Commenced in January 2007
Frequency: Monthly
Edition: International
Paper Count: 13

Search results for: radiopharmaceuticals

13 Determination of Myocardial Function Using Heart Accumulated Radiopharmaceuticals

Authors: C. C .D. Kulathilake, M. Jayatilake, T. Takahashi


The myocardium is composed of specialized muscle which relies mainly on fatty acid and sugar metabolism and it is widely contribute to the heart functioning. The changes of the cardiac energy-producing system during heart failure have been proved using autoradiography techniques. This study focused on evaluating sugar and fatty acid metabolism in myocardium as cardiac energy getting system using heart-accumulated radiopharmaceuticals. Two sets of autoradiographs of heart cross sections of Lewis male rats were analyzed and the time- accumulation curve obtained with use of the MATLAB image processing software to evaluate fatty acid and sugar metabolic functions.

Keywords: autoradiographs, fatty acid, radiopharmaceuticals, sugar

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12 Automated System: Managing the Production and Distribution of Radiopharmaceuticals

Authors: Shayma Mohammed, Adel Trabelsi


Radiopharmacy is the art of preparing high-quality, radioactive, medicinal products for use in diagnosis and therapy. Radiopharmaceuticals unlike normal medicines, this dual aspect (radioactive, medical) makes their management highly critical. One of the most convincing applications of modern technologies is the ability to delegate the execution of repetitive tasks to programming scripts. Automation has found its way to the most skilled jobs, to improve the company's overall performance by allowing human workers to focus on more important tasks than document filling. This project aims to contribute to implement a comprehensive system to insure rigorous management of radiopharmaceuticals through the use of a platform that links the Nuclear Medicine Service Management System to the Nuclear Radio-pharmacy Management System in accordance with the recommendations of World Health Organization (WHO) and International Atomic Energy Agency (IAEA). In this project we attempt to build a web application that targets radiopharmacies, the platform is built atop the inherently compatible web stack which allows it to work in virtually any environment. Different technologies are used in this project (PHP, Symfony, MySQL Workbench, Bootstrap, Angular 7, Visual Studio Code and TypeScript). The operating principle of the platform is mainly based on two parts: Radiopharmaceutical Backoffice for the Radiopharmacian, who is responsible for the realization of radiopharmaceutical preparations and their delivery and Medical Backoffice for the Doctor, who holds the authorization for the possession and use of radionuclides and he/she is responsible for ordering radioactive products. The application consists of sven modules: Production, Quality Control/Quality Assurance, Release, General Management, References, Transport and Stock Management. It allows 8 classes of users: The Production Manager (PM), Quality Control Manager (QCM), Stock Manager (SM), General Manager (GM), Client (Doctor), Parking and Transport Manager (PTM), Qualified Person (QP) and Technical and Production Staff. Digital platform bringing together all players involved in the use of radiopharmaceuticals and integrating the stages of preparation, production and distribution, Web technologies, in particular, promise to offer all the benefits of automation while requiring no more than a web browser to act as a user client, which is a strength because the web stack is by nature multi-platform. This platform will provide a traceability system for radiopharmaceuticals products to ensure the safety and radioprotection of actors and of patients. The new integrated platform is an alternative to write all the boilerplate paperwork manually, which is a tedious and error-prone task. It would minimize manual human manipulation, which has proven to be the main source of error in nuclear medicine. A codified electronic transfer of information from radiopharmaceutical preparation to delivery will further reduce the risk of maladministration.

Keywords: automated system, management, radiopharmacy, technical papers

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11 The Potential for Cyclotron and Generator-produced Positron Emission Tomography Radiopharmaceuticals: An Overview

Authors: Ng Yen, Shafii Khamis, Rehir Bin Dahalan


Cyclotrons in the energy range 10-30 MeV are widely used for the production of clincally relevant radiosiotopes used in positron emission tomography (PET) nuclear imaging. Positron emmision tomography is a powerful nuclear imaging tool that produces high quality 3-dimentional images of functional processes of body. The advantage of PET among all other imaging devices is that it allows the study of an impressive array of discrete biochemical and physiologic processes, within a single imaging session. The number of PET scanner increases every year globally due to high clinical demand. However, not all PET centers can afford a cyclotron, due to the expense associated with operation of an in-house cyclotron. Therefore, current research has also focused on the development of parent/daughter generators that can reliably provide PET nuclides. These generators (68Ge/68Ga generator, 62Zn/62Cu, 82Sr/82Rb, etc) can provide even short-lived radionuclides at any time on demand, without the need of an ‘in-house cyclotron’. The parent isotope is produced at a cyclotron/reactor facility, and can be shipped to remote clinical sites (regionally/overseas), where the daughter isotope is eluted, a model similar to the 99Mo/99mTc generator system. The specific aim for this presentation is to talk about the potential for both of the cyclotron and generator-produced PET radiopharmaceuticals used in clinical imaging.

Keywords: positron emission tomography, radiopharmaceutical, cyclotron, generator

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10 Quality Control of 99mTc-Labeled Radiopharmaceuticals Using the Chromatography Strips

Authors: Yasuyuki Takahashi, Akemi Yoshida, Hirotaka Shimada


99mTc-2-methoxy-isobutyl-isonitrile (MIBI) and 99mTcmercaptoacetylgylcylglycyl-glycine (MAG3 ) are heat to 368-372K and are labeled with 99mTc-pertechnetate. Quality control (QC) of 99mTc-labeled radiopharmaceuticals is performed at hospitals, using liquid chromatography, which is difficult to perform in general hospitals. We used chromatography strips to simplify QC and investigated the effects of the test procedures on quality control. In this study is 99mTc- MAG3. Solvent using chloroform + acetone + tetrahydrofuran, and the gamma counter was ARC-380CL. The changed conditions are as follows; heating temperature, resting time after labeled, and expiration year for use: which were 293, 313, 333, 353 and 372K; 15 min (293K and 372K) and 1 hour (293K); and 2011, 2012, 2013, 2014 and 2015 respectively were tested. Measurement time using the gamma counter was one minute. A nuclear medical clinician decided the quality of the preparation in judging the usability of the retest agent. Two people conducted the test procedure twice, in order to compare reproducibility. The percentage of radiochemical purity (% RCP) was approximately 50% under insufficient heat treatment, which improved as the temperature and heating time increased. Moreover, the % RCP improved with time even under low temperatures. Furthermore, there was no deterioration with time after the expiration date. The objective of these tests was to determine soluble 99mTc impurities, including 99mTc-pertechnetate and the hydrolyzed-reduced 99mTc. Therefore, we assumed that insufficient heating and heating to operational errors in the labeling. It is concluded that quality control is a necessary procedure in nuclear medicine to ensure safe scanning. It is suggested that labeling is necessary to identify specifications.

Keywords: quality control, tc-99m labeled radio-pharmaceutical, chromatography strip, nuclear medicine

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9 Regulation Aspects for a Radioisotope Production Installation in Brazil

Authors: Rian O. Miranda, Lidia V. de Sa, Julio C. Suita


The Brazilian Nuclear Energy Commission (CNEN) is the main manufacturer of radiopharmaceuticals in Brazil. The Nuclear Engineering Institute (IEN), located at Rio de Janeiro, is one of its main centers of research and production, attending public and private hospitals in the state. This radiopharmaceutical production is used in diagnostic and therapy procedures and allows one and a half million nuclear medicine procedures annually. Despite this, the country is not self-sufficient to meet national demand, creating the need for importation and consequent dependence on other countries. However, IEN facilities were designed in the 60's, and today its structure is inadequate in relation to the good manufacturing practices established by sanitary regulator (ANVISA) and radiological protection leading to the need for a new project. In order to adapt and increase production in the country, a new plant will be built and integrated to the existing facilities with a new 30 MeV Cyclotron that is actually in project detailing process. Thus, it is proposed to survey current CNEN and ANVISA standards for radiopharmaceutical production facilities, as well as the radiological protection analysis of each area of the plant, following good manufacturing practices recommendations adopted nationally besides licensing exigencies for radioactive facilities. In this way, the main requirements for proper operation, equipment location, building materials, area classification, and maintenance program have been implemented. The access controls, interlocks, segregation zones and pass-through boxes integrated into the project were also analyzed. As a result, IEN will in future have the flexibility to produce all necessary radioisotopes for nuclear medicine application, more efficiently by simultaneously bombarding two targets, allowing the simultaneous production of two different radioisotopes, minimizing radiation exposure and saving operating costs.

Keywords: cyclotron, legislation, norms, production, radiopharmaceuticals

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8 Characterization of Dota-Girentuximab Conjugates for Radioimmunotherapy

Authors: Tais Basaco, Stefanie Pektor, Josue A. Moreno, Matthias Miederer, Andreas Türler


Radiopharmaceuticals based in monoclonal anti-body (mAb) via chemical linkers have become a potential tool in nuclear medicine because of their specificity and the large variability and availability of therapeutic radiometals. It is important to identify the conjugation sites and number of attached chelator to mAb to obtain radioimmunoconjugates with required immunoreactivity and radiostability. Girentuximab antibody (G250) is a potential candidate for radioimmunotherapy of clear cell carcinomas (RCCs) because it is reactive with CAIX antigen, a transmembrane glycoprotein overexpressed on the cell surface of most ( > 90%) (RCCs). G250 was conjugated with the bifunctional chelating agent DOTA (1,4,7,10-Tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic acid) via a benzyl-thiocyano group as a linker (p-SCN-Bn-DOTA). DOTA-G250 conjugates were analyzed by size exclusion chromatography (SE-HPLC) and by electrophoresis (SDS-PAGE). The potential site-specific conjugation was identified by liquid chromatography–mass spectrometry (LC/MS-MS) and the number of linkers per molecule of mAb was calculated using the molecular weight (MW) measured by matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). The average number obtained in the conjugates in non-reduced conditions was between 8-10 molecules of DOTA per molecule of mAb. The average number obtained in the conjugates in reduced conditions was between 1-2 and 3-4 molecules of DOTA per molecule of mAb in the light chain (LC) and heavy chain (HC) respectively. Potential DOTA modification sites of the chelator were identified in lysine residues. The biological activity of the conjugates was evaluated by flow cytometry (FACS) using CAIX negative (SKRC-18) and CAIX positive (SKRC-52). The DOTA-G250 conjugates were labelled with 177Lu with a radiochemical yield > 95% reaching specific activities of 12 MBq/µg. The stability in vitro of different types of radioconstructs was analyzed in human serum albumin (HSA). The radiostability of 177Lu-DOTA-G250 at high specific activity was increased by addition of sodium ascorbate after the labelling. The immunoreactivity was evaluated in vitro and in vivo. Binding to CAIX positive cells (SK-RC-52) at different specific activities was higher for conjugates with less DOTA content. Protein dose was optimized in mice with subcutaneously growing SK-RC-52 tumors using different amounts of 177Lu- DOTA-G250.

Keywords: mass spectrometry, monoclonal antibody, radiopharmaceuticals, radioimmunotheray, renal cancer

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7 Preparation and Quality Control of 68Ga-1,2-Propylene Di-Amino Tetra (Methylenephosphonic Acid)

Authors: N. Tadayon, H. Yousefnia, S. Zolghadri, A. Ramazani, A. R. Jalilian


Bone metastases occur in many patients with solid malignant tumors. Recently, 1,2 propylene di-amino tetra methylenephosphonic acid (PDTMP) has been introduced as a suitable carrier in the development of therapeutic bone-avid radiopharmaceuticals. In this study, due to the desirable characteristics of 68Ga, 68Ga-PDTMP was prepared. 68Ga was obtained from SnO2 based generator. A stock solution of PDTMP was prepared by dissolving in 2 N NaOH. A certain volume of the stock solution was added to the vial containing 68GaCl3 and the pH of the mixture was adjusted to 4 using HEPES. Radiochemical purity of the radiolabelled complex was checked by thin layer chromatography. 68Ga-PDTMP was prepared in only 15 min with radiochemical purity of more than 98%. This new bone-seeking complex can be considered as a good candidate of PET-based radiopharmaceutical for imaging of bone metastases.

Keywords: bone metastases, Ga-68, imaging, PDTMP

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6 Radiochemical Purity of 68Ga-BCA-Peptides: Separation of All 68Ga Species with a Single iTLC Strip

Authors: Anton A. Larenkov, Alesya Ya Maruk


In the present study, highly effective iTLC single strip method for the determination of radiochemical purity (RCP) of 68Ga-BCA-peptides was developed (with no double-developing, changing of eluents or other additional manipulation). In this method iTLC-SG strips and commonly used eluent TFAaq. (3-5 % (v/v)) are used. The method allows determining each of the key radiochemical forms of 68Ga (colloidal, bound, ionic) separately with the peaks separation being no less than 4 σ. Rf = 0.0-0.1 for 68Ga-colloid; Rf = 0.5-0.6 for 68Ga-BCA-peptides; Rf = 0.9-1.0 for ionic 68Ga. The method is simple and fast: For developing length of 75 mm only 4-6 min is required (versus 18-20 min for pharmacopoeial method). The method has been tested on various compounds (including 68Ga-DOTA-TOC, 68Ga-DOTA-TATE, 68Ga-NODAGA-RGD2 etc.). The cross-validation work for every specific form of 68Ga showed good correlation between method developed and control (pharmacopoeial) methods. The method can become convenient and much more informative replacement for pharmacopoeial methods, including HPLC.

Keywords: DOTA-TATE, 68Ga, quality control, radiochemical purity, radiopharmaceuticals, TLC

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5 Determination of Critical Organ Doses for Liver Scintigraphy Using Cr-51

Authors: O. Maranci, A. B. Tugrul


Scintigraphy is an imaging method of nuclear events provoked by collisions or charged current interactions with radiation. It is used for diagnostic test used in nuclear medicine via radiopharmaceuticals emitting radiation which is captured by gamma cameras to form two-dimensional images. Liver scintigraphy is widely used in nuclear medicine.Tc-99m and Cr-51 gamma radioisotopes can be used for this purpose. Cr-51 usage is more important for patients’ organ dose that has higher energy and longer half-life as compared to Tc-99m. In this study, it is aimed to determine the required dose for critical organs of patient through liver scintigraphy via Cr-51 gamma radioisotope. Experimental studies were conducted on patients even though conducting experimental studies on patients is extremely difficult for determination of critical organ doses. Torso phantom was utilized to simulate the liver scintigraphy by using 20 mini packages of Cr-51 that were placed on the organ. The radioisotope was produced by irradiation in central thimble of TRIGA MARK II Reactor at 250 KW power. As the results of the study, critical organ doses were determined and evaluated with different critic organs.

Keywords: critical organ doses, liver, scintigraphy, TRIGA Mark-II

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4 Evaluation of Labelling Conditions, Quality Control, and Biodistribution Study of 99mTc- D-Aminolevulinic Acid (5-ALA)

Authors: Kalimullah Khan, Samina Roohi, Mohammad Rafi, Rizwana Zahoor


Labeling of 5-Aminolevulinic acid (5-ALA) with 99 mTc was achieved by using tin chloride dihydrate (Sncl2.2H2O) as reducing agent. Radiochemical purity and labeling efficiency was determined by Whattman paper No.3 and instant thin layer chromatographic strips impregnated with silica gel (ITLC/SG). Labeling efficiency was dependent on many parameters such as amount of ligand, reducing agent, pH, and incubation time. Therefore, optimum conditions for maximum labeling were selected. Stability of 99 mTc- 5-ALA was also checked in fresh human serum. Tissue bio-distribution of 99 mTc-5-ALA was evaluated in Spargue Dawley rats. 5-ALA was 98% labeled with 99 mTc under optimum conditions, i.e. 100µg of 5-ALA, pH: 4, 10µg of Sncl2.2H2O and 30 minutes incubation at room temperature. 99 mTc labelled 5- ALA remained stable for 24 hours in human serum. Bio-distribution study (%ID/gm) in rats revealed that maximum accumulation of 99 mTc-5-ALA was in liver, spleen, stomach and intestine after half hour, 4 hours, and 24 hours. Significant activity in bladder and urine indicated urinary mode of excretion.

Keywords: 99mTc-ALA, aminolevulinic acid, quality control, radiopharmaceuticals

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3 Absorbed Dose Estimation of 68Ga-EDTMP in Human Organs

Authors: S. Zolghadri, H. Yousefnia, A. R. Jalilian


Bone metastases are observed in a wide range of cancers leading to intolerable pain. While early detection can help the physicians in the decision of the type of treatment, various radiopharmaceuticals using phosphonates like 68Ga-EDTMP have been developed. In this work, due to the importance of absorbed dose, human absorbed dose of this new agent was calculated for the first time based on biodistribution data in Wild-type rats. 68Ga was obtained from 68Ge/68Ga generator with radionuclidic purity and radiochemical purity of higher than 99%. The radiolabeled complex was prepared in the optimized conditions. Radiochemical purity of the radiolabeled complex was checked by instant thin layer chromatography (ITLC) method using Whatman No. 2 paper and saline. The results indicated the radiochemical purity of higher than 99%. The radiolabelled complex was injected into the Wild-type rats and its biodistribution was studied up to 120 min. As expected, major accumulation was observed in the bone. Absorbed dose of each human organ was calculated based on biodistribution in the rats using RADAR method. Bone surface and bone marrow with 0.112 and 0.053 mSv/MBq, respectively, received the highest absorbed dose. According to these results, the radiolabeled complex is a suitable and safe option for PET bone imaging.

Keywords: absorbed dose, EDTMP, ⁶⁸Ga, rats

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2 Radio Labeling and Characterization of Cysteine and Its Derivatives with Tc99m and Their Bio-Distribution

Authors: Rabia Ashfaq, Saeed Iqbal, Atiq ur Rehman, Irfanullah Khan


An extensive series of radiopharmaceuticals have been explored in order to discover a better brain tumour diagnostic agent. Tc99m labelling with cysteine and its derivatives in liposomes shows effective tagging of about 70% to 80 %. Due to microscopic size it successfully crossed the brain barrier in 2 minutes which gradually decreases in 5 to 15 minutes. HMPAO labelled with Tc99m is another important radiopharmaceutical used to study brain perfusion but it comes with a flaw that it’s only functional during epilepsy. 1, 1 ECD is purely used in Tc99m ECD formulation; because it not only tends to cross the blood brain barrier but it can be metabolized which can be easily entrapped in human brain. Radio labelling of Cysteine with Tc99m at room temperature was performed which yielded no good results. Hence cysteine derivatives with salicylaldehyde were prepared that produced about 75 % yield for ligand. In order to perform it’s radio labelling a suitable solvent DMSO was selected and physical parameters were performed. Elemental analyser produced remarkably similar results for ligand as reported in literature. IR spectra of Ligand in DMSO concluded in the absence of SH stretch and presence of N-H vibration. Thermal analysis of the ligand further suggested its decomposition pattern with no distinct curve for a melting point. Radio labelling of ligand was performed which produced excellent results giving up to 88% labelling at pH 5.0. Clinical trials using Rabbit were performed after validating the products reproducibility. The radiopharmaceutical prepared was injected into the rabbit. Dynamic as well as static study was performed under the SPECT. It showed considerable uptake in the kidneys and liver considering it suitable for the Hypatobilliary study.

Keywords: marcapto compounds, 99mTc - radiolabeling, salicylaldicysteine, thiozolidine

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1 Implementation of Synthesis and Quality Control Procedures of ¹⁸F-Fluoromisonidazole Radiopharmaceutical

Authors: Natalia C. E. S. Nascimento, Mercia L. Oliveira, Fernando R. A. Lima, Leonardo T. C. do Nascimento, Marina B. Silveira, Brigida G. A. Schirmer, Andrea V. Ferreira, Carlos Malamut, Juliana B. da Silva


Tissue hypoxia is a common characteristic of solid tumors leading to decreased sensitivity to radiotherapy and chemotherapy. In the clinical context, tumor hypoxia assessment employing the positron emission tomography (PET) tracer ¹⁸F-fluoromisonidazole ([¹⁸F]FMISO) is helpful for physicians for planning and therapy adjusting. The aim of this work was to implement the synthesis of 18F-FMISO in a TRACERlab® MXFDG module and also to establish the quality control procedure. [¹⁸F]FMISO was synthesized at Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN/Brazil) using an automated synthesizer (TRACERlab® MXFDG, GE) adapted for the production of [¹⁸F]FMISO. The FMISO chemical standard was purchased from ABX. 18O- enriched water was acquired from Center of Molecular Research. Reagent kits containing eluent solution, acetonitrile, ethanol, 2.0 M HCl solution, buffer solution, water for injections and [¹⁸F]FMISO precursor (dissolved in 2 ml acetonitrile) were purchased from ABX. The [¹⁸F]FMISO samples were purified by Solid Phase Extraction method. The quality requirements of [¹⁸F]FMISO are established in the European Pharmacopeia. According to that reference, quality control of [¹⁸F]FMISO should include appearance, pH, radionuclidic identity and purity, radiochemical identity and purity, chemical purity, residual solvents, bacterial endotoxins, and sterility. The duration of the synthesis process was 53 min, with radiochemical yield of (37.00 ± 0.01) % and the specific activity was more than 70 GBq/µmol. The syntheses were reproducible and showed satisfactory results. In relation to the quality control analysis, the samples were clear and colorless at pH 6.0. The spectrum emission, measured by using a High-Purity Germanium Detector (HPGe), presented a single peak at 511 keV and the half-life, determined by the decay method in an activimeter, was (111.0 ± 0.5) min, indicating no presence of radioactive contaminants, besides the desirable radionuclide (¹⁸F). The samples showed concentration of tetrabutylammonium (TBA) < 50μg/mL, assessed by visual comparison to TBA standard applied in the same thin layer chromatographic plate. Radiochemical purity was determined by high performance liquid chromatography (HPLC) and the results were 100%. Regarding the residual solvents tested, ethanol and acetonitrile presented concentration lower than 10% and 0.04%, respectively. Healthy female mice were injected via lateral tail vein with [¹⁸F]FMISO, microPET imaging studies (15 min) were performed after 2 h post injection (p.i), and the biodistribution was analyzed in five-time points (30, 60, 90, 120 and 180 min) after injection. Subsequently, organs/tissues were assayed for radioactivity with a gamma counter. All parameters of quality control test were in agreement to quality criteria confirming that [¹⁸F]FMISO was suitable for use in non-clinical and clinical trials, following the legal requirements for the production of new radiopharmaceuticals in Brazil.

Keywords: automatic radiosynthesis, hypoxic tumors, pharmacopeia, positron emitters, quality requirements

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