RAD Conference Proceedings, vol. 6, pp. 8–14, 2022 ISSN 2466-4626 (online) | DOI: 10.21175/RadProc.2022.02 www.rad-proceedings.org A NEW PRODUCTION METHOD OF HIGH SPECIFIC ACTIVITY RADIONUCLIDES TOWARDS INNOVATIVE RADIOPHARMACEUTICALS: THE ISOLPHARM PROJECT E. Vettorato 1,2* , L. Morselli 1 , M. Ballan 1 , A. Arzenton 1,11 , O. S. Khwairakpam 1,11 , M. Verona 2 , D. Scarpa 1 , S. Corradetti 1 , P. Caliceti 2 , V. Di Marco 3 , F. Mastrotto 2 , G. Marzaro 2 , N. Realdon 2 , A. Zenoni 4,5 , A. Donzella 4,5 , M. Lunardon 6,7 , L. Zangrando 7 , M. Asti 8 , G. Russo 9,10 , E. Mariotti 11,12 , D. Maniglio 13,14 , A. Andrighetto 1 1 National Institute of Nuclear Physics, Legnaro National Laboratories (INFN-PV), Legnaro (PD), Italy 2 University of Padua, Department of Pharmaceutical Sciences (UNIPD-DSF), Padova, Italy 3 University of Padua, Department of Chemical Sciences (UNIPD-DiSC), Padova, Italy 4 University of Brescia, Department of Mechanical and Industrial Engineering (DIMI-UNIBS), Brescia, Italy 5 National Institute of Nuclear Physics, Pavia Department (INFN-PV), Pavia, Italy 6 University of Padua, Department of Physics and Astronomy (UNIPD-DFA), Padova, Italy 7 National Institute of Nuclear Physics, Padua Department (INFN-PD), Padova, Italy 8 Radiopharmaceutical Chemistry Section, Nuclear Medicine Unit, Reggio Emilia AUSL-IRCCS, Reggio Emilia, Italy 9 National Research Council, Institute of Molecular Bioimaging and Physiology (CNR- IBFM), Cefalù (PA), Italy 10 National Institute of Nuclear Physics, Southern National Laboratories (INFN-LNS), Catania, Italy 11 University of Siena, Department of Physical, Geological and Environmental Sciences (UNISI-DSFTA), Siena, Italy 12 National Institute of Nuclear Physics, Pisa Department, Siena Group (INFN-PI), Siena, Italy 13 University of Trento, Department of Industrial Engineering and BIOtech Research Center (UNITN), Trento, Italy 14 National Institute of Nuclear Physics, Trento Institute for Fundamental Physics and Applications (INFN-TIFPA), Trento, Italy Abstract. Radionuclides of interest in nuclear medicine are generally produced in cyclotrons or nuclear reactors, with associated issues such as highly enriched target costs and undesired contaminants. The ISOLPHARM project (ISOL technique for radioPHARMaceuticals) explores the feasibility of producing extremely high specific activity β - emitting radionuclides as radiopharmaceutical precursors. This technique is expected to produce radiopharmaceuticals very hardly obtained in standard production facilities. Radioactive isotopes will be obtained from nuclear reactions induced by accelerating 40 MeV protons in a cyclotron to collide on a UCx target. By means of: high working temperatures and high vacuum conditions, the migration of the radioactive elements towards an ion source, a potential difference up to 40 kV, and a mass separation device, an isobaric beam of desired radionuclides will be produced and implanted on a deposition target. The availability of innovative isotopes can potentially open a new generation of radiopharmaceuticals, based on nuclides never studied so far. Among these, a very promising isotope could be Ag-111, a β - emitter with a half-life (7.45 d), an average β - energy of 360 keV, a tissue penetration of around 1 mm, and a low percentage of γ-emission. The proof of principle studies on Ag-111 production and radiolabeling are currently under investigation in the ISOLPHARM_EIRA project, where both its production and possible application as a radiopharmaceutical precursor will be evaluated in its computational/physics, radiochemistry, and radiobiology tasks. Currently, innovative macromolecules meeting the specific requirements for the chelation and targeted delivery of Ag-111 are being developed, which will be further tested in vitro on 2D and 3D models, as well as in vivo for their pharmacokinetics and therapeutic potential onto xenograft models. Keywords: Ag-111, chelators, cyclotron, deposition targets, radionuclides production, gamma detection, ISOL, radiopharmaceuticals, radiotherapy 1. INTRODUCTION One of the biggest challenges in medicine is providing efficient tools for diagnosing and treating a wide range of diseases and tumors. Among the most widely studied and developed tools in nuclear medicine, radiopharmaceuticals, i.e., drugs containing radionuclides delivering a predefined dose of radiation to target tissues for diagnostic or therapeutic purposes, have been extensively and efficiently exploited [1]. High penetrating radiation, such as γ emission, is mainly used for early diagnosis, while particle emission such as * elisa.vettorato@unipd.it α, β - and Auger electrons, induces cell death. For this reason, particle emission is widely considered a very efficient tool for anticancer therapy. The final goal of radionuclide therapy is to deliver a cytotoxic level of radiation onto a disease site without compromising the healthy tissues [2]. The rapid advance of nuclear medicine has recently led to the marketing authorization of the theranostic pair [ 68 Ga]Ga- DOTATOC (as SomaKit TOC ® ) and [ 177 Lu]Lu- DOTATATE (as Lutathera ® ) in 2017 both in Europe and the US [3].