ISOL technique for radiopharmaceuticals development XIV Seminar on Software for Nuclear, Subnuclear and Applied Physics, Alghero, 8th June 2017 The ISOLPHARM Project ISOL technique for radiopharmaceuticals development Michele Ballan INFN –LNL michele.ballan@lnl.infn.it Michele Ballan

Overview ⚛ Radiopharmaceutical production: current techniques ⚛ The SPES project at LNL ⚛ Radiopharmaceutical production: current techniques ⚛ ISOLPHARM: a new method based on ISOL technique ⚛ Innovative radio-isotopes for nuclear medicine (ISOLPHARM2) ⚛ Experimental activities ⚛ Conclusions Michele Ballan

SPES Facility Layout New infrastructure for: Application Facility Unico punto in cui si parla di building&infrastr., poi c’è la visita. E’ stato realizzato l’edificio per il ciclotrone, le stazioni di irraggiamento ISOL e per le aree applicative, il sistema di selezione in massa. Il nuovo edificio è collegato all’edificio ALPI. The new building has a surface of almost 3600 mq with an underground level connected to the third experimental hall and the ALPI building. The beam transport, together with the CB and the Medium Resolution Mass Separator, will be mounted inside the third exp hall and the RFQ will be inside the ALPI building. New infrastructure for: Application Facility Cyclotron RIB facility Michele Ballan

SPES: The future of LNL SPES-RIB facility SPES Neutron facility 22/04/2018 SPES is: 1) A second generation ISOL facility (for neutron-rich ion beams) 2) An interdisciplinary research center (for p,n applications) SPES-DRIVER SPES-RIB facility Financed & Under construction In commissioning Cyclotron installation & commissioning: E=70 MeV proton beam, I= 750 mA Production & re-acceleration of exotic beams, from p-induced Fission on UCx SPES for medicine SPES Neutron facility Proposal Financed LARAMED & ISOLPHARM projects Radisotopes for medical applications Accelerator based neutron source (Proton and Neutron Facility for Applied Physics) Michele Ballan

What is a radiopharmaceutical? Radiopharmaceuticals are medicines that deliver a predefined amount of radiation to a target tissue for diagnostic or therapeutic purposes depending on the mechanism of decay Nuclear medicine applications Therapeutic agents Diagnostic agents Radionuclides properties: Decay properties Chemical properties Half-life Feasibility of large scale production Michele Ballan

Traditional methods New method: ISOL vs others Nuclear reactor Traditional methods Low specific activity levels High neutron fluxes required Irradiation of targets of the same element → Isotopic impurities (carrier added - radioisotopes) Cyclotron New method: β- radionuclides can be easily produced as carrier-free isotopes No nuclear reactor required Michele Ballan

Carrier-added radionuclides The Specific activity The specific activity is a measure of the activity per mass and is usually expressed in units of GBq/mg or Ci/mg. A) Radioisotopes diluted by non therapeutic atoms of the same element have low specific activity. Carrier-added radionuclides B) Radioisotopes present only in the mass of the element of interest have high specific activity. Carrier-free radionuclides Michele Ballan

ISOLPHARM Method overview The ISOLPHARM method is capable of selecting and isolating a SINGLE ISOTOPE → extremely high specific activity ISOL PHARM Michele Ballan

The ISOLPHARM patent Patent title: The use of ISOL technique for the production of radiopharmaceuticals is a INFN PATENT Patent title: «Method for producing beta emitting radiopharmaceuticals and beta emitting radiopharmaceuticals thus obtained» EU patent US patent CANADA patent Michele Ballan

ISOLPHARM (1st phase): produced radionuclides In target production of 89Sr and 90Y* using a standard UCx target Already developed and tested! In target production of 64Cu using a Ni-based target Under development Michele Ballan

Specific activity (the case of 89Sr) Traditional production methods (reactor) New method Isotopic contamination in the substrate Isobaric contamination in the substrate Difficult chemical separation Easy chemical separation Low specific activity High specific activity ~ 0,004 GBq/mg ~ 597 GBq/mg Michele Ballan

Isotope production: UCX target PPB: 40 MeV, 200 μA b) a) [nuclide/s] b) a) Michele Ballan

SPES UCX target yield: other isotopes? A lot of ISOL beams can be potentially produced: Only a few of the produced isotopes are currently used/studied in nuclear medicine (traditional techniques allow the production of a limited variety of radioisotopes) Is it possible that other isotopes will be interesting as radiopharmaceuticals “active core”? Other ISOL isotopes? ISOLPHARM2 ISOLPHARM isotopes [nuclide/s] Michele Ballan

Other ISOL Isotopes of medical interest? (light) Selection criteria Diagnosis Theragnostics Therapy Michele Ballan

Almost 60 ISOL isotopes were found! Other ISOL Isotopes of medical interest? (heavy) Almost 60 ISOL isotopes were found! (up to now) Diagnosis Theragnostics Therapy Michele Ballan

Three target concepts are currently under investigation: Innovative Target concepts: overview ISOL production of the desired isotopes requires specific targets. Targets have to be: Solid Refractory (more refractory than the element for which they were designed) Three target concepts are currently under investigation: ⚛ UCX target (Operation temperature: 2200°C) ⚗ Target R&D and state of art: ☢ Innovative isotopes production: 111Ag ⚛ ZrGe target (Operation temperature: 1800°C) ☢ Innovative isotopes production: As & Ga isotopes ☢ 64/67Cu unexpected production! ⚛ TiC/TiB2 target (Operation temperature: 2000°C) ☢ Innovative isotopes production: Sc isotopes Nuclear reactions studied Designed Tested Nuclear reactions studied Designed Tested Nuclear reactions studied Designed Tested Michele Ballan

111Ag 64-67Cu 43-44-47Sc SPES TiC target PPB 40 MeV , 200 µA 111Ag, 64-67Cu, 43-44-47Sc production (ISOLPHARM 2) 111Ag SPES UCx target PPB 40 MeV , 200 µA 64-67Cu SPES ZrGe target PPB 70 MeV , 100 µA Up to 2 Ci in target after 5 days! Up to 40 mCi (67Cu) – 1500 mCi (64Cu) in target after 5 days! 43-44-47Sc SPES TiC target PPB 40 MeV , 200 µA Up to 870 mCi (43Sc) – 6450 mCi (44Sc) – 2200 mCi (47Sc) in target after 5 days! Michele Ballan

Activity done so far at LNL - UNIPD-DSF Beam deposition @ LNL Simulation of the process using stable ion beams thanks to the SPES test bench (front-end off-line) Activities @ UNIPD-DSF Extraction from the substrate, quantification and chemical separation of the deposited element Ion beams produced, deposited, dissolved and analyzed: Sr+, Y+, I+, Cu+ (4 master, 2 PhD. students) Michele Ballan

Conclusions: what’s next? ⚛ Cross check of the Fluka calculated yields using different models (Geant4) ⚛ Performing of the first studies with radioactive ion beams (after 2019) ⚛ Building an ISOLPHARM national community: UNIPD (Industrial Engineering, Pharmaceutical Sciences, Physics & Chemistry Departments), INFN (INFN-PD, INFN-FE, INFN-NL, INFN-TIFPA) and hospitals (Castelfranco Veneto, Reggio Emilia) are involved. ⚛ Building an ISOLPHARM international community: POLATOM (Poland) & NCSR-DEMOKRITOS (Greece) are involved in an European project. Some interest also from PSI & CERN ISOLDE – MEDICIS (Switzerland). Michele Ballan

Thank you for your kind attention Michele Ballan

& to the RIB production group… 22/04/2018 & to the RIB production group… Michele Ballan