Newsletter 2 – editorial by Ferid Haddad, ARRONAX - WP Leader Access Platform

PRISMAP – The European medical radionuclide programme is now active for more than a year. Tremendous work has been made to set up the whole organisation scheme, which is now effective and working every day to promote the availability of non-conventional radionuclides at the European level, and ease their use in the coming years.

This is a very important achievement as the interest and use of a radionuclide depends in part to its physical and chemical characteristics but mostly on its availability. Availability is a key concern and especially for non-conventional radionuclide that, at the beginning, are produced in a limited number of centres and interest only few end-users.

On one side, to launch the production of a novel radionuclide, as a producer, potential users are contacted. Before joining a programme, those users discuss the future availability to see if it will be compatible with a potential clinical trial in terms of activity and quality. They are also very keen on redundancy and consistency of quality among the limited number of producers. It is then often difficult to raise their interest in novel radionuclides. On the other side, when a user asks to a producer about a novel radionuclide, the latter studies the potential market and, as it is often limited at the beginning, he is reluctant to start developing it.

Thanks to PRISMAP - The European medical radionuclide programme, this chicken and egg situation can be solved. Production centres all over Europe have come together to propose novel radionuclides to interested users through a call for project standing every 6 month during the duration of the project (link to 3.4 PRISMAP’s first call and 3.5PRISMAP’s second call). For most novel radionuclides, several production centres can provide them allowing whole year availability. In parallel, in-depth work is conducted on specifications and product comparisons to ensure quality (link to 3.7 Standards for clinical translation). Having in mind the quality of service, PRISMAP’s team launched a survey to identify the needs of the scientific community through a survey (link to 3.1PRISMAP survey) and also looked to the too often forgotten aspect of transportation (link to radionuclide transport and logistics) that is very important in the case of radioactive material. Finally a strong training programme is being set-up to make researchers from physics, chemistry, biology, pharmacy, and medicine acquainted to the use to these novel radionuclides (link to 6.Training Office).

All these aspects are illustrated in the present newsletter. By working at the same time on all these aspects, we intend to make novel-radionuclides more readily available and expect to strongly support developments of molecular imaging, internal targeted therapy, and the theranostic approach in nuclear medicine.

Consortium meeting in Riga

The PRISMAP consortium meeting 3 was organized by the team from the University of Latvia (LU) and gathered 23 participants in Riga, Latvia on-site at LU Campus (Science building) and 49 participants on-line on June 13-16th, 2022.

This forum brought together existing PRISMAP consortium partners and advisors, as well as industrial partners for best strategies on how to build the united network of available and novel radionuclides/radiopharmaceuticals in Europe.

Four days of discussions included invited speakers from the UK, USA, Austria, and Spain who highlighted the importance of this initiative for the emerging infrastructures, clinical community, and patients.

The first call for innovative and collaborative projects applications was described as very successful with high interest during the public event (attended by more than 100 participants).

The industrial and clinical collaboration is evolving as shown by growing participation in the PRISMAP survey (see map) and more than 75% of respondents confirm the necessity of PRISMAP as the way to unite the radionuclide manufacturing, researcher and end user communities.

A public event was held to also exchange with our users, entitled PRISMAP grows up; the recording is available online. We presented some of the recent achievements of PRISMAP, especially concerning the training resources (detailed below), our first public results, and our online communication platforms.

We invited a few of the applicants from our first call to share their experience and present to all what their research entails, as much to inspire as to show the breadth of fields of research that can be covered within PRISMAP. We concluded the public event with a round table on how to target communities or regions that are not yet involved with PRISMAP. If you feel your colleagues could be interested, feel free to share this newsletter and invite them to join the user forum!

A session titled Science, opportunities without borders was dedicated to the networking importance and impact of global events on the availability of radionuclides, complemented by a discussion on recent efforts on how to ensure the security of supply of radioisotopes.

The social programme was organized by prof. Maija Radzina (radiologist, Latvia) and her team Edgards Mamis and Laura Saule, and included a visit to the Riga Cyclotron/PET centre – NUCLEO (18MeV). Each evening event was a delightful experience with variety of local cuisine and sightseeing opportunities, guided by local organizers, such as an Old Riga walking tour, seaside walk with early summer swimming event, and sunset in the Baltic Sea.

PRISMAP's first call

Twelve user proposals from seven different countries, requesting eleven different radionuclides, were received for the first PRISMAP call, thereunder two proposals that requested access to PRISMAP medical facilities and ten that requested delivery of PRISMAP radionuclides to their user laboratory. The eleven-headed PRISMAP user selection panel, led by Cornelia Hoehr (TRIUMF, Canada), analysed the proposals in terms of scientific excellence, project implementation, expected outcome, and competences of the research team.

After a first preselection, nine proposals qualified for the next step. The panel then discussed details with the proposers per email and video conference. In particular, the selection of adequate radionuclides and frequency of delivery was discussed with the proposers to optimize the efficient use of PRISMAP radionuclides. While PRISMAP does propose a wide range of radionuclides, the available activities and frequency of production do vary considerably. E.g., for the quadruplet of terbium isotopes, the longer-lived 161Tb and 155Tb are available more frequently and at higher activities than the shorter-lived 152Tb and 149Tb. It is therefore strongly recommended to structure projects as to perform basic research on Tb radiolabelling or pharmacokinetic studies rather with the longer-lived isotopes, while keeping the shorter-lived ones for a later stage when the individual decay properties are really essential for a given application. If you have any question on how to shape your own project, don’t hesitate to contact our helpdesk!

Eventually all nine preselected proposals were approved, but sometimes only a first part up to a milestone where the feasibility of the full programme can be further assessed. The successful proposers (from BE, DE, ES, FR and IT) were informed of the outcome and user agreements with the supplying or hosting PRISMAP facilities were prepared. You can browse the public summary of the selected projects on our website.

Standards for clinical translation

PRISMAP, the European Medical Radionuclide Programme, brings together key nuclear research centres and leading clinical translational research facilities across Europe to provide a sustainable source of high purity grade new radionuclides for the starting research community. One of PRISMAP`s paramount aims is to standardise and harmonise research and development activities with novel radionuclides to cope with pharmaceutical regulatory requirements and provide guidance for clinical translation. The PRISMAP workshop: “Radionuclide Production to Nuclear Medicine Clinical Applications: Regulatory Standards and Harmonisation of Quality and Safety”, held in February 2022, brought together members of PRISMAP, professionals from industry, regulatory bodies, and overseas experts. It provided the basis for a dedicated document, which gives guidance for the early phase clinical research with novel radionuclides. It describes the current standards and provides a harmonised view of the European regulatory framework thereby complementing the existing regulatory framework without being legally binding.

The document includes terms and nomenclature for quality specifications of novel radionuclides within PRISMAP, followed by major aspects in production of radionuclides and the implementation of good manufacturing practices (GMP). The subsequent chapters cover quality specifications and quality control, with a designated chapter on metrology and medical physics aspects in clinical translation. The final chapter describes non-clinical safety and pharmacology aspects and provides an overview of the current regulatory guidance documents for preclinical testing.

This guidance document from the PRISMAP consortium serves as an essential and comprehensive source for radionuclide producers, radiopharmaceutical translational scientists, clinical and hospital based radiopharmaceutical development researchers through the complex jungle of pharmaceutical regulations and guidelines. It provides a harmonised view to standardise data required for clinical translation of novel radionuclides. The document can be found amongst our published reports.

MARIA - Can you imagine a nicer name for a nuclear research reactor?

It’s not difficult to guess that it was named after Maria Skłodowska-Curie. This nuclear reactor was designed and constructed entirely by Polish engineers. In 1974 MARIA reached its first criticality. Soon it took over the duties of radioisotope production from the first nuclear research reactor in Poland, EWA, which was launched in 1958 and served the irradiation of radioisotopes until 1995. MARIA was modernized significantly in the 1980s and is continuously upgraded, keeping up with the regulatory requirements. Today MARIA belongs to the busiest research reactors worldwide and the radioisotopes produced here serve millions of patients.

Did you know that in 2010 MARIA reactor started the irradiation of uranium for production of Molybdenum-99, the parent radionuclide of Technetium-99m? Since then MARIA plays an important role in the global supply chain of medical radioisotopes.

As TNA2 facility, MARIA will produce Tb-161 for PRISMAP users; other radioisotopes of potential interest are Lu-177, Ho-166, Sm-153, I-131, Sc-47 and more.

The high flux research reactor MARIA is a water and beryllium moderated reactor of a pool type with graphite reflector and pressurized channels containing concentric six-tube assemblies of fuel elements. It has been designed to provide high degree of flexibility. The fuel channels are situated in a matrix containing beryllium blocks and enclosed by lateral reflector made of graphite blocks in aluminum cans. MARIA is equipped with vertical channels for irradiation of target materials, a rabbit system for short irradiations and six horizontal neutron beam channels.

The neutron-thermal characteristics for the research channels:

  • fast neutron flux 1.0 – 1.5 × 1014 n cm-2 s-1
  • thermal neutron flux 1.0 × 1014 n cm-2 s-1
  • heat generation 3 – 4 W g-1

Neutron irradiation services provided at the MARIA research reactor are mainly related to the radioisotope production, other research activities such as testing of fuel and structural materials for nuclear power engineering, neutron radiography, neutron activation analysis, neutron transmutation doping are also carried out. MARIA is also involved in education and training of young researchers, so it is a pity that the access to these facilities had to be stopped due to covid pandemic.

More can be found at: The MARIA research reactor | National Centre for Nuclear Research (ncbj.gov.pl)

Defining the ISOL@MYRRHA facility

ISOL@MYRRHA is the new ISOL facility under implementation at the Belgian Nuclear Research Center SCK CEN in Mol, within phase 1 of the project MYRRHA1 accelerator driven system (ADS). In this first phase, the facility will receive a proton beam of 100 MeV with up to 500 μA on target (200 μA for actinide targets). ISOL@MYRRHA will feature a research programme including fundamental research in subatomic physics, research with radioactive probes in condensed and soft matter, and radioisotope production for nuclear medicine.

A first Users Workshop was organized in June 22-24, with the aim to inform the various user communities and technical collaborators about the status of the MYRRHA project and implementation of its ISOL facility, but also to discuss the main scientific challenges that this facility could tackle and to brainstorm on how the facility can best answer the needs of its future user community. The workshop took place online, on the ZOOM platform, in three consecutive afternoons from 13:00 until 17:00. To maximize the participation and stimulate discussions, the registration was kept open and the link to the various sessions was communicated to the participants on the first day of the workshop. The event was a success, with more than 180 registrations.

The presentations and discussions during the plenary and parallel sessions, provided valuable feedback on potential applications to be implemented, technical suggestions, points of view on user expectations as well as user needs. This workshop gathered information as well on the operation of various experiments by the users, which is both timely and relevant for the operational concept description, which is currently drafted at ISOL@MYRRHA. In preparation for day-1 experiments, it is now the time for future users to shape the facility to their needs and expectations on the basis of their future plans.

The three major user communities gathered in parallel topical panels at the end of the second day of the workshop. The conveners of these panels presented the conclusion of the brainstorming sessions in the last day of the workshop. Fundamental interactions, Nuclear Structure, Solid state & soft matter physics as well as Medical Radioisotopes user communities expressed interest in the new opportunities at ISOL@MYRRHA. Although availability of extended beam times is appreciated by all these communities, there are differences in the needs and expectations of the different communities. ISOL@MYRRHA aims to be complementary to current ISOL facilities, therefore its scientific programme but also operational approach will be defined to ensure this complementarity.

You can find different contributions on our event page

Density functional theory calculations for the enrichment of calcium and titanium

Within PRISMAP, we are investigating innovative isotope enrichment techniques that could lead to a new European supply chain. We investigate the technique of laser-enhanced isotopically selective condensation, that has been demonstrated by the team of Hubert van den Bergh from Ecole Polytechnique de Lausanne in the 1980s. It consists in the nucleation and clusterisation of argon atoms to a volatile molecule as the mixture of argon and titanium- or calcium-containing molecules is expanding through the nozzle of a gas cell. During the gas expansion, dramatic cooling of the gas mixture from room temperature (~300K) down to ~15K occurs, enabling this process. However, by applying infrared (IR) excitation at a frequency specific to an isotopomer (molecule containing a specific isotope), that molecule can be heated up hereby preventing the nucleation and thus the cluster formation. The clusters and the free molecules experience then different drag forces in the jet that allows their physical separation.

In our recent investigation at KU Leuven, we have explored many different titanium- or calcium-containing molecules with density functional theory (DFT) calculations. Those have allowed to identify different IR transitions in those molecules, as well as which ones are sensitive to the mass of the titanium or calcium isotopes. Simple calculations were first performed on TiFx [x=1,2,3,4] molecules to benchmark the approach and challenge the DFT calculations against experimental IR spectra. We then proceeded on exploring the binding with argon atoms as TiFxArn at room temperature and 15K, which demonstrated the lack of cluster formation at room temperature while more than 20 atoms can cluster around a cold molecule.

Finally, we performed our calculations on more complex molecules that might be more practical to synthesize and manipulate. From this investigation, it was concluded that the IR region where the sensitive transitions were identified do not vary substantially between molecules and are all located around 12µm to 13µm, corresponding to those transitions arising from a substantial motion of the titanium or calcium atom, while transitions in more accessible IR regions are originating from the motion of other parts of the molecule, which are thus not sensitive to the different isotopes of titanium or calcium.

Research into the efficient production of laser light in that region, as well as the experimental validation of those DFT spectra will now be investigated at CERN.

Radionuclide transport and logistics

In May 2022, PRISMAP work package 9 (WP9-transport and logistics) published a report, which describes and outlines the existing rules and means of transport (primarily air and road) and how these rules and their implementation induces important constraints on the optimal distribution of novel radionuclides within the network. Based on input from the project partners and the analysis of the most urgent transportation needs arising from the first round of user projects, the report describes important bottlenecks for the efficient and reliable transport of novel PRISMAP radionuclides.

The medical use of open radioactive sources (radioactive material) for diagnosis and therapy has traditionally relied heavily on transport of the radionuclide and/or the relevant radioactive compound from the point of production (typically reactors or accelerators) to the point of use (typically departments of nuclear medicine in major hospitals). Over decades, a specialized transportation system has been developed by the radionuclide and radiopharmaceutical industry, but it has proven difficult for the specialized producers of the novel PRISMAP radionuclides to utilize such distribution channels effectively.

In the report, the present and future needs (including the mass separation steps) and the perceived shortcomings of existing transport channels are highlighted. The aim of this report is to establish a commonly useful transportation system for air and road transport of radioactivity between partners together with the establishment of a common, easily applicable set of rules and guidelines allowing the easy and swift transport within Europe of non-standard, developmental, preclinical and early clinical radionuclides, thus resulting in a faster and more efficient shipping process across the consortium and to the end-users of the research community.

The report highlighted that all the day-1 radionuclide production facilities already have experience with the transport of radioactive materials (type A and type B), and they can by existing methods reach the PRISMAP medical facilities more or less rapidly. The problems at present mainly lie with the short-lived isotopes with half-lives under 1 day. Here, even conventional air transport has led to significant, perhaps even prohibitive decay losses, because of the combined delays in the connecting road transports and the now necessary check-in/check-out procedures. An additional problem arises from the vulnerability of such transports to delays far beyond the planned time. Reasons can be attributed to: road congestion, airport congestion, delays in dangerous goods clearing, denied or delayed boarding of the radioactive transports to passenger planes (where airlines will often prioritize differently from our PRISMAP needs), cancelled flights, and bad weather. It was deduced that some of the delays could in some part be prevented by better procedures and better contact and understanding between the shipping laboratories and the carriers.

Based on the first PRISMAP user project requests received, we have analysed the challenges and provided solutions to the delivery plan of the required radionuclides in a timely manner. It was established that most radionuclide shipments for the first call of project requests could be delivered from the producer to the end-user faster through road transport than air transport. Subsequent PRISMAP user project requests will also be critically reviewed in a similar manner and advice will be provided accordingly.

Typical Type A package for shipping novel PRISMAP radionuclides

Going forward, it is the intention during PRISMAP to develop a set of simple-to-use packaging and shipping instructions that can help prevent common errors in preparing packages and shipping documents. Additional gains may be made through a dialogue with selected airlines that can commit to priority handling of our PRISMAP shipments. Similarly, it will be attempted to make existing international courier services interested in serving our needs. However, this will require both high-level business decisions in the courier sectors as well as time for implementation. If such schemes are to work, many drivers, handlers and cargo agents will need to be additionally trained in radioactive transports. However, none of the above proposals can solve all the time and reliability issues. Under this background, the possible use of small fixed-wing aircrafts for point-to-point services between local airports/airfields shall be further investigated. This will require a further clarification of rules and procedures for such small aircraft transports. Some of these steps will require the assistance from both the national and international regulators.

PhD Label — Edgar Mamis: From Latvia to CERN

Since I always had a great interest in radioactivity, right after obtaining my bachelor’s degree in chemistry, I took the opportunity and began to work in the field of radiopharmaceutical manufacturing for PET/CT diagnostics. In principle, they are radioactive drugs that aid to diagnose cancer in early stages and as small as tip of a match. The radiopharmaceuticals or tracers consist of two parts – suitable radionuclide and biochemically active molecule with high affinity for specific tissue. And as the saying goes, one shoe does not fit every foot. Therefore, vast amount of different disease requires for vast number of appropriate tracers. Now, with this in mind we can really enjoy the process of discover, investigate, characterize, study and translate various combinations of these two elements to achieve more successful results.

Consequently, it led to my master’s thesis to be developed in the same topic of radiopharmaceuticals. Once we experienced the possibility to use therapeutic radionuclides - emitting electrons instead of positrons – to also treat patients, it did not take long to continue with my PhD studies. Now I investigate methods how to produce and purify novel same chemical element radioisotopes for radiopharmaceutical synthesis towards diagnostics and treatment of cancer. The ultimate theragnostic goal – treat what you see.

By starting my PhD in University of Latvia, I also gravitated more towards scientific research as young researcher at Institute of Chemical Physics, University of Latvia. Fortunately, I was offered the possibility to extend my toolbox for my research with CERN-MEDICIS. MEDICIS is a facility within CERN that can produce and purify novel and exotic medical radionuclides for research with 1.4 GeV protons, delivered by PSB at CERN or external collaborators coupled with mass-separator - a device that can physically separate same chemical element isotopes with respect to their atomic mass. It is worth mentioning that chemically it is impossible to achieve such purity level if one does not use expensive and highly enriched target materials in the first place. Therefore, it is obvious that mass-separation becomes a key part in the success of such “perfect match” theragnostic radiopharmaceutical development. Now with PRISMAP such “tools” become available for more and more research centres across Europe and they will definitely aid radionuclide and radiopharmaceutical translational research.

Ever since I have worked and did research in this field, people have asked me, if there really are no drugs that cure cancer? I would always reply that now there are, but huge effort and improvement still is needed. Therefore, I believe that with such projects as PRISMAP more and more breakthroughs are soon to be expected.

After obtaining his master’s degree in chemistry at the University of Latvia, Edgars continued to pursue his career as radiochemist by producing radiopharmaceuticals for PET/CT diagnostics and radionuclide therapy. Recently he started as a PhD student in chemistry/radiochemistry at the University of Latvia and CERN-MEDICIS. His research focusses on novel “matched pair” theragnostic radionuclide production, purification and radiopharmaceutical synthesis.


Edgar Mamis

After obtaining his master’s degree in chemistry at the University of Latvia, Edgars continued to pursue his career as radiochemist by producing radiopharmaceuticals for PET/CT diagnostics and radionuclide therapy. Recently he started as a PhD student in chemistry/radiochemistry at the University of Latvia and CERN-MEDICIS. His research focusses on novel “matched pair” theragnostic radionuclide production, purification and radiopharmaceutical synthesis.

Newsletter 1 — Editorial by Thierry Stora, PRISMAP Coordinator

Our first Newsletter is starting with the new year of the Tiger, and it is certainly no surprise to most of you as it also coincides with the anniversary for the discovery of isomers in radionuclides, without which the most frequent SPECT scans with 99m-Technetium performed across the globe would not be possible.

With the starting PRISMAP – The European medical radionuclide programme, we indeed hope new isomers will find their way into clinical research and practices. This is precisely the idea behind our consortium and this first Newsletter. We are aiming at reaching out to researchers spread across life sciences and their related technologies at large, in biomedical research and in nuclear medicine. European researchers – maybe you? – will be able to receive non-conventional radionuclides offered through our web portal, and potentially also benefit from your project directly developed in one of our associated biomedical platforms for preclinical and clinical studies.

The portfolio of radionuclides with special research grades offered by the federation of our large-scale facilities, is made available thanks to efforts of our colleagues in charge of developing the tools and the coordination of the consortium, Iris, Thomas, Clemens, Renata and many others. A particular highlight was the recent meeting of the consortium after the severe restrictions imposed to travels, that partially took place at CERN and in Geneva nearby in the now popular hybrid format. This allowed us to physically meet for the first time, exchange on the first milestones that were met, launch the first call for projects, receive feedback from our external advisors, and already project ourselves in the future.

You will find in this first Newsletter insights on institutes in charge of radionuclides delivery and of biomedical research, together with advanced data and developments of techniques required by PRISMAP services. And if you are undertaking graduate studies in a related field of nuclear and radiopharmaceutical science, please consider getting a dedicated PRISMAP label and get in touch with our training office as soon as possible!

Dear reader, enjoy this first PRISMAP Newsletter, don’t hesitate to distribute it further and provide us with feedback; and let this Year of the Tiger be a successful year for yourself and all of our colleagues!

Transport

Transport and logistics is collecting knowledge about the many small and big obstacles to rapid transfer of radioactivity between the PRISMAP partners. At present the focus is on the transport to ARRONAX in France of Cu-64 samples for the intercomparison tests. Negotiations with airlines, transport companies, handling agents and authorities are under way to clarify the possibilities for short-term exceptions and also more general solutions in the future. When off-line mass separation is to be used regularly there is a double pressure on the rapid transfer, as activity first needs to go from reactor/cyclotron to the mass separator, and then from the separator to the end user.

An interim report describing the present transport situation will be delivered within the next few months.

PhD Label — From producing radioisotopes to dosimetry

During my studies in nuclear physics, I learned all about the atomic nucleus. I was stumped when I learned how the nuclear structure could be described completely by quantum mechanical formalisms and how this naturally leads to radioactive decay as it was observed by M. Curie and her husband. Even more fascinating is the fact that this physical phenomenon eventually contributes to the treatment of cancer patients. However, the transition from a radionuclide into a medicinal product is not evident and requires large efforts and excellent collaborations between various disciplines. Until now, I had the opportunity to dig into two different aspects of radionuclide therapy. After studying the production of medical radioisotopes, I am currently investigating the tumour dosimetry of radionuclide therapy.

For my master thesis, I investigated the potential of a new detector at the MEDICIS laboratory at CERN. This facility was founded especially to promote research in nuclear medicine and to introduce novel radiopharmaceuticals. It makes use of a target that is irradiated by the PSB which is one of the preaccelerators of the large hadron collider, the largest man-made machine on earth. At the MEDICIS facility itself, the aim is to obtain a pure radionuclide sample by extracting it from a target which contains a whole bunch of different radionuclides after irradiation. This can be done by a combination of high temperatures, high electric fields, large electromagnets and high power lasers such that one can play with various physical and chemical properties of the nuclides. The fact that the production of radionuclides requires such large and highly technical infrastructures is not surprising since one needs to overcome the enormous forces that keep the atomic nucleus together in order to destabilise the nuclear conformation.

Once the radionuclides are created, it comes down to optimising the usage of the emitted radiation such that the cancerous cells receive a maximal absorbed dose while limiting the radiation burden to the healthy tissue. With this goal in mind, a team of researchers with expertise in chemistry, pharmacy, biology, and dosimetry develop novel radiopharmaceuticals and try to understand the underlying mechanisms to optimise the treatments.

Recently I got the opportunity to also discover this side of the story as a PhD candidate in the dosimetry group at the Belgian nuclear research centre SCK CEN. Herein I try to develop a model that will be able to predict the treatment outcome on a preclinical level. Such a model will be valuable in the development and evaluation of novel radiopharmaceuticals.

I am blessed with the opportunity to contribute to this interesting field of research. It is inspiring to see how each discipline faces its specific problems and at the same time shares common difficulties of working with radionuclides. Furthermore, the short half-life of the relevant isotopes asks for an excellent collaboration, for which PRISMAP can act as a catalyst. In the end, the combined expertise will aid to reach the common final goal: providing better treatments for the patients.


Kaat Spoormans

After finishing her master in nuclear physics at the KU Leuven, Kaat recently started as a PhD student in the dosimetry group at the Belgian nuclear research centre SCK CEN in collaboration with the group of nuclear medicine and molecular imaging at KU Leuven. Her research focusses on TCP modeling in preclinical radionuclide therapy.

Radiolanthanides

The use of radionuclides in nuclear medicine for diagnostics and therapy has significantly increased over the last decay. As a result, there is an urgent need to explore the usage of new radionuclides and relative innovative production methods. Depending on both half-life and decay emission, these radionuclides can be used for imaging, via positron emission tomography (PET) or single-photon emission computed tomography (SPECT), and for therapy via α, β−, or conversion and /or Auger electron emission. Within each of these categories, there are several radiolanthanides with a variety of tissue ranges and half-lives offering attractive decay properties.

Production of sufficient amounts of high quality radiolanthanides requires systematic research in targetry, irradiation, radiochemistry and quality control. In some cases, it is difficult to produce carrier-free and/or radionuclidically pure products with conventional reactor-based or accelerator-driven production routes. Thus, the use of mass separators to produce carrier-free radionuclides for nuclear medicine is becoming an attractive method. In the frame of PRISMAP WP12, together with eleven universities and research laboratories, scientists are going to investigate the potential of novel radiolanthanides for nuclear medicine applications.

The main tasks of this WP are the development of specific radiochemical separation methods and preclinical research studies for novel radiolanthanides (149Tb, 152Tb, 155Tb, 161Tb, 175Yb, 153Sm, 167Tm, 165Er, 169Er, and 135La). In particular, an assessment of the quality control and radiolabelling processes of these radiolanthanides will be established. This information will be of great interest for developing clinical methods using different Tb radionuclides for theragnostic applications. The produced data will also implement the use of conversion/Auger-electron-emitting radionuclides towards the treatment of disseminated tumor cells and small metastases. Enhanced knowledge of these novel radiolanthanides and exploration of their therapeutic effects will be greatly appreciated by the scientific community of nuclear medicine and will pave the way towards more efficient cancer treatments.

Bringing metrology to PRISMAP

As PRISMAP looks to make a new generation of radionuclides easily accessible to researchers, it is vital that any pre-clinical and clinical research is underpinned by accurate and reproducible measurements of activity and dosimetry. In the clinical setting these measurements are typically performed using a radionuclide calibrator before administration to a patient, with traceability to a national metrology institute such as the National Physical Laboratory (UK) or the Institute of Radiation Physics (Switzerland). This traceability comes through the primary standardisation of activity and underpins all clinical use of any radiopharmaceutical. To this end, the translational data generation work package (WP11) will seek to provide this traceability for the novel radionuclides being generated by the PRISMAP consortium and disseminate these standards to the wider community. Alongside this development, accurate nuclear decay data will be determined to provide confidence in this fundamental data. A challenge of molecular radiotherapy is the understanding of the dose delivered at a cellular level and the biological effect of the emissions of a radionuclide to tumour cells. To improve our understanding, Riga Technical University (Lativia) will investigate the doses absorbed from the emissions from the radioactive decay of radionuclides using nano-dosimeters. The University of Oslo will look at developing a traceable link of the activity standards of the PRISMAP radionuclides to their relative biological effectiveness through the dose response. 

Radioisotope production research

Production of medical radionuclides has always benefited from high level technologies developed in the context of nuclear and accelerator physics research. In particular, some important ISOL technologies adopted for targets, ion sources, and isotope separation demonstrated an enormous potential for medical radionuclides. WP10-JRA2 is organised in three different tasks: target design and characterisation (task 1), ion sources (task 2), and isotope separation techniques (task 3). They are all oriented to improve the scientific instruments and the technologies required for the production of medical radionuclides. This approach will benefit from the collaboration among prestigious international research institutes in the framework of PRISMAP.

Task 1 and task 2 will mainly focus on the optimization of targets and ion sources, respectively, with the aim to increase as much as possible the production rate of specific medical radionuclides. In particular, new high performance materials will be studied and characterized, especially at high temperature ranges. New targets and ion sources will be designed making use of complex multiphysics simulation tools.

The object of task 3 is the strong enrichment of Ca and Ti isotopes from their natural abundance to an abundance useful for radionuclide production in reactors or cyclotrons. Indeed, production of theranostic scandium isotopes (43Sc, 44Sc, 44mSc and 47Sc) relies on the availability of highly enriched Ca or Ti isotopes respectively. With this in mind, task 3 will investigate the enrichment via laser-enhanced isotopically selective condensation, an innovative technique pioneered at EPFL and successfully used in the past for the enrichment of different isotopes.

As a concluding remark, it is clear that WP10-JRA2 will lay the foundations for a structured community of scientists and research engineers deeply focused on the technologies for the production of pure medical radionuclides.

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