The CERN-MEDICIS (MEDical Isotopes Collected from ISolde) facility has delivered its first radioactive ion beam at CERN (Switzerland) in December 2017 to support the research and development in nuclear medicine using non-conventional radionuclides. Since then, fourteen institutes, including CERN, have joined the collaboration to drive the scientific program of this unique installation and evaluate the needs of the community to improve the research in imaging, diagnostics, radiation therapy and personalized medicine. The facility has been built as an extension of the ISOLDE (Isotope Separator On Line DEvice) facility at CERN. Handling of open radioisotope sources is made possible thanks to its Radiological Controlled Area and laboratory. Targets are being irradiated by the 1.4 GeV proton beam delivered by the CERN Proton Synchrotron Booster (PSB) on a station placed between the High Resolution Separator (HRS) ISOLDE target station and its beam dump. Irradiated target materials are also received from external institutes to undergo mass separation at CERN-MEDICIS. All targets are handled via a remote handling system and exploited on a dedicated isotope separator beamline. To allow for the release and collection of a specific radionuclide of medical interest, each target is heated to temperatures of up to 2,300°C. The created ions are extracted and accelerated to an energy up to 60 kV, and the beam steered through an off-line sector field magnet mass separator. This is followed by the extraction of the radionuclide of interest through mass separation and its subsequent implantation into a collection foil. In addition, the MELISSA (MEDICIS Laser Ion Source Setup At CERN) laser laboratory, in service since April 2019, helps to increase the separation efficiency and the selectivity. After collection, the implanted radionuclides are dispatched to the biomedical research centers, participating in the CERN-MEDICIS collaboration, for Research & Development in imaging or treatment. Since its commissioning, the CERN-MEDICIS facility has provided its partner institutes with non-conventional medical radionuclides such as Tb-149, Tb-152, Tb-155, Sm-153, Tm-165, Tm-167, Er-169, Yb-175, and Ac-225 with a high specific activity. This article provides a review of the achievements and milestones of CERN-MEDICIS since it has produced its first radioactive isotope in December 2017, with a special focus on its most recent operation in 2020.

Background: In order to support the ongoing research across Europe to facilitate access to novel radionuclides, the PRISMAP consortium (European medical radionuclides programme) was established to offer the broadest catalog of non-conventional radionuclides for medical and translational research. The aim of this article is to introduce readers with current status of novel radionuclides in Europe. Main body: A consortium questionnaire was disseminated through the PRISMAP consortium and user community, professional associations and preclinical/clinical end users in Europe and the current status of clinical end-users in nuclear medicine were identified. A total of 40 preclinical/clinical users institutions took part in the survey. Clinical end users currently use the following radionuclides in their studies: ¹⁷⁷Lu, ⁶⁸ Ga, ¹¹¹In, ⁹⁰Y, other alpha emitters, ²²⁵Ac, ⁶⁴Cu and Terbium isotopes. Radionuclides that would be of interest for users within the next 2–5 years are ⁶⁴Cu, Terbium radionuclide “family” and alpha emitters, such as ²²⁵Ac. Conclusions: Thanks to a questionnaire distributed by the PRISMAP consortium, the current status and needs of clinical end-users in nuclear medicine were identified.

In the field of medical and scientific research, radionuclides are used to investigate various physiological and pathological processes. PRISMAP - the European medical radionuclide programme was created to bring together production facilities including intense neutron sources, an isotope mass separation facility, high-power accelerators, biomedical research institutes, and hospitals to support medical research. The aim of this article is to introduce readers with the current status of innovative radionuclides in Europe. A survey was created targeting the latest trends mainly focused on the demand, the production and the distribution of non-routinely used medical radionuclides for use in research, and for pre-clinical and clinical trials. This survey has been disseminated through the PRISMAP community. 16 of 104 respondents were working in the field of radionuclide production. The data found common aspects from all producer-facility respondents: the biggest challenge for the producers is the availability of target materials, which goes hand-in-hand with their purity/enrichment grade. The results show that there are sufficient national or international distribution routes and methods established, although having reported challenges due to legislation constraints, especially for novel radionuclides. Thanks to a questionnaire distributed by the PRISMAP consortium, the current status in radionuclides production was identified. Understanding the current status of radionuclide production is essential for assessing the continent’s capabilities and addressing the burgeoning demands for cutting-edge medical radionuclides.

This work presents the production cross-sections of Ce, Tb and Dy radionuclides produced by 300 MeV to 1.7 GeV proton-induced spallation reactions in thin tantalum targets as well as the related Thick Target production Yield (TTY) values and ratios. The motivation is to optimise the production of terbium radionuclides for medical applications and to find out at which energy the purity of the collection by mass separation would be highest. For that purpose, activation experiments were performed using the COSY synchrotron at FZ Jülich utilising the stacked-foils technique and γ spectrometry with high-purity germanium detectors. The Al-27(p,x)Na-24 reaction has been used as monitor reaction. All experimental data have been systematically compared with the existing literature.

Samarium-153 is a promising theranostic radionuclide, but low molar activities (A_m) resulting from its current production route render it unsuitable for targeted radionuclide therapy (TRNT). Recent efforts combining neutron activation of ¹⁵²Sm in the SCK CEN BR2 reactor with mass separation at CERN/MEDICIS yielded high-A_m ¹⁵³Sm. In this proof-of-concept study, we further evaluated the potential of high-A_m ¹⁵³Sm for TRNT by radiolabeling to DOTA-TATE, a well-established carrier molecule binding the somatostatin receptor 2 (SSTR₂) that is highly expressed in gastroenteropancreatic neuroendocrine tumors. DOTA-TATE was labeled with ¹⁵³Sm and remained stable up to 7 days in relevant media. The binding specificity and high internalization rate were validated on SSTR₂-expressing CA20948 cells. In vitro biological evaluation showed that [¹⁵³Sm]Sm-DOTA-TATE was able to reduce CA20948 cell viability and clonogenic potential in an activity-dependent manner. Biodistribution studies in healthy and CA20948 xenografted mice revealed that [¹⁵³Sm]Sm-DOTA-TATE was rapidly cleared and profound tumor uptake and retention was observed whilst these were limited in normal tissues. This proof-of-concept study showed the potential of mass-separated ¹⁵³Sm for TRNT and could open doors towards wider applications of mass separation in medical isotope production.

The radionuclides ⁴³Sc, ${ }^{44g/m}$Sc, and ⁴⁷Sc can be produced cost-effectively in sufficient yield for medical research and applications by irradiating ${ }^{nat}$Ti and ${ }^{nat}$V target materials with protons. Maximizing the production yield of the therapeutic ⁴⁷Sc in the highest cross section energy range of 24–70 MeV results in the co-production of long-lived, high-$\gamma$-ray-energy ⁴⁶Sc and ⁴⁸Sc contaminants if one does not use enriched target materials. Mass separation can be used to obtain high molar activity and isotopically pure Sc radionuclides from natural target materials; however, suitable operational conditions to obtain relevant activity released from irradiated ${ }^{nat}$Ti and ${ }^{nat}$V have not yet been established at CERN-MEDICIS and ISOLDE. The objective of this work was to develop target units for the production, release, and purification of Sc radionuclides by mass separation as well as to investigate target materials for the mass separation that are compatible with high-yield Sc radionuclide production in the 9–70 MeV proton energy range. In this study, the in-target production yield obtained at MEDICIS with 1.4 GeV protons is compared with the production yield that can be reached with commercially available cyclotrons. The thick-target materials were irradiated at MEDICIS and comprised of metallic ${ }^{nat}$Ti, ${ }^{nat}$V metallic foils, and ${ }^{nat}$TiC pellets. The produced radionuclides were subsequently released, ionized, and extracted from various target and ion source units and mass separated. Mono-atomic Sc laser and molecule ionization with forced-electron-beam-induced arc-discharge ion sources were investigated. Sc radionuclide production in thick ${ }^{nat}$Ti and ${ }^{nat}$V targets at MEDICIS is equivalent to low- to medium-energy cyclotron-irradiated targets at medically relevant yields, furthermore benefiting from the mass separation possibility. A two-step laser resonance ionization scheme was used to obtain mono-atomic Sc ion beams. Sc radionuclide release from irradiated target units most effectively could be promoted by volatile scandium fluoride formation. Thus, isotopically pure ${ }^{44g/m}$Sc, ⁴⁶Sc, and ⁴⁷Sc were obtained as mono-atomic and molecular ScF${ }_2^{+}$ ion beams and collected for the first time at CERN-MEDICIS. Among all the investigated target materials, ${ }^{nat}$TiC is the most suitable target material for Sc mass separation as molecular halide beams, due to high possible operating temperatures and sustained release.