Dedicated to Professor Apolodor Aristotel Răduţă’s 70th Anniversary

THE RADIOPHARMACEUTICALS RESEARCH CENTER (CCR) OF IFIN-HH AT START

I. URSU1, L. CRACIUN1, D. NICULAE1, N.V. ZAMFIR1 1Horia Hulubei National Institute for Nuclear Physics and Engineering, P.O.Box MG-6, RO-077125

Bucharest-Magurele, Romania, E-mail: ursui@nipne.ro; E-mail: cliviu@nipne.ro; E-mail: dana.niculae@nipne.ro;

E-mail: zamfir@tandem.nipne.ro

Received July 15, 2013

The present status of IFIN-HH CCR (Radiopharmaceuticals Research Centre) project is reviewed and its development perspectives are addressed.

Key words: accelerator systems, radiopharmaceuticals, radiotracers.

1. INTRODUCTION

The extraordinary evolution in medical imaging [1-3] and the foreseen breakthrough in targeted radiotherapy [4-6] have raised the interest worldwide and brought tremendous development in producing a wealth of radiopharmaceuticals, specific radiotracers and innovative targeting therapeutic agents [7].

In line with these developments and exploiting the significant achievements of IFIN-HH in the past decades [8-15] in medical applications of nuclear technologies, in radiopharmaceutical research and production and seeking also to respond to a particularly critical societal need, the absence of a national source for PET isotopes, IFIN-HH has engaged in the first major projects for PET isotopes in Romania [16, 18] and finally in establishing a state of the art Centre, dedicated to the study of radiopharmaceuticals, both for medical imaging and targeted therapy, in view of their future implementation in medical practice.

Remaining committed to its steady goals of developing a sound in-house capability, in order to stay in the forefront of the current nuclear science and technology and to widening the impact of nuclear technologies on industry, other business areas, as well as on the society at large, IFIN-HH has implemented during 2009–2013 an investment project entitled “Infrastructure development for frontier research in nuclear physics and related fields” [19].

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As part of this wider development plan, the CCR facility is thought to bring an impetus to relevant and valuable interdisciplinary scientific research in life sciences. The project consists of a more than 1330 m² state-of-the-art center comprising one of the newest generation of cyclotrons (TR19) and a highly specialized radiopharmaceutical facility. Providing suitable working conditions, facilities and methods required substantial effort.

The above mentioned ideas have appropriately shaped the profile of the Centre and determined its mission and goals [Fig. 1].

Fig. 1 – The CCR lay-out.

2. EXPERIMENTAL FACILITY

The core of CCR is represented by a TR19 cyclotron (Advanced Cyclotron Systems Inc.), a versatile and fully automated and computer controlled machine. This cyclotron accelerates negative ions (H-), on a vertically arranged plane, up to 19 MeV energy, and is provided with two target stations and dual extraction capabilities. It is also the only one in its class to have an external ion source, with the advantage of “Zero dose” routine maintenance of Ion Source and Extraction System (see Fig. 2 a-d).

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With at least double production capability compared to other PET cyclotrons, TR19 will not only serve the most demanding radioisotope production need today but will also ensure that the facility has built in capacity for future growth.

• Guaranteed 15 Ci/hr 18F • Capability > 30 Ci/run 18F • Reliability: consistent high uptime • Automated Target Changer with precise real-time target position alignment • Flexible Dual Simultaneous Irradiation:

– Irradiate any combination of targets – Irradiate simultaneously at different beam energies – Wide range of radioisotopes: 18F, 11C, 15O, 13N, 124I, 64Cu and more.

Technical overview of TR19 cyclotron Type of cyclotron: Negative Hydrogen External Ion Source Local Shielding 2 Extracted Beams 8 External Targets Beam current up to 300µA Variable energy: Energy Range 14 MeV to 19 MeV Clean cryogenic vacuum system 1E-6 Torr. TR19 has an innovative design: • simple Ion Source service • modular: remove, replace or add components quickly and efficiently • partial shielding: compact and easy to install • ability to select and set optimal energy for different radioisotopes • small Footprint: less dedicated space required • vertical Magnet Orientation: designed for easier maintenance • Cryopump Vacuum System: higher performance vacuum system that

completely eliminates oil contamination • High power and very stable RF system.

The accelerator design offers the possibility of working simultaneously in a “dual beam” configuration, an essential feature that permits to address simultaneously the production of short-lived radionuclides on one beam and on the other to perform multi-disciplinary research, and thus opens clear perspectives for extending the capabilities of the present equipment setup.

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On the right hand side the extraction beam line for protons can be observed.

Future development in the Experimental Hall To attain our research program objectives it is necessary to build the

extension of the irradiation capabilities in the experiment hall from TR-19 cyclotron through dedicated beam lines of protons.

For experimental beam lines in the experiment hall (target hall), a commuting

magnet will be placed allowing the addition of up to four beam lines, as shown in the scheme below. The experimental hall has a total area of 125 m2 and allows the experimental development. The protection walls have a thickness of 1 m and the area is provided with a rolling bridge of 5 tf, HVAC and all the other necessary utilities (technical gases, compressed air, cooling water). The commuting magnet,

Fig. 2a – TR19 cyclotron with 6 meters external beam. Fig. 2b – Local shielding, that reduces vault thickness and maintenance costs.

Fig. 2c – The Target station, quick-release targets. Fig. 2d – A view of the dees.

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quadrupolar magnets on the extension line are major components that are already available. The electric power system of the magnets will be projected in agreement with the beam optics simulation. For the precise characterization of the proton beam a system for beam diagnosis will be developed.

Fig. 3 – The Lay-out of the TR19 cyclotron vault, external beam line

and the future development in the experimental hall.

CCR comprises of radiochemistry and radiopharmacy laboratories, including quality control, dedicated for labeling with medical isotopes, compliant with the EU current Good Manufacturing Practice (cGMP) regulations. The Centre was designed based on the flows and the compliance to above regulations as well as to radiological safety regulations. The radiochemistry units are hosted in hot cells and are handled remotely. Hot cells are designed to work with highly radioactive solutions being structured on carbon steel, 75 mm Pb (98%) shielding, by first fusion ingots, and stainless steel (AISI 304) finished. The cells are interlocked with the environmental monitoring and safety systems of the units and connected with the cyclotron through capillaries inside a steel square tube, internally shielded with

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50 mm lead, for radioactive fluids arrival and also with the automatic filling system, thus avoiding any vial handling. The hot cells have ventilation systems (negative pressure, particulate contents class B), which guarantee both the protection of the product and of the user and connect automatically with an air compressing station whenever a too high radioactive value is measured in the cell.

According to their designated use, there are different types of hot cells installed in the clean-room area. The synthesis modules were carefully selected allowing adaptation of synthesis parameters and preparation of a large scale of radiopharmaceuticals working in “open” mode, or in “closed” system, with single-use cassettes. There are modules dedicated to F-18 labeling (FDG, MISO, FLT, DOPA, FETNIM, EF5 – to name a few biomolecules of interest), Ga-68 labeling (conjugate peptides for targeting specific receptors), and intention to expand the options to Cu-64/67, I-124 and Tc-99m produced via cyclotron. Some of the routes use pre-purification or other preparative steps which are also done with remote control devices. The fully automated dispensing unit is a shielded isolator, working in aseptic environment (class A) and using a robotic arm to fill and calibrate vials.

Radioanalytical and microradiobiological assessment of the radio-pharmaceutical products is to be done in dedicated laboratories, GLP-compliant, testing the (radio) chemical and nuclide purities, filter integrity, bioburden presence of endotoxins and microbial contamination, osmolarity, residual solvents a.s.o., using chromatographic techniques (HPLC, TLC, GC), gamma spectrometry and specific methodologies.

Fig. 4 – Automated radiosynthesis units working in: left-Open mode and right-closed system.

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Fig. 5 – Robotic dispensing unit and general view of the radiopharmacy lab.

The system also includes a microPET, to be used for research on small animals.

3. RESEARCH PROGRAMME

The CCR Research Programme addresses three different domains: a) Interdisciplinary basic research in physics, biology, chemistry, etc. b) Applied research towards clinical applications of novel radiopharmaceuticals c) Applied research focused on the development of new pharmaceuticals - in cooperation with partners from the pharmaceutical industry.

a) The new capability of irradiation in the experiment hall TR-19 will represent an unique facility in Romania with the following potential:

– Neutron activator for nanostructure activation for brachytherapy; – Neutron activation of nanoparticles for industry; – Irradiation system of high currents for Tc-99m production with “rabbit” for automatic transfer to hot-cells; – TLA/UTLA (Thin Layer Activation/ Ultrathin Layer Activation) for wear corrosion studies; – Positron source in line with the cyclotron for accelerating slow positrons (advanced stage build-up); – Irradiation for electronic device testing; – Experimental physics, dosimetry, etc.

The originality of the experimental program envisages the possibility that the Research Center of Radiopharmaceutical products from IFIN-HH becomes an important and unique cluster of nuclear medicine in research and a future provider both for radioisotopes for diagnosis (PET, PET-CT, SPECT) and for treatment (through the Neutron Activator).

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b) Applied research towards clinical applications of novel radiopharmaceuticals: The production of medical radionuclides via cyclotron is especially

envisaged. Production and post-processing of positron/gamma/beta emitters radioisotopes (short lived) require improvements in targetry, chemical separation processes and purification. Production of F-18, C-11, N-13, O-15, I-124, Cu-64, Tc-99m, can be achieved; the development of experimental set-ups for irradiations are in various stages of development.

Based on sophisticated radiotracers and focused on the molecular level, nuclear medicine offers unique opportunities for studying the functionality of the organs. To fully exploit the in vivo biochemistry, a great commitment to interdisciplinary research is required. Contributions from radiochemistry, organic and inorganic chemistry, radiopharmacy, radiopharmacology, physics, biology and medicine all have to be combined in each tracer design.

A number of potential radiopharmaceuticals were tested at IFIN-HH (2000-2012), but only preclinical research was conducted because of missing GMP premises for clinical trial preparations. Molecules with specific biological activity and preferential tumor uptake involved in pathological mechanisms, such as antibodies, peptides and hormones were radiolabelled with gamma/positrons/ beta emitters, showing promising results for clinical trial and applications. Some of the following tracers will be further investigated with this aim and new tracers will also be proposed: 188Re-antiVEGF, 188Re-antiCEA, 188Re-antiMUC1, 68Ga-DOTA-VIP, 68Ga-NOTA-TOC, 99mTc-mannose-dextran, 99mTc-DPZM, 99mTc-folates, 99mTc-antiSelectin, 123/124I-mIBG, 177Lu-DOTAM-EGF, 177Lu-DOTA-NT, and 177Lu-DOTA-TATE.

c) Applied research focused on the development of new pharmaceuticals - in cooperation with the pharmaceutical industry. Molecular imaging is expected to play an increasingly important role in drug

discovery and development. Positron Emission Tomography (PET), as a non-invasive imaging technique, which provides quantitative information about a drug target’s distribution, its interaction with drug molecules and changes over time and upon therapeutic intervention, has been increasingly recognized as a powerful imaging modality that provides a specific and sensitive biomarker for drug development (administration-distribution-metabolism-elimination, uptake, receptor occupancy studies). This high resolution technique allows to conduct proof-of-target, proof-of-mechanism and proof-of-efficacy studies and contributes significantly to the understanding of the molecular mechanisms and also to practical questions such as effective biological dose quantification of the new drugs or determination of the potential interactions. This kind of studies use C-11 or O-15 as organogenic elements, to label small molecules or synthons, to be integrated in the drug molecule; the scope can be reached only with rapid synthesis (i.e. click chemistry approach). Animal models and experience in handling special type of modified models are also required.

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4. CONCLUSIONS

CCR represents a state of the art experimental facility, dedicated to research in the fields of radiochemistry, radiopharmacy and nuclear applications.

The outstanding characteristics and performances of CCR’s infrastructure and its researcher’s expertise are expected to open bright perspectives in this multidisciplinary research field.

Acknowledgments. The realization of the CCR project was a collective effort, initiated in 2006,

by accomplishing the feasibility study, supported by the IMPACT Programme (Complex system: cyclotron, radiochemical annexes and PET camera, for medical applications – CICPROPET). Furthermore, as part of the 7 PM / 29.X.2008 contract [19], entitled “Infrastructure development for frontier research in nuclear physics and related fields”, the CCR project was eventually funded via the Capacities Programme (2010-2013). CCR has also received a substantial support from IAEA, in the form of a TC grant (ROM6017), comprising expert missions to the site, trainings, scientific visits, fellowships and equipment. The collaboration with colleagues from similar centers in Europe was also important and should be highlighted.

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