Comparison of receptor affinity of natSc-DOTA-TATE versus natGa-DOTA-TATE

BACKGROUND: 44Sc as a positron emitter can be an interesting alternative to 68Ga (T½ = 67.71 min) due to its longer half-life (T½ = 3.97 h). Moreover, the b– emitter 47Sc can be used for therapy when attached to the same biomolecule vectors. DOTA as a chelating agent has been proven suitable for the radiolabelling of peptides recognising tumour cell receptors in vivo with M3+ radiometals. DOTA-derivatized peptides have been successfully labelled with 90Y and 177Lu for therapy, and with 68Ga for PET imaging. However, published data on 44Sc-labelled DOTA-biomolecules as potential PET radiotracers are still very limited. The aim of this study was to compare the affinity of natGa- and natSc-labelled DOTA-TATE to somatostatin receptors subtype 2 expressed in rat pancreatic cancer cell line AR42J. MATERIAL AND METHODS: The cold complexes of DOTA-TATE with natGa and natSc were synthesized and identified by HPLC and MS analysis and evaluated in vitro for competitive binding to cancer cell line AR42J expressing somatostatin receptors subtype 2 (sstr2). RESULTS: The IC50 values calculated from the displacement curve of {125I-Tyr11}-SST-14 were: 0.20 ± 0.18, 0.70 ± 0.20, 0.64 ± 0.22 and 0.67 ± 0.12 for natGa-DOTA-TATE, natSc-DOTA-TATE, DOTA-TATE, and {Tyr11}-SST-14 complexes, respectively, with the affinity lowering in the decreasing order: natGa-DOTA-TATE > DOTA-TATE > Tyr11-SST-14 > natSc-DOTA-TATE. CONCLUSIONS: The binding affinity of natGa-DOTA-TATE appeared higher than that of natSc-DOTA-TATE. Further in vitro and in vivo studies are needed to verify the influence of the chelated metal on the affinity and uptake of the respective radiolabelled compounds. This information might be crucial when the in vivo applications of peptides labelled with 68Ga and 44Sc for PET, as well as the use of 47Sc for radiotherapy are considered. Nuclear Med Rev 2011; 14, 2: 85–8

Tryptophan metabolism in experimental necrotizing acute pancreatitis

Pancreatic encephalopathy is a serious, often lethal complication of acute pancreatitis (AP). Its pathomechanism remains obscure. We have previously described increased blood levels of quinolinic acid (QUIN) – an endogeneous neurotoxine – during edematous experimental acute pancreatitis. Several other metabolites of tryptophan (TRP) are also known to be neuroactive. The aim of the present study was to assess tryptophan and its main metabolites: kynurenine (KYN), 3-hydroxykynurenine, quinolinic acid (QUIN), kynurenic acid (KYNA), serotonin (5HT) during experimental acute necrotizing acute pancreatitis. Experimental necrotizing acute pancreatitis was induced in rats by intraductal injection of 5% sodium taurocholate. Control groups consisted of sham-operated and not operated rats. The animals were sacrificed 5 and 24 hours after the operation. We evaluated -amylase, pancreas weight and histology as parameters of pancreatitis. A simplified neurological scoring system was applied. To assess TRP and its metabolites in plasma, we used high performance liquid chromatography. Five hours after the onset of AP we found significant increase in TRP metabolites: QUIN, KYNA, KYN, and 3HKYN in the plasma of animals with AP, as compared to the control group. When assessed 24 hours after induction of AP, those changes were no longer observed in blood. Instead, a decrease in TRP level appeared. Increase in plasma QUIN was associated with neurologic disturbances. In the present study we demonstrated transient activation of kynurenine pathway during early stages of experimental necrotizing AP, with increased blood levels of QUIN, KYNA, KYN, and 3HKYN and subsequent depletion of TRP. As some kynurenine derivatives, e.g. quinolinic acid, are endogenous toxins, they might contribute to neurologic and other organs disturbances during AP

Investment appraisal practice in the European Union countries

Purpose: The goal of the paper was to perform a literature study, to determine the state of the theory and practice of investment valuation in the countries of the European Union which should be the starting point for further research. Design/Methodology/Approach: In this paper, an analysis of literature sources was carried out about assessing the effectiveness of investments in European Union countries. The conducted review and description of the found scientific sources is aimed at determining the current state of investment valuation practice, a description of the research carried out so far, which will allow us to determine the starting point for a new study. Findings: During preliminary research found it profoundly surprising that despite the huge potential impact of better capital allocation, there are two main problems regarding investment appraisal practices in European companies. First and foremost, a large part of even the largest European corporations do not use advanced investment appraisal techniques or apply them only to a limited extent. Secondly, yet there has not been a research into practical applications of investment appraisal methodologies that would cover the entire Single Market, i.e., the European Economic Area and Switzerland. Practical Implications: Obtained conclusions allowed us to recommend a study of the relationship between investment appraisal practice and company performance for all the countries of the European Single Market. Originality/value: Further research should identify the differences regarding the use of investment appraisal methods between countries as well as sectors. It is expected that the conclusions from projected future research will considerably broaden the knowledge about a particularly important area of corporate activity – making decisions regarding resource allocation.peer-reviewe

Studies on the separation of 99mTc from large excess of molybdenum

BACKGROUND: Due to aging and unexpected prolonged shutdown of nuclear reactors producing 99Mo for 99Mo/ 99mTc generators it was necessary to explore the alternative methods of technetium-99m production. The first choice were the accelerators. Three years ago IAEA (International Atomic Energy Agency) initiated the Coordinated Research Project “Accelerator-based Alternatives to Non-HEU production of Mo-99 /Tc-99m” aimed at direct production of 99mTc in proton accelerators using the 100Mo(p,2n)99mTc reaction. POLATOM is participating in this enterprise together with the Heavy Ion Laboratory of Warsaw University and the Institute of Nuclear Chemistry and Technology. MATERIAL AND METHODS: 99Mo/99mTc solutions and pure 99mTc used for generators production or milked from ready to use generators were used in experiments. Commercial chromatographic and laboratory-prepared columns were used for separation. The peristaltic pumps were used for solutions delivery onto the columns. Radioactivity of eluted 99Mo and 99mTc was measured using high resolution gamma spectrometry or ionisation chamber in case of high radioactivity. For separation, three different chromatographic methods were used, one based on ion exchange and two on extraction. RESULTS: Synthetic mixtures simulating the real solutions were used. 99mTc is quantitatively bound in the Dowex-1 × 8 column whereas molybdenum is only slightly retained and totally rinsed with 2M NaOH. 99mTc is eluted with TBAB. The elution yield has been reproducible and amounted to 78%. The AnaLig Tc-02 resin column was used for 99mTc retention. Residual Mo was removed by rinsing with 2M NaOH and 99mTc eluted using small volume of water. The recovery was equal to about 85%. Using C-18 column coated with PEG over 80% of 99mTc was recovered in about 50 mL of water. The reduction of volume was necessary. CONCLUSIONS: The recovery of 99mTc was the highest using AnaLig Tc-02 resin. Time of 99mTc separation is the shortest for AnaLig Tc-02 resin and it is not higher than 100 minutes and it can further be shortened

The radiometal makes a difference. Synthesis and preliminary characterisation of DOTA-minigastrin analogue complexes with Ga, Lu and Y

BACKGROUND: The minigastrin analogue — CP04: DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 has been developed for CCK2R targeting. This analogue can be radiolabelled with 111In or 68Ga for imaging, or with 90Y and 177Lu for therapy. However, affinity of the chelator-peptide conjugates to the cell membrane receptors may vary depending on the metal incorporated into the complex. So far, there are no such studies for the ligands of gastrin/cholecystokinin receptor CCK2R. It is supposed that the reason for the differentiation of receptor affinity to the respective receptors is in the changes of structure of chelating system and their influence on the bioactive conformations of the metal conjugated peptides. Herein, we report on the radiolabeling of CP04 with 90Y, 177Lu and 68Ga and synthesis of cold CP04 complexes with respective stable metals for further structural and physico-chemical and biological studies. MATERIALS AND METHODS: From 200 to 600 MBq of 90Y, 177Lu or 68Ga were used for radiolabelling of 20 μg of CP04 dissolved in ascorbic acid solution (50 mg/mL, pH 4.5). Non-radioactive complexes with Lu and Ga were synthesized in milligram amounts starting from 0.5 mg up to 5 mg of CP04 dissolved in ascorbic acid solution (50 mg/mL, pH 4.5) when using 2-molar excess of the metal ions. Complex formation needed 5 min in microwave oven or 12 min in thermo-block at 95°C. RP-HPLC isocratic method (Kinetex 150/4.6 mm; 25% AcN/0.1% TFA, 1 mL/min) with UV/Vis and radiometric detection was developed for investigation of the radiolabelled and “cold” complexes. For LC-MS investigations, HPLC method was modified replacing TFA by formic acid. RESULTS AND DISCUSSION: Yields of CP04 radiolabelling were greater than 90% for all three radionuclides. The HPLC method enabled identification of these radio-complexes based on comparison to their non-radioactive equivalents. In all cases, chromatograms revealed peaks that could be attributed to the metal-CP04 complexes and to impurities (including methionine oxidation). LC-MS analysis of Ga and Lu complexes revealed conformity of the observed molecular ions to the predicted formulas (m/z 2116 and 2220 Da for Ga and Lu, respectively). Different chromatographic behaviour observed for Ga-CP04 complex comparing to Lu- and Y- labelled peptide (relative retention to CP04: 1.08, 0.86 and 0.85, respectively) suggest different coordination of the metal ions. Therefore, further studies are planned using the non-radioactive complexes in order to assess their structural conformations

Different technical possibilities of post- -therapeutic tandem 90Y/ /177Lu-DOTATATE imaging

BACKGROUND: Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms derived from endocrine stem cells.These tumors are characterized by overexpression of somatostatinreceptors (SSTR), which is utilized for imaging using SSTR analogs. Peptide receptor radionuclide therapy (PRRT) somatostatinanalogs labeled with 90Y and 177Lu in neuroendocrine tumors (NETs) results in symptomatic improvement, prolonged survival,and enhanced quality of life. The post-therapeutic imaging leadsto possibility of biodistribution of therapy. The aim of our study was to describe different possibilities of post-therapeutic imaging in patients underwent tandem therapy90Y/177Lu-DOTATATE with preliminary results of 90Y PET imaging.MATERIAL AND METHODS: Thirty patients (11 men, 19 women; the mean age 55 ± 10.9 y) with histological confirmationof metastatic neuroendocrine tumors (G1 and G2) were treated with tandem therapy 90Y/177Lu-DOTATATE. WHBA scan and SPECT acquisition of the abdomen were performed 24 hours post therapy injection, on the dual-headVaricam camera (ELSCINT) using 177Lu photopeak and 90Y bremsstrahlung. PET imaging of 90Y component was done on Siemens Biograph Truepoint PET/CT (window 511 keV ± 15%) 4 hours after 90Y/177Lu-DOTATATE. Additionally phantom studies were performer to analyze the spatial resolution of different protocols.RESULTS: Out of all the patients, median OS was 49.8 months and median EFS time 24.3 months. Spatial resolution achieved for 90Y, 177 Lu and PET imaging of 90Y componentmeasured using the phantom of the torso filled up with water was 20 mm, 8 mm and 4–5 mm FWHM, respectively. Spatial resolution in human body in our study was about 30 mm for 90Y, 15 mm for 177Lu and 25–30 mm for PET imaging of 90Y component.CONCLUSIONS: The theoretically best spatial resolution offers PET scanner, however it is important to keep in mind that90Y-imaging PET is not used for diagnosis purposes (small activities)but rather to present new possibility of post-therapeutic imaging (substantially higher activities). For post-therapeutic imaging after intravenous radiopharmaceutical administration the best spatial resolution offers standard scintigraphic camera for 90Y/177Lu DOTATATE imaging, withusing 177Lu photopeaks. The worst spatial resolution offers standard scintigraphic camera for 90Y/177Lu DOTATATE imaging, with using 90Y bremsstrahlunggammas

Evaluation of radiological and clinical efficacy of ^{90}Y-DOTATATE} therapy in patients with progressive metastatic midgut neuroendocrine carcinomas

Background: To evaluate the radiological and clinical therapeutic effectiveness of ^{90}Y-octreotate [DOTATATE] inpatients with progressive somatostatin receptor-positive midgut neuroendocrine carcinomas (GEPNETs). Material/Methods: The study group: 34 patients, with histological proven extensive non-resectable and progressive midgut GEP-NETs. Radionuclide therapy (^{90}Y-DOTATATE) was given i.v. with a mean activity per administration 3,82 GBq. Initial clinical tumor responses were assessed 6-7 weeks after therapy completion and then once 3-monthly. The objective tumor response was classified according to the RECIST, initially between 4-6 months and then after each of the 6 months interval. Results: At 6 months after treatment completion, radiological tumor response was observed in 6 subjects with PR (19%), 25 presented SD (78%) and single had PD (3%). Overall clinical response to therapy at 6 months follow-up was observed in 23 patients (68%), SD in 5 patients (15%) and PD in 6 (18%). A year after therapy radiological tumour response was seen in 11 patients (44%), SD had 12 subjects (44%) and DP was noted in 2 patients. Two years after completed therapy PR was seen in 6 patients (33%), SD in additional 11 subjects (61%), single patient had PD. Clinical response to treatment in terms of PR and SD were noted in 22 patients (88%) after 1 year and in 14 patients (87%) after 2 years. Median PFS was 20 months, while the median OS was 23 months. In the 6 patients with clinical PD within initial 6 months the median PFS was 6 months and OS 11 months, while in those with SD or PR PFS was 22 months and OS 26 months (P<0.05). Conclusions: Therapy with ^{90}Y-DOTATATE} is effective in terms of clinical response, however the radiological response measured by the RECIST criteria underestimates benefits of this type of therapy in patients with progressive somatostatin receptor-positive midgut neuroendocrine carcinomas

Investment appraisal practice in the biggest companies in Poland

Purpose: The preliminary research carried out in 2020 in the group of the largest public companies in Poland was to check whether these companies use the NPV method and whether the method of assessing investment proposals is consistent with the indications of the theory. Design/Methodology/Approach: An empirical research was conducted in Poland in 2020 by interviews with management board members responsible for investment decisions, representing the largest public companies in Poland, information was obtained about the organization of the process of evaluating investment proposals. Findings: The survey confirmed the popularity of NPV application in the largest public companies in Poland, as all surveyed entities use this method. It is also no surprise that as many as 93.3% of the surveyed companies use IRR. What is surprising, however, is the frequency of using the payback period commonly criticized in the theory as a project evaluation criterion. This method is used by 80.0% of the largest public companies. Originality/value: This survey is one of the few studies on investment appraisal procedures in the largest Polish public companies.peer-reviewe

Comparison of chromatographic methods for quality control of DMSA complexes with 99mTc and 188Re at (III) and (V) oxidation states

BACKGROUND: The reliable method for determination ofidentity and radiochemical purity (RCP) is of great importancein radiopharmaceutical development. This is especially relevantwhen more than one form of radiometal/ligand complex can beformed during radiolabelling, such as complexes of 99mTc or 188Rewith meso-2,3-dimercaptosuccinic acid (DMSA), where dependingon the pH, metal can occur either at +3 or +5 oxidation state.The aim of our study was to evaluate possibilities for optimizationof chromatographic systems leading to specific and reliableanalytical method for determination of the identity and RCP ofDMSA complexes with 99mTc or 188Re.MATERIAL AND METHODS: The commercial DMSA kits(POLATOM) were used for preparation of technetium-99m (III) and (V) complexes with DMSA. 99mTc(V)-DMSA complexeswere prepared by addition of NaHCO3 to the kit vial prior to99mTc-eluate to obtain pH ~8. 188Re(V)-DMSA was prepared eitherdirectly or using intermediate 188Re(III)-EDTA complex addedto DMSA. RCP was evaluated by TLC using: ITLC-SG developedin methylethylketon, SG60 coated plates developed in:n-BuOH/H2O/CH3COOH and n-PrOH/H2O/CH3COOH systems,and in H2O. Comparative biodistribution studies were performedin normal Wistar rats.RESULTS: Using silica gel plates and n-PrOH, H2O and aceticacid in the developing solution, we observed that 99mTc/188Re(III)-DMSA and 99mTc/188Re(V)-DMSA complexes could be wellseparated from each other and from the impurities in the formof free pertechnetate/perrhenate. In vivo studies showed quitedifferent biodistribution of 99mTc(III)- and 99mTc(V)-DMSA. Thetrivalent complex accumulated mainly in kidneys (&gt;40%ID),while 99mTc(V)-DMSA revealed high excretion with urine andrelatively high concentration in osseous tissue (ca. 2 %ID/g).Accumulation of this complex in kidneys was very low (ca.2.5 %ID). Biodistribution pattern of 188Re(V)-DMSA prepareddirectly was almost identical to that of 99mTc(V)-DMSA. Biodistributionresults of the 188Re preparation obtained using 188Re(III)-EDTA intermediate indicated that the preparation contained themixture of penta- and trivalent 188Re complexes. The quite highaccumulation of radioactivity in kidneys (23 %ID) gave evidenceof the presence of 188Re(III)-DMSA in this preparation, what wasalso confirmed by the results of TLC analysis performed usingsilica gel plate and n-propanol/water/acetic acid as developingsystem. CONCLUSIONS: Based on our study, we have made recommendationon the suitable methods for investigations of RCP ofDMSA complexes, i.e.: SG60 plates developed in the mixtureof n-propanol/water/acetic acid, which enable determination of the tri- and pentavalent DMSA complexes, as well as, thepertechnetate/perrhenate impurity, and developed in water fordetermination of the colloidal residue.BACKGROUND: The reliable method for determination ofidentity and radiochemical purity (RCP) is of great importancein radiopharmaceutical development. This is especially relevantwhen more than one form of radiometal/ligand complex can beformed during radiolabelling, such as complexes of 99mTc or 188Rewith meso-2,3-dimercaptosuccinic acid (DMSA), where dependingon the pH, metal can occur either at +3 or +5 oxidation state.The aim of our study was to evaluate possibilities for optimizationof chromatographic systems leading to specific and reliableanalytical method for determination of the identity and RCP ofDMSA complexes with 99mTc or 188Re.MATERIAL AND METHODS: The commercial DMSA kits(POLATOM) were used for preparation of technetium-99m (III) and (V) complexes with DMSA. 99mTc(V)-DMSA complexeswere prepared by addition of NaHCO3 to the kit vial prior to99mTc-eluate to obtain pH ~8. 188Re(V)-DMSA was prepared eitherdirectly or using intermediate 188Re(III)-EDTA complex addedto DMSA. RCP was evaluated by TLC using: ITLC-SG developedin methylethylketon, SG60 coated plates developed in:n-BuOH/H2O/CH3COOH and n-PrOH/H2O/CH3COOH systems,and in H2O. Comparative biodistribution studies were performedin normal Wistar rats.RESULTS: Using silica gel plates and n-PrOH, H2O and aceticacid in the developing solution, we observed that 99mTc/188Re(III)-DMSA and 99mTc/188Re(V)-DMSA complexes could be wellseparated from each other and from the impurities in the formof free pertechnetate/perrhenate. In vivo studies showed quitedifferent biodistribution of 99mTc(III)- and 99mTc(V)-DMSA. Thetrivalent complex accumulated mainly in kidneys (&gt;40%ID),while 99mTc(V)-DMSA revealed high excretion with urine andrelatively high concentration in osseous tissue (ca. 2 %ID/g).Accumulation of this complex in kidneys was very low (ca.2.5 %ID). Biodistribution pattern of 188Re(V)-DMSA prepareddirectly was almost identical to that of 99mTc(V)-DMSA. Biodistributionresults of the 188Re preparation obtained using 188Re(III)-EDTA intermediate indicated that the preparation contained themixture of penta- and trivalent 188Re complexes. The quite highaccumulation of radioactivity in kidneys (23 %ID) gave evidenceof the presence of 188Re(III)-DMSA in this preparation, what wasalso confirmed by the results of TLC analysis performed usingsilica gel plate and n-propanol/water/acetic acid as developingsystem.CONCLUSIONS: Based on our study, we have made recommendationon the suitable methods for investigations of RCP ofDMSA complexes, i.e.: SG60 plates developed in the mixtureof n-propanol/water/acetic acid, which enable determination of the tri- and pentavalent DMSA complexes, as well as, thepertechnetate/perrhenate impurity, and developed in water fordetermination of the colloidal residue