes Notni · Jakub Simeček · Hans-Jürgen Wester
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    ABSTRACT: Given the wide application of positron emission tomography (PET), positron-emitting metal radionuclides have received much attention recently. Of these, gallium-68 has become particularly popular, as it is the only PET nuclide commercially available from radionuclide generators, therefore allowing local production of PET radiotracers independent of an on-site cyclotron. Hence, interest in optimized bifunctional chelators for the elaboration of (68) Ga-labeled bioconjugates has been rekindled as well, resulting in the development of improved triazacyclononane-triphosphinate (TRAP) ligand structures. The most remarkable features of these ligands are unparalleled selectivity for Ga(III) , rapid Ga(III) complexation kinetics, extraordinarily high thermodynamic stability, and kinetic inertness of the respective Ga(III) chelates. As a result, TRAP chelators exhibit very favorable (68) Ga-labeling properties. Based on the scaffolds NOPO (1,4,7-triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid]) and TRAP-Pr, tailored for convenient preparation of (68) Ga-labeled monomeric and multimeric bioconjugates, a variety of novel (68) Ga radiopharmaceuticals have been synthesized. These include bisphosphonates, somatostatin receptor ligands, prostate-specific membrane antigen (PSMA)-targeting peptides, and cyclic RGD pentapeptides, for in vivo PET imaging of bone, neuroendocrine tumors, prostate cancer, and integrin expression, respectively. Furthermore, TRAP-based (68) Ga-labeled gadolinium(III) complexes have been proposed as bimodal probes for PET/MRI, and a cyclen-based analogue of TRAP-Pr has been suggested for the elaboration of targeted radiotherapeutics comprising radiolanthanide ions. Thus, polyazacycloalkane-based polyphosphinic acid chelators are a powerful toolbox for pharmaceutical research, particularly for the development of (68) Ga radiopharmaceuticals.
    No preview · Article · Dec 2014 · ChemMedChem
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    ABSTRACT: Due to its high expression in prostate cancer, PSMA (prostate-specific membrane antigen) represents an ideal target for both diagnostic imaging and endoradiotherapeutic approaches. Based on a previously published highly specific PSMA ligand ([(68)Ga]DOTA-FFK(Sub-KuE)), we developed a corresponding metabolically stable 1,4,7,10-tetraazacyclododececane,1-(glutaric acid)-4,7,10-triacetic acid (DOTAGA) construct for theranostic treatment of prostate cancer. All ligands were synthesized by a combined solid phase and solution phase synthesis strategy. The affinity of the (nat)gallium and lutetium complexes to PSMA and the internalization efficiency of the radiotracers were determined on PSMA-expressing LNCaP cells. The (68)Ga- and (177)Lu-labelled ligands were further investigated for lipophilicity, binding specificity, metabolic stability, as well as biodistribution and μPET in LNCaP-tumour-bearing mice. Radiochemical yields for (68)Ga (3 nmol, 5.0 M NaCl/2.7 M HEPES (approximately 5/1), pH 3.5 to 4.5, 5 min, 95°C) and (177)Lu labelling (0.7 nmol, 0.1 M NH4OAc, pH 5.5, 30 min, 95°C) were almost quantitative, resulting in specific activities of 250 to 300 GBq/μmol for the (68)Ga analogues and 38 GBq/μmol for (177)Lu complexes. Due to metabolic instability of L-amino acid spacers, D-amino acids were implemented resulting in a metabolically stable DOTAGA ligand. Compared to the DOTA ligand, the DOTAGA derivatives showed higher hydrophilicity (logP = -3.6 ± 0.1 and -3.9 ± 0.1 for (68)Ga and (177)Lu, respectively) and improved affinity to PSMA resulting in an about twofold increased specific internalization of the (68)Ga- and (177)Lu-labelled DOTAGA analogue. Especially, [(68)Ga]DOTAGA-ffk(Sub-KuE) exhibits favourable pharmacokinetics, low unspecific uptake and high tumour accumulation in LNCaP-tumour-bearing mice. The pair of diagnostic/therapeutic PSMA-ligands [(68)Ga/(177)Lu]DOTAGA-ffk(Sub-KuE) possess remarkable potential for the management of prostate cancer.
    Full-text · Article · Dec 2014 · EJNMMI Research
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    ABSTRACT: Although antigen-binding fragments (Fabs) of antibodies constitute established tracers for in vivo radiodiagnostics, their functionality is hampered by a very short circulation half-life. PASylation, the genetic fusion with a long, conformationally disordered amino acid chain comprising Pro, Ala and Ser, provides a convenient way to expand protein size and, consequently, retard renal filtration. Humanized αHER2 and αCD20 Fabs were systematically fused with 100 to 600 PAS residues and produced in E. coli. Cytofluorimetric titration analysis on tumor cell lines confirmed that antigen-binding activities of the parental antibodies were retained. The radio-iodinated PASylated Fabs were studied by positron emission tomography (PET) imaging and biodistribution analysis in mouse tumor xenograft models. While the unmodified αHER2 and αCD20 Fabs showed weak tumor uptake (0.8% and 0.2% ID/g, respectively; 24 h p.i.) tumor-associated radioactivity was boosted with increasing PAS length (up to 9 and 26-fold, respectively), approaching an optimum for Fab-PAS400. Remarkably, 6- and 5-fold higher tumor-to-blood ratios compared with the unmodified Fabs were measured in the biodistribution analysis (48 h p.i.) for αHER2 Fab-PAS100 and Fab-PAS200, respectively. These findings were confirmed by PET studies, showing high imaging contrast in line with tumor-to-blood ratios of 12.2 and 5.7 (24 h p.i.) for αHER2 Fab-PAS100 and Fab-PAS200. Even stronger tumor signals were obtained with the corresponding αCD20 Fabs, both in PET imaging and biodistribution analysis, with an uptake of 2.8% ID/g for Fab-PAS100 vs. 0.24% ID/g for the unmodified Fab. Hence, by engineering Fabs via PASylation, plasma half-life can be tailored to significantly improve tracer uptake and tumor contrast, thus optimally matching reagent/target interactions.
    Full-text · Article · Nov 2014 · mAbs
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    ABSTRACT: Current imaging procedures for prostate cancer including positron emission tomography (PET) exhibit considerable limitations and are not always able to meet the diagnostic needs. Recently, a 68Gallium-labeled ligand of the prostate-specific membrane antigen (68Ga-PSMA) has been introduced in PET-imaging of prostate cancer with first promising results. Due to relatively exclusive expression of PSMA in prostatic tissue as well as increased expression in prostate cancer, 68 Ga-PSMA was reported to exhibit a favorable lesion to background ratio. Together with the novel development of combined PET/MRI, the combination of excellent morphological detail, multiparametric functional information, and molecular PET data might lead to a significant improvement in detection of prostate cancer. We present an exemplarily case of primary staging using multiparametric 68Ga-PSMA PET/MR by combining molecular and structural information.
    Full-text · Article · Nov 2014 · Abdominal Imaging

  • No preview · Article · Nov 2014 · European Urology Supplements

  • No preview · Article · Nov 2014 · European Urology Supplements

  • No preview · Article · Nov 2014 · European Urology Supplements
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    ABSTRACT: Purpose Carbon-11- and fluorine-18-labeled choline derivatives have been introduced as promising tracers for prostate cancer imaging. However, due to limited specificity and sensitivity, there is a need for new tracers with higher sensitivity and specificity for diagnosing prostate cancer to improve tracer uptake and enhance imaging contrast. The aim of this study was to compare the properties of [11C]choline ([11C]CHO) with S(+)-β-methyl-[11C]choline ([11C]SMC) as tracer for prostate cancer imaging in a human prostate tumor mouse xenograft model by small-animal positron emission tomography/X-ray computed tomography (PET/CT). Procedures We carried out a dual-tracer small-animal PET/CT study comparing [11C]CHO and [11C]SMC. The androgen-independent human prostate tumor cell line PC3 was implanted subcutaneously in the flanks of Naval Medical Research Institute (NMRI) (nu/nu) mice (n = 11). Mice—6 weeks post-xenograft implantation—were injected with 37 MBq [11C]CHO via the tail vein. On a separate day, the mice were injected with 37 MBq [11C]SMC. Dynamic imaging was performed for 60 min with the Inveon animal PET/CT scanner (Siemens Medical Solutions) on two separate days (randomizing the sequence of the tracers). The dynamic PET images were acquired in list mode. Regions of interest (5 × 5 × 5 mm) were placed in transaxial slices in tumor, muscle (thigh), liver, kidney, and blood. Image analysis was performed calculating tumor to muscle (T/M) ratios based on summed images as well as dynamic data. Results For [11C]SMC, the mean T/M ratio was 2.24 ± 0.56 while the corresponding mean [11C]CHO T/M ratio was 1.35 ± 0.28. The T/M ratio for [11C]SMC was significant higher compared to [11C]CHO (p
    No preview · Article · Aug 2014 · Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging
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    ABSTRACT: Due to favourable in vivo characteristics, its high specificity and the longer half-life of 18F (109.8 min) allowing for remote-site delivery, O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) has gained increased importance for molecular imaging of cerebral tumors. Consequently, the development of simple and efficient production strategies for [18F]FET could be an important step to further improve the cost-effective availability of [18F]FET in the clinical environment. In the present study [18F]FET was synthesized via direct nucleophilic synthesis using an earlier developed chiral precursor, the NiII complex of an alkylated (S)-tyrosine Schiff base, Ni-(S)-BPB-(S)-Tyr-OCH2CH2OTs. The purification method has been developed via solid phase extraction thereby omitting cumbersome HPLC purification. The suggested SPE purification using combination of reverse phase and strong cation exchange cartridges provided [18F]FET in high chemical, radiochemical and enantiomeric purity and 35 % radiochemical yield (decay-corrected, 45 min synthesis time). The method was successfully automated using a commercially available synthesis module, Scintomics Hotboxone. Based on the current results, the proposed production route appears to be well suited for transfer into an automated cassette-type radiosynthesizers without using HPLC.
    Full-text · Article · Aug 2014 · Journal of Radioanalytical and Nuclear Chemistry
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    Full-text · Article · Jul 2014 · International Journal of Urology
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    ABSTRACT: Purpose: 68Ga-labelled compounds are increasingly used for somatostatin-receptor scintigraphy because of their favourable biokinetic properties, a higher tumour-to-background contrast and higher diagnostic accuracy compared to the gamma-emitting tracer 111In-DTPA-octreotide. Recently, we have introduced the new tracer 68Ga-DOTA-3-iodo-Tyr3-Thr8-octreotide (68Ga-HA-DOTATATE). The present study demonstrates the biodistribution and radiation dosimetry of this tracer in humans. Patients, methods: Seven men were enrolled in this analysis. Every patient underwent a 20 min dynamic PET scan after intravenous injection of about 114 ± 9 MBq of 68Ga-HA-DOTATATE. This was followed by two whole-body scans at 30 min p. i. and 120 min p. i. Blood radioactivity concentration was determined non-invasively from a ROI drawn over the aorta. Urine was collected until the time of the last scan. Liver, spleen, kidneys and urinary bladder wall were included in the dosimetric estimation that was carried out with the software package OLINDA 1.0. Results: Physiological 68Ga-HA-DOTATATE uptake was observed in the pituitary gland, thyroid, salivary glands, liver, spleen, kidneys, urinary bladder, adrenals and intestine. Organs with the highest absorbed dose were spleen (0.26 ± 0.11 mSv/MBq), kidneys (0.14 ± 0.03 mSv/MBq) and liver (0.12 ± 0.02 mSv/MBq).The estimated effective dose was 0.024 ± 0.001 mSv/MBq. Conclusion: Our study demonstrates biokinetics and radiation exposure of the 68Ga-labelled tracer HA-DOTATATE to be comparable to other 68Ga-labelled SSR analogues in clinical use.
    Full-text · Article · Jul 2014 · Nuklearmedizin
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    ABSTRACT: Background and purpose: Inter- and intratumor heterogeneity and the variable course of disease in patients with glioma motivate the investigation of new prognostic factors to optimize individual treatment. Here we explore the usefulness of standard static and more sophisticated dynamic (18)F-fluoroethyltyrosine-PET imaging for the assessment of patient prognosis. Materials and methods: Thirty-four consecutive patients with untreated, first-diagnosed, histologically proved glioma were included in this retrospective study. All patients underwent dynamic PET scans before surgery (± standard treatment) and were followed up clinically and by MR imaging. Static and dynamic tumor-to-background ratio, TTP, and slope-to-peak were obtained and correlated with progression-free survival. Results: Twenty of 34 patients experienced progression, with a median progression-free survival of 28.0 ± 11.1 months. Dynamic TTP was highly prognostic for recurrent disease, showing a strong correlation with progression-free survival (hazard ratio, 6.050; 95% CI, 2.11-17.37; P < .001). Most interesting, this correlation also proved significant in the subgroup of low-grade glioma (hazard ratio, 5.347; 95% CI, 1.05-27.20; P = .044), but not when using established static imaging parameters, such as maximum tumor-to-background ratio and mean tumor-to-background ratio. In the high-grade glioma subgroup, both dynamic and static parameters correlated with progression-free survival. The best results were achieved by defining ROIs around "hot spots" in earlier timeframes, underlining the concept of intratumor heterogeneity. Conclusions: (18)F-fluoroethyltyrosine-PET can predict recurrence in patients with glioma, with dynamic analysis showing advantages over static imaging, especially in the low-grade subgroup.
    Full-text · Article · Jun 2014 · American Journal of Neuroradiology
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    ABSTRACT: Despite improved survival in the Rituximab (R) era, a considerable number of patients with diffuse large B-cell lymphoma (DLBCL) ultimately die from the disease. Functional imaging using [18F]fluorodeoxyglucose-PET is suggested for assessment of residual viable tumor very early during treatment but is compromised by non-specific tracer retention in inflammatory lesions. The PET tracer [18F]fluorodeoxythymidine (FLT) as surrogate marker of tumor proliferation may overcome this limitation. We present results of a prospective clinical study testing FLT-PET as superior and early predictor of response to chemotherapy and outcome in DLBCL. 54 patients underwent FLT-PET prior to and one week after the start of R-CHOP chemotherapy. Repetitive FLT-PET imaging was readily implemented into the diagnostic work-up. Our data demonstrate that the reduction of FLT standard uptake valuemean (SUVmean) and SUVmax one week after chemotherapy was significantly higher in patients achieving complete response (CR, n=48; non-CR, n=6; p<0.006). Martingale-residual and Cox proportional hazard analyses showed a significant monotonous decrease of mortality risk with increasing change in SUV. Consistent with these results, early FLT-PET response showed relevant discriminative ability in predicting CR. In conclusion, very early FLT-PET in the course of R-CHOP chemotherapy is feasible and enables identification of patients at risk for treatment failure.
    Full-text · Article · May 2014 · Oncotarget

  • No preview · Article · Apr 2014 · The Journal of Urology
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    Full-text · Article · Apr 2014 · The Journal of Urology

  • No preview · Article · Apr 2014 · European Urology Supplements
  • Jakub Simeček · Johannes Notni · Tobias G Kapp · Horst Kessler · Hans-Jürgen Wester
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    ABSTRACT: The αvβ3-integrin addressing cyclic pentapeptide cyclo(RGDfK) was conjugated to NOPO, 1,4,7-triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid], a bifunctional chelator with exceptional Gallium-68 labeling properties. NOPO-c(RGDfK) and its Ga(III)- and Cu(II)-complexes showed high affinity to αvβ3 integrin (IC50 = 0.94 ± 0.06, 1.02 ± 0.09 and 0.51 ± 0.06 nM, respectively). 68Ga-labeling of NOPO-c(RGDfK) in an automated GMP-compliant procedure was performed with near-quantitative radiochemical yield, using precursor amounts as low as 0.5 nmol (approx. 0.6 µg). 68Ga-NOPO-c(RGDfK) was obtained with high purity (>99% by radio-HPLC/TLC) and, optionally, could be produced with specific activities up to 6 TBq/µmol. M21/M21L (human melanoma with high/low αvβ3 integrin expression) xenografted athymic CD-1 nude mice were used for biodistribution, in vivo stability studies and PET imaging. 68Ga-NOPO-c(RGDfK) showed rapid and specific uptake in M21 tumor xenografts (2.02 ± 0.34 % ID/g at 60 min p.i.) and was found stable in vivo. Owed to its high hydrophilicity, reflected by an octanol-water distribution coefficient (logD = -4.6) which is more than one order of magnitude lower compared to respective NOTA- or DOTA analogs, 68Ga-NOPO-c(RGDfK) showed fast renal clearance from non-targeted tissues. We conclude that NOPO is a useful means to improve renal clearance of corresponding radiopharmaceuticals by increasing the polarity of its bioconjugates. Favorable labeling properties render NOPO conjugates highly recommendable for reliable routine production of 68Ga-radiopharmaceuticals in a clinical setting.
    No preview · Article · Mar 2014 · Molecular Pharmaceutics
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. Late detection of then nonresectable or metastasized tumors emphasizes the need for novel imaging approaches. Here, we report on so far nonexploited potentials of αvβ3 integrin-targeted molecular imaging technologies for detection of PDAC using genetically engineered mouse models. Immunohistochemistry and Western blot were used for characterization of αvβ3 expression in murine and human PDAC. We applied IntegriSense 680 fluorescence molecular tomography, intraoperative fluorescence imaging, and (68)Ga-NODAGA-RGD PET for αvβ3 integrin molecular in vivo imaging of spontaneous PDAC occurring in Ptf1a(+/Cre);Kras(+/LSL-G12D);p53(LoxP/LoxP) mice. (NODAGA is 1,4,7-triazacyclononane-1,4-bis[acetic acid]-7-[2-glutaric acid] and RGD is arginine-glycine-aspartic acid.) RESULTS: αvβ3 integrin is expressed in tumor cells of human and murine PDAC. IntegriSense fluorescence molecular tomography and (68)Ga-NODAGA-RGD PET enabled faithful visualization of PDAC. Furthermore, intraoperative optical imaging with IntegriSense 680 allowed good delineation of tumor borders. Imaging approaches targeting αvβ3 integrin expand the potential of molecular imaging for identification of αvβ3-positive PDAC with potential implications in early detection, fluorescence-guided surgery, and therapy monitoring.
    Full-text · Article · Feb 2014 · Journal of Nuclear Medicine
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    ABSTRACT: Purpose Over recent decades interest in diagnosis and treatment of neuroendocrine tumours (NET) has steadily grown. The basis for diagnosis and therapy of NET with radiolabelled somatostatin (hsst) analogues is the variable overexpression of hsst receptors (hsst1–5 receptors). We hypothesized that radiometal derivatives of DOTA-iodo-Tyr3-octreotide analogues might be excellent candidates for somatostatin receptor imaging. We therefore explored the diagnostic potential of 68Ga-DOTA-iodo-Tyr3-octreotate [68Ga-DOTA,3-iodo-Tyr3,Thr8]octreotide (68Ga-HA-DOTATATE; HA, high-affinity) compared to the established 68Ga-DOTA-Tyr3-octreotate (68Ga-DOTATATE) in vivo. Methods The study included 23 patients with known somatostatin receptor-positive metastases from NETs, thyroid cancer or glomus tumours who were investigated with both 68Ga-HA-DOTATATE and 68Ga-DOTATATE. A patient-based and a lesion-based comparative analysis was carried out of normal tissue distribution and lesion detectability in a qualitative and a semiquantitative manner. Results 68Ga-HA-DOTATATE and 68Ga-DOTATATE showed comparable uptake in the liver (SUVmean 8.9 ± 2.2 vs. 9.3 ± 2.5, n.s.), renal cortex (SUVmean 13.3 ± 3.9 vs. 14.5 ± 3.7, n.s.) and spleen (SUVmean 24.0 ± 6.7 vs. 22.9 ± 7.3, n.s.). A somewhat higher pituitary uptake was found with 68Ga-HA-DOTATATE (SUVmean 6.3 ± 1.8 vs. 5.4 ± 2.1, p < 0.05). On a lesion-by-lesion basis a total of 344 lesions were detected. 68Ga-HA-DOTATATE demonstrated 328 lesions (95.3 % of total lesions seen), and 68Ga-DOTATATE demonstrated 332 lesions (96.4 %). The mean SUVmax of all lesions was not significantly different between 68Ga-HA-DOTATATE and 68Ga-DOTATATE (17.8 ± 11.4 vs. 16.7 ± 10.7, n.s.). Conclusion Our analysis demonstrated very good concordance between 68Ga-HA-DOTATATE and 68Ga-DOTATATE PET data. As the availability and use of 68Ga-HA-DOTATATE is not governed by patent restrictions it may be an attractive alternative to other 68Ga-labelled hsst analogues.
    Full-text · Article · Feb 2014 · European Journal of Nuclear Medicine

Publication Stats

10k Citations
1,204.74 Total Impact Points

Institutions

  • 1999-2016
    • Technische Universität München
      • • Section of Radiochemistry and Pharmaceutical Radiochemistry
      • • Nuklearmedizinische Klinik und Poliklinik
      München, Bavaria, Germany
  • 2002-2014
    • Deutsches Herzzentrum München
      • Department of Cardiovascular Surgery
      München, Bavaria, Germany
  • 2012
    • University Medical Center Hamburg - Eppendorf
      Hamburg, Hamburg, Germany
  • 2005
    • ATOS Klinik Munich
      Münchenbernsdorf, Thuringia, Germany
  • 1994-1996
    • Forschungszentrum Jülich
      • Institute of Neurosciences and Medicine (INM)
      Jülich, North Rhine-Westphalia, Germany