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PET RADIOPHARMACY & PRACTICE EANM Marie Curie Training Report 2008 N.Selcan Türker 27 Oct-28 Nov, 2008

Introduction: Molecular imaging (MI) is based on the selective and specific interaction of a molecular probe with a biological target which is visualized through nuclear, magnetic resonance, near infrared or other methods (1). PET ( emitting tomography), a nuclear modality, is ideally suited to produce three-dimensional images of various targets or processes and it enables us to obtain in vivo biological information quantitatively and noninvasively with a wide variety of PET . The rapidly increasing demand for highly selective probes for MI strongly pushes the development of new PET tracers and PET chemistry (1,2).

The training project was initiated at PET Radiopharmacy, Department of , Sant’Orsola University Hospital, during 27 th October-28 th November. The cyclotron-PET center in Bologna is a national reference center for the production of 2-[18F]fluorodeoxyglucose ([18F]FDG) as well as non-FDG radiopharmaceuticals. At the above mentioned center, about 10.000 PET radiopharmaceuticals doses per year are routinely produced in addition to research tracers. FDG accouts for about 82% of the total number of doses. Additionally, molecular imaging section with microPET and microCT is available.

Purpose of the Project: The aim of my training programme at University of Bologna, Sant’Orsola Hospital, Department of PET & Nuclear Medicine was mainly to observe the cyclotron-PET Radiopharmacy practice on- site and to have an overview about an active cylotron-PET center in Europe. The purpose of my training programme included:

- Organisation scheme and resources of a Cyclotron-PET center - Responsibilities, training and the qualification of the personnel - Site-planning and operation of a Cyclotron-PET center - Operation of the cyclotron: liquid and gas targets, daily operating procedures, safety transfer of - Production, quality control of PET-Radiopharmaceuticals: [18F]FDG - Production, quality control of PET-Radiopharmaceuticals: 11 C-radiopharmaceuticals for clinical PET in : 11 C-, 11 C-, 11 C-choline - General aspects of PET radiopharmaceuticals for research use - Trouble shooting and complaint handling - General knowledge about the maintenance, calibration and cleaning frequency of the instruments

EANM Marie Curie Training Grant Report, S. Türker, 2008 Page 1 sur 4 - Radioactive waste management - Standart Operation Procedures (SOP) and Documentation - General knowledge of European regulations and directives.

Report:

During the training I had the opportunity to observe the cyclotron-PET center in Bologna according to the mentioned goals above.

In the center, radiopharmacists, chemistry technologists, medical phycisicist and physics technologist are in charge of production. It was observed that the production, quality control and quality assurance responsibilities were seperated according to the regulations. The center is divided into different rooms such as, bunker, technical room, radiochemistry lab, quality control room, changing room, control area and research lab. The rooms are equipped with sound/visual signaling, phones/handsfree communication systems and radiation/toxic gas detectors (part of enviromental radiation/conditions monitoring system in the control room).

The center has its onsite cyclotron, producing F-18 for [18F]FDG and CO 2 for C-11 labelled radiopharmaceuticals including 11 C-acetate, 11 C-methionine and 11 C-choline. Routine production starts with the daily checks of the gases and technical equipments including enviromental checks and cyclotron master system. To check the performance of the target and to control the constancy of the related parameters, all the documents (daily test report, bombardment report and logbook) are kept systematically. The operation of the cyclotron has a SOP which is written according to manuals. In the center, I had the oppurtunity to learn the technical details about the components and run of the cyclotron. The fault analysis reports are kept to facilitate the trouble shooting and to analyse the faults. I participated the production of F-18 and C-11.

F-18 is the most often used for routine diagnosis with PET because of its almost perfect chemical and nuclear properties. The use of the 18O(p,n)18F reaction on 18O-enriched is the most effective method and delivers F-18 of high molar radioactivity (2). The half-life of 109 .7 min allows time-consuming multi-step radiosyntheses as well as extended PET studies of slower biochemical processes. The most important route for obtaining 18F-labeled compounds is nucleophilic substitution based on no-carrier-added 18F, which is directly available from the target without any carrier addition (3). Nucleophilic substitution is a chemical reaction involving the

EANM Marie Curie Training Grant Report, S. Türker, 2008 Page 2 sur 4 addition of a nucleophilic molecule (highly negatively charged molecule) into a molecule with a leaving group (electron drawing group attached to the parent molecule through an unstable chemical bond) (2,3).

In the center Carbon-11 was produced by bombardment of natural nitrogen through the 14 N(p,a) 11 C (2). The chemistry of F-18 and C-11 was explained to clarify the synthesis of F-18 and C-11 labelled radiopharmaceuticals.

After the production of radionuclides, automatic delivery of the activity to the proper hot cells is provided. The hot cells are cleaned, the reagents are preapared and put in the vials in the module before the synthesis. The reagents are prepared under LAF cabinets. I observed the production of [18F]FDG and C-11 labelled radiopharmaceuticals including 11 C-acetate, 11 C-methionine and 11 C- choline during my training.

The best known and widely used F-18 labelled radiopharmaceutical is [18F]FDG which is a analogue in which the hydroxyl group on the 2-carbon of a glucose molecule is replaced by a fluoride atom (4). Cancer diagnosis and management (diagnosis of malignancy, grading malignancy, staging disease, residual disease, detection of recurrences, measuring response to therapy, to identify the site of disease, to identify the primary tumour when secondary cancers are present) is the most important clinical application of [18F]FDG (5). [18F]FDG is also used for the study of in the and and for the detection of epilepsy(4). 11C-acetate, 11C- methionine and 11C-choline is used for the measurement of oxygen consumption in the heart and brain; for the detection of different types of malignancies, reflecting the amino acid utilization and prostate imaging respectively (2).

In the center, everyday there were two bombardment for the production of F-18. The synthesis based on Standard “Hamacher” synthesis in which Deoxyglucose is labeled with 18F by nucleophilic displacement reaction of an acetylated sugar derivative followed by hydrolysis (4). The yield was approximately 50%, and the preparation time was approximately 30 min. The final solution was diluted with saline. Terminal sterilization was achieved either by aseptic filtration and validated autoclave in the dispensing unit. Individual patient doses were prepared manually with saline and the syringes labelled properly. Quality control (QC) test were routinely performed on each lot of 18F FDG according to European Pharmacopea including pH, radiochemical purity ([18F]FDG, 18F-FDM, 18F, partially acetylated [18F]FDG), chemical purity (TBA, ethanol, aceton, acetonitril), radionuclidic purity and sterility/bacterial endotoxins (10 lots/week).

It was observed that synthesis, dispensing and QC of the radiopharmaceuticals was adequately described by written SOPs and the date were recorded in the synthesis and QC report.

EANM Marie Curie Training Grant Report, S. Türker, 2008 Page 3 sur 4 During the training I also participated the labelling and quality control of Octreotide anolog 68Ga- DOTA-NOC which is a potential PET tracer showing the highest affinity for somatostatin receptors (6).

Moreover radiation protection requirements, radiation dose monitoring and the maintanence of the equipment was discussed with the physicist.

Conclusion: The planning and financing of a PET center is an extensive, time-intensive process that entails the consideration of many factors, including budgeting, reimbursement and other financing strategies, facility design, vendor selection, staffing requirements, and licensing. In addition the transfer of knowledge and the experiences to the developed and developing countries is going to construct new collaborations and networks.

References: 1. Schubiger, P.A. (2007) Molecular Imging with PET-Open Questions? In Schubiger, P.A., Lehmann, L., Friebe, M (Eds.), PET Chemistry-The Driving Force in Molecular Imaging (pp 1-14) Heidelberg, Berlin, Germany, Springer-Verlag. 2. Saha, G.B. (2003) Characteristics of Spesific Radiopharmaceuticals. In Saha, G.B (Eds.), Fundamentals of Nuclear Pharmacy (pp.111-49) New York, USA, Springer-Verlag. 3. Elsinga, P.H. (2002) Radiopharmaceutical Chemistry for Positron Emission Tomography. Methods , 27, 208-17. 4. Yu, S. (2006) Review of 18F-FDG Synthesis and Quality Control. Biomed Imaging Interv J, 2(4), 1-11. 5. Maisey, N.M. (2004) Positron Emission Tomography in Clinical Medicine. In Bailey, D.L., Townsend, D.W., Valk, P.E. and Maisey, M.N (Eds.), Positron Emission Tomography (pp. 1-12) London, UK, Springer-Verlag. 6. Di Pierro, D., Rizzello, A., Cicoria, G., Lodi, F., Marengo, M., Pancaldi, D., Trespidi, S., Boschi. Radiolabelling, quality control and radiochemical purity assessment of the Octreotide analogue 68 Ga DOTA NOC. Appl Rad Iso , 66(8), 1091-6.

Acknowledgements: European Association of Nuclear Medicine (Marie Curie Training Grant). Dr.Stefano Boschi, Head, PET Radiopharmacy, Nuclear Medicine, S Orsola Hospital, Bologna- Italy. Prof.Dr.Biray Caner, Head, Nuclear Medicine, Hacettepe University, Ankara-Turkey.

N.Selcan Türker Fac Medicine, Dep Nuclear Medicine, Hacettepe University, Ankara-Turkey.

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