Research on Emerging Medical radionuclides from the X-sections (REMIX): The Accelerator-based Production of 47Sc, 149Tb, 152Tb, 155Tb and 161Tb

The REMIX project is focused on the cyclotron-based production of 47Sc, 149Tb, 152Tb, 155Tb and 161Tb radionuclides, whose decay characteristics make them suitable for medical applications. This work will outline the main results achieved withing the REMIX collaboration, that is organized in the following Work Packages (WP): WP1. Target manufacturing (49Ti, 50Ti and 155Gd2O3) and characterization; WP2. Nuclear cross section (XS) measurements with 49Ti and 50Ti targets for 47Sc production; WP3. Nuclear XS measurements with natDy, 159Tb and natEu targets for xxTb production; WP4. Nuclear XS modeling for 47Sc and 155Tb production; WP5. Dosimetric calculations for 47Sc- and xxTb-labelled radiopharmaceuticals; WP6. 155Tb Thick Target Yield (TTY) measurements; WP7. Apparatus design and realization for irradiation tests with the LARAMED beamline. Since the LARAMED bunkers and ancillary laboratories are currently under completion at the INFN-LNL, the nuclear XS experiments are carried out in collaboration with the GIP ARRONAX facility (Saint-Herblain, France) and the Thick Target Yield (TTY) measurements are performed at the Sacro Cuore Don Calabria hospital (SCDCh, Negrar, Verona, Italy).


Introduction
REMIX is a project funded by INFN-CSN5 in 2021-2023, with the goal of studying 47 Sc and medical Terbium isotopes ( 149 Tb, 152 Tb, 155 Tb and 161 Tb) production routes by using accelerators.The framework of REMIX is the LARAMED (LAboratory of RADionuclides for MEDicine) program [1,2], that will exploit the 70 MeV proton cyclotron installed at the INFN-LNL for the SPES project [3].Since the LARAMED bunkers and ancillary laboratories are currently under completion (WP7), nuclear cross section (XS) experiments of the REMIX project are carried out in collaboration with the GIP (Groupement d'Intérêt Public) ARRONAX (Accélérateur pour la Recherche en Radiochimie et Oncologie à Nantes Atlantique) facility (Nantes, France) [4] while the Thick Target Yield (TTY) measurements are performed in collaboration with the Sacro Cuore Don Calabria hospital (SCDCh, Negrar, Verona, Italy).All the radionuclides of interest in the REMIX project, except for the therapeutic 161 Tb, can be used to obtain theranostic radiopharmaceuticals, since they emit radiation suitable for both therapeutic and diagnostic purposes, as shown in Table 1 [5].The study of the possible production routes of 47 Sc are under the spotlight of the scientific community since 2016, as underlined by the IAEA project focused on "Therapeutic Radiopharmaceuticals Labelled with New Emerging Radionuclides ( 67 Cu, 186 Re, 47 Sc)" (CRP no.F22053) [6,7].Studies to find the best 47 Sc production route have to consider not only the resulting 47 Sc yield but also the simultaneous minimization of the co-production of all possible contaminants: particular attention must be paid to the Sc-isotopes since they cannot be chemically separated from the produced 47 Sc and to their impact on the patient dose (WP5).As already reported, the proton-based production of 47 Sc was first studied in the PASTA project [8][9][10][11] and the goal of REMIX is to measure the proton-induced nuclear reactions by using isotopically enriched 49 Ti and 50 Ti targets (WP1, WP2).On the other hand, the medically relevant Tb-isotopes are obtaining increasing attention in the last years [12], but there are many challenges in their production.For this reason, within the REMIX project nuclear XS for Tbproduction are investigated both experimentally (WP3) and theoretically (WP4), with a focus on the low energy 155 Gd(p,n) 155 Tb route, investigated at the SCDCh (WP6).
During 2021 and up to June 2022 the WP1 realized with the HIgh energy VIbrational Powder Plating (HIVIPP) method and characterized with Ion Beam Analysis (IBA) techniques the isotopically enriched 49 Ti and 50 Ti thin targets (ca.550 μg/cm 2 ) [13], to be irradiated at GIP ARRONAX cyclotron for nuclear XS measurements (WP2).From July 2022 to December 2023, the WP1 will study the manufacturing of Gd2O3 targets by Spark Plasma Sintering (SPS) to be irradiated at the SCDCh first by using nat Gd and then by using the isotopically enriched 155 Gd to produce 155 Tb (WP6).A dedicated capsule designed by WP7 will be used for this purpose. 49Ti and 50 Ti targets for 47 Sc production.

WP2. Nuclear cross section (XS) measurements with
(resp.L. Mou).The thin targets realized by WP1 are irradiated with the proton-beam available at GIP ARRONAX having a tunable energy 35-70 MeV.Considering the pandemic and up to mid-2022, no.6 irradiation runs have been performed: in total no.12 of 49 Ti and no.6 50 Ti targets were irradiated.Figure 1 shows the preliminary results of the 49 Ti(p,x) 47 Sc XS.Further WP2 experiments are scheduled for autumn 2022 and 2023.
WP3. Nuclear XS measurements with nat Dy, 159 Tb and nat Eu targets for xx Tb production (resp.S. Manenti).These thin targets are available on the market and are irradiated at the GIP ARRONAX facility to find out the best production parameters for Tb-radionuclides, in collaboration with WP4.
The γ-spectrometry measurements are carried out at the LASA lab.Up to mid-2022, no.4 irradiation runs have been performed on no.16 nat Dy targets.Figure 2 shows the preliminary results of the nat Dy(d,x) 155 Tb XS.The nuclear codes TALYS [14], EMPIRE [15] and FLUKA [16] are used to estimate the production of 47 Sc [9], 155 Tb and 161 Tb.Experimental data from WP2 and WP3 will be compared with theoretical results, to find out the most promising production routes for these radionuclides.It is important to remind the need to properly estimate the co-production of contaminants, including the ones that are difficult to be measured, such as the fast-decaying ones and stable isotopes. 47Sc-and xx Tb-labelled radiopharmaceuticals (resp.L. Meléndez-Alafort and L. De Nardo).As already done for 47 Sc production using nat V targets [10], the OLINDA code is used to estimate the dose increase, due to the presence of contaminants in the labelling of specific radiopharmaceuticals.These results, carried out with both 47 Sc and Tb-isotopes, will indicate whether radionuclides obtained with the production route under investigation could be used in clinical practice.

WP6
. 155 Tb Thick Target Yield (TTY) measurements (resp.P. Martini).During 2023, the enriched 155 Gd2O3 target realized by WP1 will be irradiated at the 19 MeV cyclotron of the SCDCh.Dissolution of the target will be performed to take an aliquot of the solution, determine thick target yield and measure 155 Tb RadioNuclidic Purity (RNP) by γ-spectrometry, in collaboration with WP2.
2.6.WP7.Apparatus design and realization for irradiation tests with the LARAMED beamline (resp.G. Sciacca).The target-station and the beam-dump to be installed in the LARAMED beam-line devoted to XS measurements is designed and will be realized at the LNL.Additional mechanical devices, useful for the REMIX project (e.g.collimator for the GIP ARRONAX facility, capsule for the SCDCh target station, etc.), are designed and realized within WP7.

Conclusions: a mid-report of the REMIX project
REMIX project started in 2021, a year still affected by the pandemic.However, results have been achieved without delay, also thanks to the solid network of collaborations and the mutual support in the team.A more detailed description of REMIX major outcomes can be found in specific works.

Table 1 .
Main nuclear data of the radionuclides of interest in REMIX.