Harald Hauser

German Cancer Research Center, Heidelburg, Baden-Württemberg, Germany

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Publications (18)69.86 Total impact

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    ABSTRACT: Bombesin (BN), a 14-amino-acid peptide, shows high affinity for the human gastrin-releasing peptide receptor (GRP-r), which is overexpressed on several types of cancer, including prostate, breast, gastrointestinal, and small cell lung cancer. Thus, radiolabeled BN or BN analogs may prove to be specific tracers for diagnostic and therapeutic targeting of GRP-r-positive tumors in nuclear medicine. This study evaluated a novel BN analog labeled with the positron emitter 68Ga for receptor imaging with PET. DOTA-PEG2-[D-Tyr6,beta-Ala11,Thi13,Nle14] BN(6-14) amide (BZH3) (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid; PEG is ethyleneglycol (2-aminoethyl)carboxymethyl ether) was synthetized using the Fmoc strategy and radiolabeled with either 67Ga or 177Lu for in vitro and biodistribution experiments. 68Ga for PET was obtained from a 68Ge/68Ga generator. In vitro binding, internalization, and efflux were determined using the pancreatic tumor cell line AR42J. Biodistribution of the peptide as a function of time and dose was studied in AR42J tumor-bearing mice. In vitro assays demonstrated a high affinity of 67Ga-BZH3 (dissociation constant = 0.46 nmol/L), a rapid internalization (70% of total cell-associated activity was endocytosed after a 15-min incubation), and an intracellular retention half-life (t1/2) of the 67Ga activity of 16.5 +/- 2.4 h. Biodistribution indicated a dose-dependent uptake in the tumor and a prolonged tumor residence time (t1/2 approximately 16 h). Clearance from GRP-r-negative tissues was fast, resulting in high tumor-to-tissue ratios as early as 1 h after injection. Replacing 67Ga by 177Lu, a therapeutic radionuclide, for peptide labeling resulted in a slightly reduced (approximately 20%) tumor uptake and tumor residence time of 177Lu-BZH3. In contrast, 177Lu decline in the pancreas was significantly accelerated by a factor of 3 compared with that of 67Ga. PET of mice with 68Ga-BZH3 clearly delineated tumors in the mediastinal area. The promising in vivo data of 68Ga-BZH3 indicate its potential for an improved localization of GRP-r-positive tumors and also suggest its application in patients. PET may also be favorably used for GRP-r density determination, a prerequisite for therapeutic applications.
    Journal of Nuclear Medicine 05/2005; 46(4):691-9. · 5.56 Impact Factor
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    ABSTRACT: We recently demonstrated the feasibility of combining enhanced tumor-to-tissue contrast and PET imaging for immunoscintigraphic tumor localization in pancreas and colon carcinoma bearing nude mice. Contrast enhancement was obtained with a multistep targeting technique that consists of the sequential administration of an antitumor/antihapten bispecific antibody (BS-MAb), a blocker to saturate the antihapten binding sites of the BS-MAb that remains in circulation, and a low molecular weight Ga chelate, labeled with the positron emitter 68Ga, which serves as the hapten. To evaluate the efficacy of this pretargeting technique for breast cancer localization, we synthesized a BS-MAb from the F(ab')(2) fragments of the anti-MUC1 MAb 12H12 which reacts with the vast majority of human breast carcinomas, and the F(ab') fragment of an anti-Ga chelate MAb using a bifunctional chemical linker. The BS-MAb was tested for its affinity and its biokinetics in nude mice bearing a human mammary carcinoma. Equilibrium binding of the BS-MAb for mammary carcinoma cells was low (1.2 x 10(7) M(-1)) while the binding capacity of cells was high (8.4 x 10(6) BS-MAbs per cell). Tumor uptake of the 67Ga labeled chelate in pretargeted animals was to 5.8 +/- 0.8% iD/g resulting in a tumor-to-blood ratio of 2.6 at 1h postinjection. This compares with a ratio of 0.65 and 0.85 obtained with 125I-labeled native 12H12 at 24h and 48h postinjection. No difference in the tumor uptake of both the 68Ga and 67Ga labeled chelate was observed. PET imaging of mice, started 1h postinjection of the 68Ga chelate, clearly visualized all tumors.
    Nuclear Medicine and Biology 11/2001; 28(7):821-8. DOI:10.1016/S0969-8051(01)00246-3 · 2.41 Impact Factor
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    ABSTRACT: Recently, we demonstrated the feasibility of combining improved tumor-to-tissue contrasts and PET imaging for immunoscintigraphic tumor localization using a multistep targeting technique that consists of the administration of an antitumor/antihapten bispecific monoclonal antibody (BS-MAb), a blocker to saturate the antihapten binding sites of the BS-MAb that are still present in the circulation, and a low molecular weight Ga chelate, labeled with positron emitter 68Ga, serving as the hapten. Due to this technique, the biodistribution of the radiolabeled hapten is governed mainly by the binding characteristics of both the antitumor and the antihapten part of the BS-MAb. For a future clinical implementation of the method, we investigated MAb VFF18, which is reactive with the adhesion molecule CD44V6, a tumor-associated antigen, and up-regulated in colon, squamous cell and pancreas carcinoma, and two anti-Ga chelate MAbs, which are highly selective for only one of the two enantiomers (optical isomers) of the inherently racemic Ga chelate. From the VFF18 MAb and the anti-Ga chelate MAbs, two BS-MAbs containing the same antitumor parts, but different antihapten parts, were prepared and tested for multistep targeting in human colon carcinoma-bearing nude mice. Despite identical biodistributions of both BS-MAbs and their very similar affinities for the corresponding Ga chelate enantiomers, tumor uptake of the two enantiomers 1 hr postinjection was significantly different [8.7 +/- 1.9% versus 5.8% +/- 1.6% of the injected dose/g (%i.d./g)], with tumor-to-blood ratios being higher for the BS-MAb showing the lower tumor uptake (7.6 +/- 1.6 versus 4.7 +/- 0.6). From data obtained with each BS-MAb, a similar initial tumor binding of approximately 15.5%i.d./g, but different in vivo half-lives of the corresponding BS-MAb-enantiomer immune complexes, could be estimated. Pretargeting with a mixture of both BS-MAbs followed by the administration of the racemic Ga chelate resulted in the lowest tumor uptake (3.9% +/- 1.5%i.d./g). PET imaging of nude mice with the enantiomeric, as well as with the racemic, 68Ga chelate demonstrated a clear delineation of tumors against blood pool background. Multistep immunoscintigraphy with BS-MAbs markedly increases tumor-to-tissue ratios in nude mice and enables PET imaging. Using a BS-MAb containing MAb VFF18, a more sensitive localization of CD44V6-positive tumors in patients should also be obtained.
    Journal of Nuclear Medicine 11/1998; 39(10):1769-76. · 5.56 Impact Factor
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    ABSTRACT: To improve tumor:tissue ratios in immunoscintigraphy, a three-step targeting method has been developed. The reagents used were (a) a radioactive, low molecular weight chelate prepared from ionic gallium and a phenolic polyaminocarboxylic acid, which can be labeled either with the single-photon emitter 67Ga or with the short-lived positron emitter 68Ga (t1/2 = 68 min); (b) a bispecific monoclonal antibody (bs-mAb) synthesized from the F(ab)2 fragment of the 1.1ASML antibody specific for the glycoprotein CD44v associated with a rat pancreas carcinoma cell line and the F(ab') fragment of an antibody specific for the gallium chelate; and (c) the nonradioactive gallium chelate covalently coupled to transferrin, which served as a high molecular weight blocker to prevent binding of the radioactive gallium chelate to bs-mAbs in the circulation. Targeting experiments in tumor-bearing nude mice with different doses of bs-mAbs, blocker, and 67Ga chelate were adjusted to maximize tumor to tissue contrasts and tumor uptake. Compared with the biodistribution of the 131I-labeled, native 1.1ASML antibody 24 h postinjection, a schedule using 100 pmol bs-mab 24 h later 100 pmol blocker, 15 min later 16 pmol 67Ga chelate, 1 h later examination, increased tumor:blood and tumor: liver ratios by a factor of 5 while keeping the localization of radioactivity in the tumor constant (10.1% injected dose/g). High-contrast images using either 67Ga or 68Ga were obtained within 1 h. The targeting method described enables the use of the short-lived positron emitter 68Ga and thus allows the combination of an improved immunoscintigraphy and positron emission tomography.
    Cancer Research 02/1995; 55(1):115-23. · 9.28 Impact Factor
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    ABSTRACT: To investigate whether bifunctional ligands containing chelating structures other than EDTA and DTPA and metallic radiotracers other than 111In will reduce the non-specific radioactivity uptake in the liver during immunoscintigraphy, we synthetized an isothiocyanato-substituted phenolic polyaminocarboxylic acid (HBED-CI) for labeling of MAbs with 67Ga, 111In and 59Fe. Biodistribution of HBED-CI-labeled MAbs was compared to that of 131I and 111In-DTPA labeled MAbs in nude mice bearing tumors, which differ with regard to intracellular internalization and catabolism of the corresponding MAb-antigen complex. In the liver a continuous radioactivity excretion for 67Ga-HBED-CI-labeled MAbs was observed with kinetics that parallel 131I clearance after administration of 131I-MAbs, while 111In-HBED-CI-labeling led to a constant 111In liver level quite similar to that of 111In-DTPA-MAbs. In tumors, 67Ga-HBED-CI-MAb uptake again paralleled that of 131I-MAbs, showing continuous accumulation in tumor tissues when internalization of the MAb-antigen complex was not involved. A much lower uptake, which peaked between 24 and 48 h, was found in the case of MAb-antigen internalization. 111In of 111In-HBED-CI- and 111In-DTPA-labeled MAbs continuously accumulated in both types of tumors. Compared with 111In-DTPA-MAbs, an improvement in tumor-to-liver ratios, due to the reduced liver radioactivity associated with 67Ga-HBED-CI-labeled MAbs, could only be obtained with non-internalizing tumors. The time course of radioactivity distribution in the liver and in MAb-internalizing tumors after administration of 67Ga-HBED-CI-, 111In-HBED-CI- and 111In-DTPA-labeled MAbs further indicates a dominating influence of the metallic radiotracer rather than the ligand on retention or excretion of radioactivity in MAb-catabolizing tissues.
    International Journal of Radiation Applications and Instrumentation Part B Nuclear Medicine and Biology 12/1992; 19(8):809-24. DOI:10.1016/0883-2897(92)90167-W
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    ABSTRACT: Liver uptake of indium-111 (111In) in mice was investigated following administration of 111In-DTPA murine monoclonal antibodies (111In-DTPA-MAbs) labeled by the cyclic anhydride method. Biodistribution of HPLC-purified 111In-DTPA-MAb preparations was checked with a low (0.2 micrograms) and a high (8.0 micrograms) MAb dose. Using Bio Gel P-30 for desalting the MAb-conjugates, 111In uptake in the liver amounted to 8%-9% of the injected dose (ID) and was independent from the MAb dose, the DTPA-to-MAb molar ratio, tumor growth and biologic variability (different MAbs and different strains of mice). Using Sephadex G-25 for desalting, 0.2 micrograms doses from 7 out of 26 preparations showed increased liver accumulation of 111In in non-tumor mice ranging from 15%-25% of ID. Corresponding high doses led to a "normal" value of 8%-9%. Increased liver uptake of the low dose could not be reduced by coadministration of the unconjugated MAb, but was normal after reinjection of "in vivo filtered" material. An inverse intracellular distribution of 111In activity between sediment and supernatant of liver homogenates, following the administration of the low and the high MAb dose, indicated an artifact of the labeling procedure rather than an inherent biological property of labeled MAbs.
    Journal of Nuclear Medicine 07/1990; 31(6):1084-93. · 5.56 Impact Factor
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    ABSTRACT: In 158 plasma samples, obtained from patients with lung carcinoma, lung metastases, and infectious or inflammatory lung diseases and from healthy controls, the NMR relaxation times T1 and T2 of water protons were measured at a resonance frequency of 20 MHz by pulsed NMR techniques and adjusted to a standardized total plasma protein concentration. For one-third of these samples water-suppressed 500-MHz 1H NMR spectroscopy at 37 degrees C was used (a) to determine the widths of the composite lipid methyl and methylene signals, and (b) to quantitate individual lipid methylene signal components that could be detected in resolution-enhanced spectra. In addition, hematological parameters and the plasma levels of several acute phase proteins and apolipoprotein-A were monitored. No diagnostically significant differences between lung carcinoma patients and patients with nonmalignant lung disease could be found for any of the plasma NMR parameters, nor could T1 or lipid linewidth data distinguish between any patient group and healthy controls. However, the mean T2 was significantly shortened by about 15% for any kind of lung disease compared to healthy controls. Similar but less significant results were found for apolipoprotein-A levels. A linear discriminant function, calculated from the apolipoprotein-A and T2 data, did not improve the differentiation between malignant and nonmalignant lung disease but did improve the discrimination between tumor patients and healthy controls up to a sensitivity and specificity of 80 and 96.5%, respectively. T2 correlates inversely with plasma fibrinogen levels and the blood sedimentation rate and, therefore, appears to monitor a general inflammatory status of a tumor patient rather than the presence or absence of cancer. For all groups except healthy pregnant women, the lipid methylene composite signal linewidth correlates inversely with the fraction of mobile triglyceride present (mainly as VLDL), as estimated from resolution-enhanced spectra.
    Magnetic Resonance in Medicine 02/1990; 13(1):103-32. · 3.40 Impact Factor
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    ABSTRACT: In 158 plasma samples, obtained from patients with lung carcinoma, lung metastases, and infectious or inflammatory lung diseases and from healthy controls, the NMR relaxation times T1, and T2 of water protons were measured at a resonance frequency of 20 MHz by pulsed NMR techniques and adjusted to a standardized total plasma protein concentration. For one-third of these samples water-suppressed 500-MHz 1H NMR spectroscopy at 37°C was used (a) to determine the widths of the composite lipid methyl and methylene signals, and (b) to quantitate individual lipid methylene signal components that could be detected in resolution-enhanced spectra. In addition, hematological parameters and the plasma levels of several acute phase proteins and apolipoprotein-A were monitored. No diagnostically significant differences between lung carcinoma patients and patients with nonmalignant lung disease could be found for any of the plasma NMR parameters, nor could T1, or lipid line width data distinguish between any patient group and healthy controls. However, the mean T2, was significantly shortened by about 15% for any kind of lung disease compared to healthy controls. Similar but less significant results were found for apolipoprotein-A levels. A linear discriminant function, calculated from the apolipoprotein-A and T2, data, did not improve the differentiation between malignant and nonmalignant lung disease but did improve the discrimination between tumor patients and healthy controls up to a sensitivity and specificity of 80 and 96.5%, respectively. T, correlates inversely with plasma fibrinogen levels and the blood sedimentation rate and, therefore, appears to monitor a general inflammatory status of a tumor patient rather than the presence or absence of cancer. For all groups except healthy pregnant women, the lipid methylene composite signal line width correlates inversely with the fraction of mobile triglyceride present (mainly as VLDL), as estimated from resolution-enhanced spectra.
    Magnetic Resonance in Medicine 01/1990; 13(1):103-132. DOI:10.1002/mrm.1910130111 · 3.40 Impact Factor
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    ABSTRACT: The T1 and T2 NMR relaxation times of water protons in plasma, obtained from patients with lung carcinoma, healthy volunteers, and patients with nontumor diseases were measured at a resonance frequency of 20 MHz. Additionally hematologic parameters were determined. In tumor patients the mean plasma T2 was shortened by about 20%, and an increase in the blood sedimentation rate (BSR) was noted. Similar but less pronounced results were found for the nontumor group of patients, indicating that the shortening of T2 in plasma is a secondary host response. However, a plot of plasma 1/T2 versus BSR from tumor patients showed a significant correlation between these two parameters. No such correlation could be detected in the nontumor group of patients. The correlation of 1/T2 with BSR, found solely in the tumor patient group, increased the diagnostic sensitivity of T2 measurements and may help to differentiate between malignant and nonmalignant disease. No significant variation in the T1 spin-lattice relaxation time was observed.
    Magnetic Resonance in Medicine 01/1988; 5(6):537-47. · 3.40 Impact Factor
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    ABSTRACT: The T1 and T2 NMR relaxation times of water protons in plasma, obtained from patients with lung carcinoma, healthy volunteers, and patients with nontumor diseases were measured at a resonance frequency of 20 MHz. Additionally hematologic parameters were determined. In tumor patients the mean plasma T2 was shortened by about 20%, and an increase in the blood sedimentation rate (BSR) was noted. Similar but less pronounced results were found for the nontumor group of patients, indicating that the shortening of T2 in plasma is a secondary host response. However, a plot of plasma 1/T2 versus BSR from tumor patients showed a significant correlation between these two parameters. No such correlation could be detected in the nontumor group of patients. The correlation of 1/T2 with BSR, found solely in the tumor patient group, increased the diagnostic sensitivity of T2 measurements and may help to differentiate between malignant and nonmalignant disease. No significant variation in the T1 spin-lattice relaxation time was observed. © Academic Press, Inc.
    Magnetic Resonance in Medicine 12/1987; 5(6):537 - 547. DOI:10.1002/mrm.1910050604 · 3.40 Impact Factor
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    ABSTRACT: As a chelating agent for labeling antibodies (Abs) with metallic radionuclides, a propionic acid substituted ethylenediamine N,N'-di-[(o-hydroxyphenyl) acetic acid] (P-EDDHA), which tighly complexes 67Ga, was synthesized. The 67Ga-P-EDDHA chelate was coupled in aqueous solution to IgG at a molar ratio of 1:1 via carbodiimide. The average coupling yield was 15%. A specific activity of 4 mCi/mg IgG could be obtained with commercially supplied 67Ga. In vitro stability was evaluated in human serum at 37° C and showed a half-life of about 120 h for the release of 67Ga from the labeled Ab during the initial phase of incubation. This in vitro halflife is similar to that measured for 111In-DTPA labeled Abs. Because of the high stability of the 67Ga-P-EDDHA chelate, the in vivo formation of radioactive labeled transferrin by transchelation, as described for 111In-DTPA labeled Abs, should, however, be reduced by this labeling technique.
    European journal of nuclear medicine and molecular imaging 11/1986; 12(8):397-404. DOI:10.1007/BF00252198 · 5.22 Impact Factor
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    ABSTRACT: As a chelating agent for labeling antibodies (Abs) with metallic radionuclides, a propionic acid substituted ethylenediamine N,N'-di-[(o-hydroxyphenyl) acetic acid] (P-EDDHA), which tightly complexes 67Ga, was synthesized. The 67Ga-P-EDDHA chelate was coupled in aqueous solution to IgG at a molar ratio of 1:1 via carbodiimide. The average coupling yield was 15%. A specific activity of 4 mCi/mg IgG could be obtained with commercially supplied 67Ga. In vitro stability was evaluated in human serum at 37 degrees C and showed a half-life of about 120 h for the release of 67Ga from the labeled Ab during the initial phase of incubation. This in vitro halflife is similar to that measured for 111In-DTPA labeled Abs. Because of the high stability of the 67Ga-P-EDDHA chelate, the in vivo formation of radioactive labeled transferrin by transchelation, as described for 111In-DTPA labeled Abs, should, however, be reduced by this labeling technique.
    European Journal of Nuclear Medicine 02/1986; 12(8):397-404. · 5.22 Impact Factor
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    ABSTRACT: The relaxation times of water protons in rat liver tissue were measured with a NMR spectrometer at 20 MHz. The paramagnetic trace elements Cu, Fe, and Mn were determined by neutron activation analysis. No shortening of T1 could be observed when liver Cu or Fe concentration was increased in the microgram range. T1 was strongly correlated with the liver Mn concentration of untreated animals and animals whose liver Mn concentration was artificially increased or decreased by intravenous injection of manganous acetate or a metal chelating agent with high affinity for hepatobiliary excretion. Deviations from this Mn-T1 correlation were found in the initial phase of liver cirrhosis induced by thioacetamide (elongated T1, normal Mn concentration) and after stimulation of liver growth by phenobarbital (normal T1, decreased Mn concentration). An increased or decreased enhancement factor for Mn may have contributed to the observed deviations during phenobarbital and thioacetamide treatment.
    Investigative Radiology 10/1985; 20(6):601-8. DOI:10.1097/00004424-198509000-00013 · 4.45 Impact Factor
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    ABSTRACT: The influence of a 28-week treatment with disulfiram (DSF), D-penicillamine (PA), and nitrosodiethylamine (NDEA), as well as with a combination of DSF or PA with NDEA on the concentrations of eight essential trace elements in the whole liver tissue of rats was measured by means of neutron activation analysis. While NDEA treatment lowered the Zn content of the liver, DSF alone or in combination with NDEA enhanced the Zn and Se concentration by 50%-80%. Co, Cu, and Cd levels were increased by factors of 10, 60, and 110, respectively. The Mo concentration was decreased by 50% after DSF administration. PA reduced Cu, Co, and Zn in the liver. PA/NDEA treatment also lowered Cu, Co, and Zn content, but there was no strengthening effect of PA on the decrease in Zn observed with NDEA. The change of trace element concentrations, especially of Cu, is discussed with regard to the observed tumor induction in the liver, which tended to be increased by a combined NDEA/PA administration compared with NDEA treatment alone, whereas a protective action of DSF against NDEA induced liver tumors could not be established.
    Journal of Cancer Research and Clinical Oncology 02/1985; 109(1):16-22. · 3.01 Impact Factor
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    ABSTRACT: Summary The influence of a 28-week treatment with disulfiram (DSF),d-penicillamine (PA), and nitrosodiethylamine (NDEA), as well as with a combination of DSF or PA with NDEA on the concentrations of eight essential trace elements in the whole liver tissue of rats was measured by means of neutron activation analysis. While NDEA treatment lowered the Zn content of the liver, DSF alone or in combination with NDEA enhanced the Zn and Se concentration by 50%–80%. Co, Cu, and Cd levels were increased by factors of 10, 60, and 110, respectively. The Mo concentration was decreased by 50% after DSF administration. PA reduced Cu, Co, and Zn in the liver. PA/NDEA treatment also lowered Cu, Co, and Zn content, but there was no strengthening effect of PA on the decrease in Zn observed with NDEA. The change of trace element concentrations, especially of Cu, is discussed with regard to the observed tumor induction in the liver, which tended to be increased by a combined NDEA/PA administration compared with NDEA treatment alone, whereas a protective action of DSF against NDEA induced liver tumors could not be established.
    Journal of Cancer Research and Clinical Oncology 02/1985; 109(1):16-22. DOI:10.1007/BF01884249 · 3.01 Impact Factor
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    ABSTRACT: We describe the chemical synthesis of an iminodiacetic-acid-substituted tetrabromo-o-cresolphthalein (BP-IDA), which complexes Ga-68 tightly. The liver uptake, bile excretion, and urinary excretion of the complex were examined in rats. Maximum liver uptake reached 60%, and 1-hr cumulative bile excretion was 75% of injected dose. Urinary excretion in rats with ligated common bile duct remained below 1%. Competitive action of exogenous bilirubin on hepatobiliary excretion of the Ga complex was less pronounced than that of bromosulfophthalein. The absolute activity determination of the positron emitter Ga-68, the high accumulation in the liver, the low urinary excretion, and the weak competition from exogenous bilirubin are promising features of this radiopharmaceutical for the quantitative study of hepatobiliary function.
    Journal of Nuclear Medicine 08/1983; 24(7):593-602. · 5.56 Impact Factor
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    ABSTRACT: A radiochemical separation scheme for the determination of 25 neutron activated trace elements in biological soft tissue is represented. The scheme includes wet ashing and 16 different organic and inorganic ion exchangers. The procedure is semiautomatized and a description for manufactoring the non commercial available exchangers is given. Precision of the scheme is determined for each single element as well as for a mixture of all elements together.
    Journal of Radioanalytical and Nuclear Chemistry 08/1977; 37(2):503-509. DOI:10.1007/BF02519362 · 1.42 Impact Factor
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