Novel radionuclides for use in Nuclear Medicine in Europe: where do we stand and where do we go?

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.

Radionuclides that are used in radiopharmaceuticals have different applications: for diagnostic, therapeutic and disease monitoring purposes in nuclear medicine practice, as well as research tools (European Medicines Agency 2023).Out of the more than 3000 different radioisotopes that scientists have synthesized in the laboratory, only a handful are regularly used for medical procedures, mostly for imaging, though the interest in targeted radionuclide therapy has been growing in the last few years.One of the main limits to the development of novel radio-medicinal products is the access to radionuclides during the development and early biomedical research phases.In order to support the ongoing research across Europe to facilitate access to novel radionuclides, the PRIS-MAP consortium (European medical radionuclides programme) was established to offer the broadest catalog of non-conventional radionuclides for medical and translational research.One of the aims of the European medical radionuclides program is to enable this development phase by providing access to novel radioisotopes of high purity grade for medical research (PRISMAP 2021a, b).
The most frequently used PET radionuclides are the pure positron-emitters 18 F and 11 C, which can be produced at medical cyclotrons (Gabriela and Jacek 2012).Also, 68 Ga and 111 In are used widely for positron emission tomography (PET) and single photon emission computed tomography (SPECT), respectively. 177Lu and 225 Ac are used for β −and α-radionuclide therapy, respectively (Müller et al. 2018).
PRISMAP "Production of high purity isotopes by mass separation" is the European medical isotope programme that federates a consortium of key European facilities such as intense neutron sources, isotope mass separation facilities and high-power accelerators and cyclotrons, with leading biomedical research institutes and hospitals active in the translation of the emerging radionuclides into medical diagnosis and treatment.PRISMAP creates a single-entry point for a fragmented user community distributed amongst universities, research centers, industry and hospitals, in a similar way as how the National Isotope Development Centre NIDC, supported by the Department of Energy (DOE), has provided radionuclide sources for users in the United States of America (USA).
PRISMAP brings together a consortium of 23 beneficiaries from 13 countries, one European research laboratory and an international organisation.It further receives support from leading associations and institutions in the field such as the European Association of Nuclear Medicine (EANM) and the International Atomic Energy Agency (IAEA) (PRISMAP 2021a, b).It supplies radionuclides across Europe and beyond to any user on an excellence basis, and offers support through a network of biomedical research facilities that are fully equipped and licensed to use the array of radionuclides available in the PRISMAP portfolio.
In order to find out the situation with novel radionuclides in Europe, the consortium questionnaire was created.The construction of a questionnaire was based on literature review, an expert review by a certain panel and finally a validating before the survey starts in consortium members meeting.
A questionnaire was disseminated through the PRISMAP consortium and user community, professional associations of radiology and nuclear medicine, and preclinical/ clinical end users in Europe, collecting a total of 40 responses.The survey was based online and the first results were summarized after a 9 month long period.The total number of survey candidates is undetectable, because it was not sent out to specific institutions, but disseminated through communities and associations.Moreover, the link to this questionnaire is still available on the PRISMAP public homepage to encourage new clinical users to become visible.
Presented responses presented the current status and needs of clinical end-users in nuclear medicine.This questionnaire covered novel radioisotopes, clinical exam type and advanced technology current usage and near future plans in next 2-5 years.The survey also included questions about research and development activities and education activities that respondents' institutions provide.Also, a literature review of currently used novel radionuclides in clinical and preclinical phases was carried out.

Main text
Examples of novel radionuclides usage in medicine-the review of current state in preclinical and clinical phase Scandium presents three radioisotopes for theranostic application. 43Sc (T 1/2 = 3.89 h, β + = 88.1%,< E β+ > = 476 keV) and 44 Sc (T 1/2 = 4.04 h, β + = 94.3%, < E β+ > = 632 ke V) can both be used for PET, while 47 Sc (T 1/2 = 3.35 d, β − = 100%, < E β-> = 162 keV) is the therapeutic match-also suitable for SPECT (E γ = 159 keV (68.3%)). 43Sc and 44 Sc can be radiolabelled with macrocyclic chelators, e.g.DOTA or other chelators such as NODAGA, AAZTA, pypa, mpatcn, etc., but 47 Sc-with macrocyclic chelators, in particular DOTA.Currently, 44 Sc is most advanced in terms of production, as well as with pre-clinical investigations, and has already been employed in proof-of-concept studies in patients.Even though the production of 43 Sc may be more challenging, it would be advantageous due to the absence of high-energetic γ-ray emission (E γ = 1157 keV (99.9%) for 44 Sc).The development of 47 Sc is still in its infancy, however, its therapeutic potential has been demonstrated preclinically (Müller et al. 2018;PRISMAP 2021a, b).The results of study showed that accurate quantitative scandium-43/44 PET/CT is achievable in commercial devices (Lima et al. 1826).Scandium-44 was proposed as an alternative radionuclide to 68 Ga for PET imaging allowing the user of 44 Sc-PSMA-617 as a diagnostic match to 177 Lu-PSMA-617 (Umbricht et al. 2017).Scandium-47 is a β -emitter suitable for therapeutic purposes, which also produces γ-ray emission useful for SPECT imaging (Müller et al. 2018).
Copper-64 (T 1/2 = 12.7 h, β + = 17.6%, < E β+ > = 278 keV, β − = 38.5%,< E β-> = 191 keV) labeled compounds ranging from small molecules (peptides, etc.) to antibodies are regularly used in clinics and clinical trials respectively.A recent study confirmed that radiolabeled 64 Cu-PSMA is a promising agent to target and visualize PSMA receptor positive tumor lesions with high serum stability.This was shown in preclinical evaluation by small-animal PET studies, organ distribution and a patient application (Carlos Dos Santos et al. 2020).
Copper-67 (T 1/2 = 61.83h, β − = 100%, < E β-> = 145 keV) is an emerging β − emitter of interest for therapy with γ-emission usable for SPECT/CT (E γ = 91.3 and 93.3 keV (21.1%) and E γ = 185 keV (44.2%)) that forms a theranostic pair together with 64 Cu.Promising results in SPECT/CT imaging have been already published showing the benefit of using medium energy collimators to obtain reconstructed images of a similar quality to the ones that can be obtained using 177 Lu (Merrick et al. 2021). 64Cu and 67 Cu can be radiolabelled with macrocyclic chelators.DOTA is being used, but other, specific copper chelators such as MeCOSar may provide improved stability (PRIS-MAP 2021a, b).
Silver-111 (T 1/2 = 7.45 d, β − = 100%, < E β-> = 350 keV) labeled hydroxyapatite particles have been studied preclinically for radiosynovectomy.Radiosynovectomy consists of intra-articular injection of a β − -emitting radionuclide in colloidal or particulate form, which comes into contact with synovium.The phagocytic cells absorb some of the injected dose, which is transmitted to the synovium.If the amount of radioactivity injected is large enough the tissue will be destroyed.A study has shown that regenerated tissue will be asymptomatic for 2-5 years (Chattopadhyay et al. 2008).
Samarium-153 (T 1/2 = 46.28h, β − = 100%, < E β-> = 225 keV) is suited as a source for Mößbauer spectroscopy, a highly sensitive technique to characterize the chemical state and chemical environment of samarium bound in solids or frozen ex vivo samples (Friedman et al. 1976).It can be radiolabelled with macrocyclic chelators, in particular DOTA (PRISMAP 2021a, b). 153Sm with limited specific activity is mainly used for bone pain palliation, commercially available under the brand name Quadramet ® .High specific activity 153 Sm has been recently produced using the mass separation of an activated sample, opening the door to a translation of HSA 153 Sm for therapeutic applications (Voorde et al. 2021).
Actinium-225 (T 1/2 = 9.92 d, α cumulative = 400%, < E α cumulative > = 6.88 MeV) is one of the most promising new radioisotopes in the fight against cancer. 225Ac has been used in preclinical studies for over 25 years (Beyer et al. 1997). 225Ac is suitable for many macrocyclic chelators used with other trivalent metallic ions, in particular DOTA (PRISMAP 2021a, b).Reports on the remarkable therapeutic efficacy of 225 Ac-PSMA617 for therapy of prostate cancer have stimulated significant global interest in applying 225 Ac as therapeutic nuclide in targeted alpha therapy of cancer.Moreover, further promising applications of the alpha emitters 225 Ac include the therapy of brain tumors, bladder cancer, neuroendocrine tumors, and leukemia (Morgenstern et al. 2020).The implementation of 225 Ac-PSMA-617 as a therapy tool for metastatic castration-resistant prostate cancer (mCRPC) lead to a major advancement in targeted alpha therapy (Fendler and Cutler 2017).It was reported that two patients with late-stage mCRPC came to complete remissions after treatment with 225 Ac-PSMA-617 (Kratochwil et al. 2016).One more example was reported of the therapeutic efficacy of a 225 Ac-PSMA-617 patient with mCRPC that was progressive under conventional therapy, and was treated with two cycles of 225 Ac-PSMA-617 with a cumulative activity of 14 MBq.Restaging with 68 Ga-PSMA PET/CT after 5 months showed a remarkable molecular imaging response.This patient also demonstrated a biochemical response with a decrease in PSA level from 1,301 to < 0.05 ng/ mL (Morgenstern et al. 2018).

Respondent profile
During a PRISMAP questionnaire, a scene of nuclear medicine in Europe from clinical/ preclinical end users' point of view was identified.A total of 40 preclinical/clinical users institutions took part in the survey (55% clinical hospitals, 25% research institutionhospital collaborations, 10% preclinical research institutions, 2.5% private clinics and 7.5%-other types of institutions: 2 clinical research organisations, 1 private clinic and 1 manufacturer and ambulatory clinical nuclear medicine center).
The respondents represented 22 countries among which 9 were coming from the Netherlands, 3 from Italy, 3 from the United Kingdom, 2 from France, 2 from Romania, 2 from Greece, 2 from Estonia, 2 from Slovakia, 2 from Switzerland, 1 each from Austria, Latvia, Belgium, Denmark, Poland, Turkey, Spain, Cyprus, Slovenia, Finland, Serbia, Czechia and Lithuania (see Fig. 1).
47% of the respondents conducted both preclinical and clinical studies, 37% respondents only clinical studies, 5% respondents only preclinical studies and 10% respondents other types of studies, such as medical physics, drug biodistribution, drug selection, fundamental (analytical methods), medical research.It is seen that the majority of respondents work in the clinical phase, so the results of the survey are representative of the part of the end users that use it in daily clinical practice (see Fig. 2).
Clinical imaging is common for nearly all respondents: For routine clinical practice 90% respondents have PET, PET/CT or PET/MR, 82,5% respondents SPECT, SPECT/ CT or SPECT/MR, 70% respondents planar scintigraphy, 40% respondents animal PET/ CT or PET/MR, 32% respondents experimental long term animal facilities for radionuclide therapy studies and 30% respondents animal SPECT or SPECT/CT (see Fig. 3).
Furthermore, many respondents are also involved in developments of those imaging protocols.The emerging technologies that the respondent's institutions have are the following: SPECT/CT software advances (quantification, 3D dynamics etc.) (52,5% respondents), PET new generation cameras with extended axial field of view, optimised image and dose reduction (50% respondents).Respondents also mentioned the use of Regarding emerging imaging technologies that respondents would like to work with in their facilities in 2-5 years, similar answers were obtained.The artificial intelligence in nuclear medicine concerned 57,5% respondents.PET new generation camera with extended axial field of view, optimised image and dose reduction was ticked by 50% respondents and SPECT/CT software advances (quantification, 3D dynamics etc.) for 32,5% of the respondents.CZT camera represented 20% respondents, dedicated cardiac SPECT camera 7,5% respondents and PEM-positron emission mammography and dedicated cardiac PET camera, 5% respondents each (see Fig. 5).

Use of novel radionuclides
Part of the previous section summarized activities with radionuclides that are not only used in preclinical phase or experimental laboratories, but also used by end users in their daily clinical practice.The following "novel" non-conventional radionuclides are used by clinical users in Europe: 177 Lu (80% respondents), 68 Ga (72,5% respondents), 111 In (57,5% respondents), 90 Y (52,5% respondents), other alpha emitters (42,5% respondents), 225 Ac (20% respondents), 64 Cu (15% respondents) and Terbium isotopes (10% respondents).. Other radionuclides mentioned were 223 Ra, 89 Zr, 166 Ho, 131 I, 123 I, 212 Pb, 89 Sr, and 153 Sm.Some of the radionuclides of terbium and scandium that are very promising, are not yet utilized in the clinical environment because of their poor availability at the time of the questionnaire.Novel radionuclides that respondents would be interested to use in the next 2-5 years were 225 Ac (67,5% respondents), 64 Cu (50% respondents), 68 Ga (47,5% respondents), 177 Lu (42,5% respondents), and other alpha emitters (40% respondents) and Terbium isotopes (37,5% respondents).Figure 6 shows both -radionuclides that end users use and radionuclides that end users would be interested in.It is seen that the demand for 225 Ac and the terbium quadruplet (149,152,155,161) coming from clinical end users will increase significantly in the following years.The foreseen application possibilities and an increasing demand for these radionuclides also point out the low availability of them at the moment, either by production capacity or required amounts or purity grade.
We observed that none (except for iodine radiopharmaceuticals) of the current responder institutions yet are interested in possibilities of "matched pair" from terbium and scandium radionuclides in the near future.This probably reflects the still insufficient pre-clinical data and/or availability of such radionuclides.

Improvements for daily practice
The following improvements were mentioned by preclinical/clinical users as their need for daily practice: unified licensing and registration of available radionuclides and kits in Europe (80% respondents), information about transport and logistics network in Europe (55% respondents), database of available radionuclides and the geographic location of the supply site (50% respondents), and some specified equipment/ technologies (e.g., collimators etc.) (45% respondents).On-site training with the visit of international experts is also a wish (40% respondents) as is outsourced crucial training for technical personnel (32,5% respondents) and medical doctors (30% respondents).
Some of the respondents' countries send patients to other countries for specified nuclear medicine examinations and/or treatment procedures.The reason of this outsourcing is due to unavailability of the specific radiopharmaceuticals (42,5% respondents), a lack of reimbursement by the national healthcare system (22,5% respondents), and unavailable radionuclide for radiopharmaceutical production (17,5% respondents).

Research and development activities
Out of all respondents from preclinical/clinical institutions, 87,5% mentioned that their research and development activities would benefit from collaboration/cooperation in obtaining emerging radionuclides with centralized and harmonized procedures and legislation, offered by efforts of the PRISMAP consortium.
One of the main interest of end users were novel radionuclides-some respondents indicated specific ones such as 43 Sc/ 44 Sc and 64 Cu/ 61 Cu and some indicated novel radionuclides overall-clinical translation of novel theranostic tracers, higher availability of new radiopharmaceuticals, access to new radionuclides for novel radiopharmaceuticals, enhancing clarity and regulatory procedures to enhance research with radiopharmaceuticals, improving the delivered radionuclide data and regulation, along with biomedical research capacity and speed up implementation of new radionuclides and/or broader availability of currently used radionuclides.Production of novel theranostics pairs and access to rare and exotic radionuclides and need for quick registration of radiopharmaceuticals were also mentioned.
Respondents indicated the interest in collaborating with PRISMAP consortium members with regards to the sharing of new research protocols across countries, speeding up the implementation of new radiotracers in clinical practice, extending of portfolio in performing preclinical studies.Also interest in multicentric clinical trials, international studies, and research and clinical use interest were present.
Finally, technical interests from end users were indicated, including the standardization and harmonization of the medical physics calibrations, interests to establish labeling of different probes (mostly peptide based) with different emerging radionuclides in order to promote translation to the clinic.The target audience for training provided at respondent institutions are students (31 respondents), early-stage researchers (28 respondents), technologists (27 respondents), experienced researchers (17 respondents), nurses (14 respondents), and industry professionals (5 respondents).The main limitations in the training process were identified as a lack of integration of radiopharmaceutical research in faculty courses and student curriculum, no dedicated program for nuclear medicine physicians, technologists and radiochemists in university, limited training capacity to 1-2 weeks, due to daily workflow, and limited time resource overall.
Respondents also mention a lack of personnel since there is a lack of trained preclinical scientists with a global view from radiochemistry to pharmacology and limited number of trainers overall.Some respondents indicated problems with training process regulation: training depends on the national regulatory organizations or there is a need to work within national health service training schemes.
It has also been indicated that there is insufficient access to radioisotopes, also a lack of equipment such as small animal imaging facilities and emerging new technologies.There is also a need for a good overview/database of training possibilities.Some respondents indicated that in their countries they don`t have any professional training available for radiopharmacy or radiochemistry, so their radiopharmacists are trained abroad.
These radionuclides represent only a part of overall potential as many novel radionuclides have entered the preclinical phase studies.Due to that, the European medical radionuclides programme PRISMAP was established to offer the broadest catalog of non-conventional radionuclides for medical and translational research (PRISMAP 2021a, b).
Thanks to a questionnaire distributed by the PRISMAP consortium, the current status and needs of clinical end-users in nuclear medicine were identified.It was found out that novel radionuclides in which respondents would be interested in the near future were 225 Ac, 64 Cu, 68 Ga, 177 Lu, other alpha emitters and Terbium isotopes.A lack of training possibilities and trained personnel have been identified as well as access to radionuclide to gain experience.
Also, the study has some limitations.First of all, it needs to be addressed that the study was conducted in a relatively small end users' cohort.Not all European countries were covered-the majority of responses come from Western Europe, most notably the Benelux, France and Italy.More emphasis will be needed for reaching out to responders from South-East Europe regions.Secondly, the PRISMAP programme continues and these results are preliminary, limited outcomes of this study so far.Moreover, study should be extended outside the PRISMAP consortium with the possibility to obtain data from other preclinical/clinical end users in Europe.

Conclusions
The current perspective shows that nuclear medicine specialists/clinical end users from broad parts of Europe are interested not only in new radionuclides for diagnostics, but also in therapy and technology advancements that confirm their interest in development.This study was preliminary and should be extended outside the PRISMAP consortium.

Fig. 1
Fig. 1 Map of respondents represented countries and cities

Fig. 4
Fig. 4 Emerging technologies that respondents' institutions use in daily work

Fig. 6
Fig. 6Novel radionuclides used by end users in their (green) and radionuclides that respondents would be interested to use in the next 2-5 years (blue)

Fig. 7
Fig. 7 Theranostic pairs used by end users now (green) and theranostic pairs that respondents would be interested to use in the next 2-5 years (blue)

Education 77 ,
5% of all end user institutions are involved in the training of industry experts, technicians, students, and researchers at various expertise levels.The most popular training fields are clinical trials/studies (27 respondents), radionuclide/radiopharmaceutical QC and analysis (23 respondents), radiopharmaceutical synthesis and development (20 respondents), pre-clinical studies (18 respondents), radiochemistry (16 respondents).See Fig. 8 for provided training fields from end users institutions.The most often mentioned answers about training level were workshops and seminars (26 responses), PhD programmes (21 respondents), and scientific visits (21 respondents).See Fig. 9 for other types of provided training.

Fig. 8
Fig. 8 Training and knowledge transfer fields provided by respondent's institutions

Fig. 9
Fig. 9 Types of provided training in nuclear physics, radiochemistry and radiopharmacy