EUROPEAN ORGANIZATION FOR NUCLEAR RESEARCH. Letter of Intent to the ISOLDE and Neutron Time-of-Flight Committee

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1 EUROPEAN ORGANIZATION FOR NUCLEAR RESEARCH Letter of Intent to the ISOLDE and Neutron Time-of-Flight Committee Off-line separation of reactor produced 169 Er for medical applications [11 January 2017] R. Formento Cavaier 1, K. Chrysalidis 2, V.N. Fedoseev 2, F. Haddad 1, U. Köster 3, B. Marsh 2, C. Müller 4, S. Rothe 2, T. Stora 2, D. Studer 5, E. Vermeulen 4, N. Van der Meulen 4 1 SUBATECH, Nantes, France 2 ISOLDE, CERN, Switzerland 3 Institut Laue Langevin, Grenoble, France 4 Paul Scherrer Institut, Villigen, Switzerland 5 Johannes-Gutenberg Universität Mainz, Germany CERN-INTC / INTC-I /01/2017 Spokespersons: R. Formento Cavaier (Roberto.Formento@cern.ch) U. Köster (koester@ill.fr) Local contact: T. Stora (Thierry.Stora@cern.ch) Abstract 169Er is a radiolanthanide with very promising decay properties for targeted radionuclide therapy. We propose to perform off-line mass separation of reactor-produced 169 Er to achieve optimum specific activity for medical applications. 169 Er will be produced by irradiating enriched 168 Er at the high flux reactor of ILL Grenoble, then shipped to CERN for the off-line mass separation at ISOLDE. The isolated final product will then be shipped to PSI for a preclinical study. 1

2 Various biomolecules are available or under development that may target specifically receptors which are overexpressed by certain types of cancer cells. These biomolecules can be used as vectors and labelled with radioisotopes to form targeted radiopharmaceuticals for diagnostics or therapy respectively. Radiolanthanides and other trivalent metals are of particular interest since they can all be labelled to the targeting vector with the same chelators, e.g. DOTA. Radionuclides with significant positron emission are required for Positron Emission Tomography (PET) imaging while those with suitable gamma ray emission may be used for Single Photon Emission Computed Tomography (SPECT). Therapeutic applications require radionuclides emitting charged particles with short range, i.e. alpha particles or low-energy electrons (betas, conversion electrons or Auger electrons). While the emission of a small percentage of γ-rays is generally seen as advantageous due to the option of using them for imaging, abundant emission of γ-rays is a drawback because it would cause an unnecessary dose burden to the patient as well as to the personnel who prepares the radiopharmaceutical. The table shows trivalent therapeutic radiometals with half-lives between 2 and 14 days. This covers the typical range of clinical applications with vectors of small molecular weight that show rapid targeting (e.g. peptides) to vectors of large molecular weight and slower pharmacokinetic (e.g. antibodies). Isotope T1/2 (days) Mean - energy (kev) Photon energy per decay (kev) 47 Sc Y Pr Nd Pm Pm Sm Tb Er Yb Lu It is evident that 169 Er has the most favourable nuclear decay characteristics, i.e. the lowest beta energy, assuring best geometric targeting due to an average range of just 0.15 mm, 2

3 and no disturbing γ-rays. More elaborate dosimetry calculations have validated that 169 Er would provide the best ratio of absorbed dose to the tumour versus normal tissue [1]. Unfortunately 169 Er cannot be produced directly with high specific activity. Reactor irradiation of highly enriched 168 Er leads to specific activities of GBq/mg (for thermal neutron fluxes of 1E14 1E15 cm -2 s -1 and irradiation for one half-life). This corresponds to a dilution of the radioactive 169 Er with 8000 or 800 times more stable 168 Er, respectively. Such a specific activity is far too low for receptor-targeted therapies due to saturation of the limited number of receptors per cancer cell. Carrier-added 169 Er is actually in clinical use, but only for radiosynovectomy of finger joints in the therapeutic management of arthritis [2,3]. Here the low specific activity is acceptable. A way to significantly improve the specific activity is off-line mass separation. Erbium can be either surface ionized or by resonant laser ionization, however the ionization potential of 6.11 ev makes it challenging to reach high thermal ionization efficiencies. We propose comparing by off-line experiments with stable mass markers the achievable ionization efficiencies and maximum ion current for erbium with a high temperature tungsten ionizer [4], a dye-laser based three-step RILIS scheme (622.1 nm nm nm) [5] and a Ti-sapphire based two-step RILIS scheme (400.8 nm nm) developed at LARISSA Mainz [6]. With surface ionization the experiment could be performed at MEDICIS, while RILIS requires an off-line use of the ISOLDE GPS (pending the installation of a laser system at MEDICIS). This work is part of the PhD work of R. Formento Cavaier within the Medicis-PROMED EU project. For the actual 169 Er separation few mg of highly enriched 168 Er will be irradiated in ILL s high flux reactor in a thermal neutron flux of 1.4E15 cm -2 s -1. The irradiated target will be shipped to ISOLDE and inserted into an ISOLDE target container for evaporation and offline mass separation. At a (supposed) average ion current of 400 na we could collect about 200 MBq of mass separated 169 Er per day. We ask for 3 days (9 shifts) off-line use of the ISOLDE GPS with Er RILIS. The scheduling has to be coordinated with the ILL reactor schedule. 3

4 The produced activity of 169 Er will be shipped to PSI for a pilot preclinical study. First, it will be used for labeling of a clinically-relevant biomolecule, such as PSMA-617. The results of the obtained radiochemical purity at a given specific activity will give an indication of the purity of the produced nuclide and may be considered as part of the quality control. It would be desirable to achieve at least 50 MBq/nmol. The obtained radioligand will be used at two different activities for the treatment of two groups of tumor-bearing mice in a pilot experiment performed in parallel to the treatment with the same ligand labeled with 177 Lu, a clinically-established radiolanthanide that serves as reference. A control group of mice will be injected with only saline to compare the delayed tumor growth of the treated animals. References: [1] H Uusijärvi, P Bernhardt, F Rösch, HR Maecke, E Forssell-Aronsson. Electron- and positron-emitting radiolanthanides for therapy: aspects of dosimetry and production. J Nucl Med 2006;47: [2] K Liepe. Radiosynovectomy in the therapeutic management of arthritis. World J Nucl Med 2015;14: [3] R Chakravarty, S Chakraborty, V Chirayil, A Dash. Reactor production and electrochemical purification of 169 Er: a potential step forward for its utilization in in vivo therapeutic applications. Nucl Med Biol 2014;41: [4] GJ Beyer, E Hermann, A Piotrowski, VJ Raiko, H Tyrroff. A new method for rare-earth isotope production. Nucl Instr Meth 1971;96: [5] VS Letokhov. Laser photoionization spectroscopy. Academic Press, Orlando [6] D Studer, P. Dyrauf, P Naubereit, D Matsui, R Heinke, K Wendt. LA 3 NET Laser Ion Sources Workshop, Paris

5 Appendix DESCRIPTION OF THE PROPOSED EXPERIMENT The experimental setup comprises: (name the fixed-isolde installations, as well as flexible elements of the experiment) Part of the Choose an item. Availability Design and manufacturing SSP-GLM chamber Existing To be used without any modification HAZARDS GENERATED BY THE EXPERIMENT (if using fixed installation) Hazards named in the document relevant for the fixed SSP-GLM chamber installation. Additional hazards: 5 Hazards [Part 1 of the experiment/equipment] Thermodynamic and fluidic Pressure Vacuum Temperature Heat transfer Thermal properties of materials Cryogenic fluid Electrical and electromagnetic Electricity Static electricity Magnetic field Batteries Capacitors Ionizing radiation [pressure][bar], [volume][l] [temperature] [K] [fluid], [pressure][bar], [volume][l] [voltage] [V], [current][a] [magnetic field] [T] Target material Zn coated Au foils Beam particle type (e, p, ions, Er169 etc) Beam intensity <= 3E9 ions/s Beam energy kev Cooling liquids [liquid] Gases [gas] Calibration sources: Open source Sealed source [ISO standard] Isotope Activity Use of activated material: Shipping Description Dose rate on contact and in 10 cm distance [dose][msv] [Part 2 of the experiment/equipment] [Part 3 of the experiment/equipment]

6 Isotope 169Er Activity <= 200 MBq per batch, up to 3 batches total Non-ionizing radiation Laser UV light Microwaves (300MHz-30 GHz) Radiofrequency (1-300MHz) Chemical Toxic Harmful CMR (carcinogens, mutagens and substances toxic to reproduction) Corrosive Irritant Flammable Oxidizing Explosiveness Asphyxiant Dangerous for the environment Mechanical Physical impact or mechanical energy (moving parts) Mechanical properties (Sharp, rough, slippery) Vibration Vehicles and Means of Transport Noise Frequency Intensity Physical Confined spaces High workplaces Access to high workplaces Obstructions in passageways Manual handling Poor ergonomics [frequency],[hz] 0.1 Hazard identification 6