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PET SCANdium-43: a novel radionuclide for Positron Emission Tomography

English title PET SCANdium-43: a novel radionuclide for Positron Emission Tomography
Applicant Türler Andreas
Number 156852
Funding scheme Interdisciplinary projects
Research institution Departement für Chemie und Biochemie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Physical Chemistry
Start/End 01.01.2015 - 31.12.2018
Approved amount 1'042'850.00
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All Disciplines (4)

Discipline
Physical Chemistry
Particle Physics
Pharmacology, Pharmacy
Nuclear Physics

Keywords (4)

Positron emission tomography; Metalloradiopharmaceuticals; Medical cyclotron; Scandium radionuclides

Lay Summary (German)

Lead
Mit über 20'000 Untersuchungen pro Jahr ist die Positronenemissionstomographie (PET) eine der wichtigsten Methoden um biomolekulare Vorgänge im Körper eines Patienten sichtbar zu machen. Als wichtigste Verbindung konnte sich dabei mit dem Radionuklid F-18 markierte Glukose (FDG) etablieren. F-18 wird mittels eines Zyklotrons hergestellt. Eine weiteres Radionuklid, Ga-68 aus einem Ge-68-Radionuklidgenerator, findet langsam Eingang in Routine PET Untersuchungen, allerdings erfordert seine kurze Halbwertszeit von nur 68 min eine radiopharmazeutische Synthese nahe am Ort der Anwendung. Ein von seinen chemischen als auch seinen physikalischen Eigenschaften weitaus geeigneteres Radionuklid ist Sc-43 mit einer Halbwertszeit von 3.89 h. Seine Herstellung am Zyklotron eröffnet eine breite Palette an neuen diagnostischen Radiopharmaka, die zentral hergestellt, über einen relativ grossen Radius angeboten werden können.
Lay summary
In der Nuklearmedizin wird derzeit der "theragnostische" Ansatz zur Behandlung von metastasierenden Tumorerkrankungen verfolgt. Ein Wirkstoff wird zuerst mit einem diagnostischen Radionuklid zur Bildgebung markiert. Bei einem positiven Befund kann der Patient anschliessend mit demselben Wirkstoff, diesmal markiert mit einem therapeutischen Radionuklid, behandelt werden. Die Erfolgskontrolle erfolgt wiederum mit dem diagnostischen Pendant. Idealerweise erlaubt die Diagnose eine Abschätzung der optimalen Therapiedosis um bei minimierten Nebenwirkungen den bestmöglichen Behandlungserfolg zu erzielen. Zur Behandlung von neuroendokrinen Tumoren wurden in letzter Zeit Somatostatinanaloga erfolgreich eingesetzt die entweder mit dem Radionuklid Ga-68 zur Diagnose mittels Positronenemissonstomographie oder zur Therapie mit Y-90- oder Lu-177 markiert wurden. Die technische Umsetzung ist jedoch sehr anspruchsvoll, da die entsprechenden Konjugate meist vor Ort unter GMP (good manufacturing practice) Bedingungen hergestellt werden müssen. Insbesondere die kurze Halbwertszeit von Ga-68 und die limitierte verfügbare Aktivität des Ge-68-Generatorsystems beschränken eine breite Verwendung Ga-68 basierter Radiopharmaka. Ein weitaus attraktiveres Radionuklid würde hier Sc-43 darstellen, das mit seiner idealen Halbwertszeit von 3.89 h und den dem Y oder Lu sehr ähnlichen chemischen Eigenschaften, als auch mit seiner tieferen Positronenenergie dem Ga-68 eindeutig überlegen ist. Die Produktion von Sc-43 an einem medizinischen Zyklotron mittels Protonen- oder Deuteronenstrahl erscheint möglich, ist aber vor allem hinsichtlich der radionuklidischen Reinheit nie untersucht worden. Im vorliegenden Projekt, soll eine skalierbare Produktion von Sc-43 am Berner 18-MeV Zyklotron entwickelt und die Anwendbarkeit dieses neuen Tracers in-vitro und in-vivo in Kooperation mit dem Paul Scherrer Institut untersucht werden und die Grundlagen für eine spätere Anwendung am Patienten geschaffen werden.
Direct link to Lay Summary Last update: 26.11.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Measurement of the 43Sc production cross-section with a deuteron beam
Carzaniga Tommaso Stefano, van der Meulen Nicholas P., Hasler Roger, Kottler Christian, Peier Peter, Türler Andreas, Vermeulen Etienne, Vockenhuber Christof, Braccini Saverio (2019), Measurement of the 43Sc production cross-section with a deuteron beam, in Applied Radiation and Isotopes, 145, 205-208.
A system for online beam emittance measurements and proton beam characterization
Nesteruk K.P., Auger M., Braccini S., Carzaniga T.S., Ereditato A., Scampoli P. (2018), A system for online beam emittance measurements and proton beam characterization, in Journal of Instrumentation, 13(01), P01011-P01011.
44Sc-PSMA-617 for radiotheragnostics in tandem with 177Lu-PSMA-617—preclinical investigations in comparison with 68Ga-PSMA-11 and 68Ga-PSMA-617
Umbricht Christoph A., Benešová Martina, Schmid Raffaella M., Türler Andreas, Schibli Roger, van der Meulen Nicholas P., Müller Cristina (2017), 44Sc-PSMA-617 for radiotheragnostics in tandem with 177Lu-PSMA-617—preclinical investigations in comparison with 68Ga-PSMA-11 and 68Ga-PSMA-617, in EJNMMI Research, 7(1), 9-9.
47Sc as useful β–-emitter for the radiotheragnostic paradigm: a comparative study of feasible production routes
Domnanich Katharina A., Müller Cristina, Benešová Martina, Dressler Rugard, Haller Stephanie, Köster Ulli, Ponsard Bernard, Schibli Roger, Türler Andreas, van der Meulen Nicholas P. (2017), 47Sc as useful β–-emitter for the radiotheragnostic paradigm: a comparative study of feasible production routes, in EJNMMI Radiopharmacy and Chemistry, 2(1), 5-5.
Measurement of 43 Sc and 44 Sc production cross-section with an 18 MeV medical PET cyclotron
Carzaniga Tommaso Stefano, Auger Martin, Braccini Saverio, Bunka Maruta, Ereditato Antonio, Nesteruk Konrad Pawel, Scampoli Paola, Türler Andreas, van der Meulen Nicholas (2017), Measurement of 43 Sc and 44 Sc production cross-section with an 18 MeV medical PET cyclotron, in Applied Radiation and Isotopes, 129, 96-102.
First-in-Human PET/CT Imaging of Metastatic Neuroendocrine Neoplasms with Cyclotron-Produced 44 Sc-DOTATOC: A Proof-of-Concept Study
Singh Aviral, van der Meulen Nicholas P., Müller Cristina, Klette Ingo, Kulkarni Harshad R., Türler Andreas, Schibli Roger, Baum Richard P. (2017), First-in-Human PET/CT Imaging of Metastatic Neuroendocrine Neoplasms with Cyclotron-Produced 44 Sc-DOTATOC: A Proof-of-Concept Study, in Cancer Biotherapy and Radiopharmaceuticals, 32(4), 124-132.
44Sc for labeling of DOTA- and NODAGA-functionalized peptides: preclinical in vitro and in vivo investigations
Domnanich Katharina A., Müller Cristina, Farkas Renata, Schmid Raffaella M., Ponsard Bernard, Schibli Roger, Türler Andreas, van der Meulen Nicholas P. (2017), 44Sc for labeling of DOTA- and NODAGA-functionalized peptides: preclinical in vitro and in vivo investigations, in EJNMMI Radiopharmacy and Chemistry, 1(1), 8-8.

Collaboration

Group / person Country
Types of collaboration
Center of Radiopharmaceutical Sciences (CRS)/PSI+ETHZ Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Department of Chemistry/University of Oslo Norway (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Theranostics Center for Molecular Radiotherapy and Molecular Imaging, Zentralklinik Bad Berka Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Laboratory of Ion Beam Physics / ETHZ Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Associated projects

Number Title Start Funding scheme
180352 PHOtonuclear Reactions (PHOR): breakthrough research in radionuclides for theranostics 01.09.2018 Sinergia
175749 An active irradiation system for advanced radioisotope production using a medical PET cyclotron 01.10.2017 Project funding (Div. I-III)
180352 PHOtonuclear Reactions (PHOR): breakthrough research in radionuclides for theranostics 01.09.2018 Sinergia

Abstract

Positron Emission Tomography, in conjunction with other biomedical imaging methods like X-ray Computed Tomography or Magnetic Resonance Imaging, is one of the routinely-used diagnostic molecular imaging methods in nuclear medicine for the visualization of in vivo processes in cardiology, neurology, oncology or immunology. The most widely-used radionuclide is F-18, having a half-life of 1.83 h, mostly in the form of FDG. This is due to its nuclear decay properties and its availability, from a constantly growing number of biomedical cyclotrons. F-18-labeled compounds can be synthesized in large quantities in centralized GMP-certified radiopharmacies and delivered over longer distances to hospitals operating PET centers. F-18 is suitable to label small organic molecules, but has some disadvantages in labeling peptides or proteins. Radiometals are more viable for these kinds of molecules. In recent years Ga-68, obtained from a Ge-68/Ga-68 radionuclide generator system and having a half-life of 1.13 h rose in prominence for PET in the form of a number of Ga-68-labeled compounds. Despite the numerous advantages of Ga-68-labeled compounds for PET diagnostics, there are a few relevant drawbacks. On the one hand, the relatively short half-life requires, in essence, each site operating a PET scanner to also set-up a radiopharmaceutical production facility, fulfilling all requirements imposed by legislation. On the other hand, Ge-68/Ga-68-generators are able to provide a limited amount of radioactivity, for a maximum of about two patient doses per elution. Furthermore, it has been shown that Ga-68-labeled somatostatin analogues show different affinity profiles for human somatostatin receptor subtypes SSTR1-SSTR5, compared to their Lu-177 and Y-90-labeled counterparts used for therapy. As a result a correct therapy planning and dosimetry of patients, based on Ga-68 PET imaging, appears questionable. To overcome these limitations, the search for a more appropriate alternative to Ga-68 would require the following properties: a positron-emitting radionuclide with a half-life of several hours; high positron yield but low positron energies; a low number of accompanying low-energy gamma-rays with low intensities; and complex-chemical properties similar to Y-90 or Lu-177 to allow its introduction in the diagnostic approach using existing clinically-relevant radiopharmaceuticals. Furthermore, its production should be attained in large activities at a biomedical cyclotron in a cost-effective manner and its chemical isolation accomplished in a short, relatively simple procedure, so that it can be directly used for subsequent labeling reactions. In search for such a longer-lived, positron-emitting radionuclide the applicants have identified Sc-43 as a more appropriate candidate than Ga-68, with chemical properties more similar to Y and the lanthanides and, thus, a more appropriate match than its Ga counterpart. Its decay occurs with a low average positron energy of 0.476 MeV (Ga-68: 0.830 MeV), a high total positron yield of 88.1 % (Ga-68: 88.9 %), and an ideal half-life of 3.89 h (Ga-68: 1.13 h), thereby, allowing its transport over long distances to the costumer (i.e. >500 km). Its decay is associated with a relatively low energy gamma-ray of 373 keV and 23 % abundance (Ga-68: 1077 keV, 3.2 %), which will not influence PET imaging negatively, as modern PET scanners can be operated using a relatively narrow energy window (i.e. 440 - 665 keV). As a result, this radioisotope has the potential to overcome the above-mentioned limitations of Ga-68, while offering superior properties. A yet unsolved problem remains its production in sufficient quantities and radionuclidic purity by means of a biomedical cyclotron, i.e. with proton beams in the energy range of 10-20 MeV (or deuteron beams in the energy range of 5-10 MeV). The applicants propose to develop the production of this radionuclide using an interdisciplinary approach, taking advantage of existing infrastructure in Switzerland. On the premises of the Bern University Hospital (Inselspital), a new public/private endeavor resulted in the construction of a five-story building, a multipurpose facility containing a biomedical cyclotron, a state-of-the-art radiopharmacy, and a modern patient ward for nuclear medical treatments. The complex is operated by SWAN Isotopen AG, producing FDG on a commercial basis, while the University of Bern is engaged with its Physics Department, operating a beam transfer line at the cyclotron dedicated to research in nuclear and particle physics, and its Chemistry Department, operating a research radiopharmacy including hot-cells in a GMP-certified environment. The project combines the nuclear- and particle physics, accelerator technology, and targetry expertise of the Albert Einstein Center for Fundamental Physics - Laboratory of High Energy Physics with the radiochemical expertise of the Laboratory of Radiochemistry and Environmental Chemistry to install a solid target at the Bern cyclotron for the large-scale production of non-standard radionuclides and, in particular, to develop the required radiochemical procedures to extract Sc-43 from its target material in quality and quantity suitable for direct labeling reactions and for future medical application. In addition, procedures to recover the valuable, enriched target materials will be developed. In collaboration with the Center for Radiopharmaceutical Sciences at Paul Scherrer Institute, the in vitro properties and in vivo behavior of Sc-43-labeled compounds will be compared with Ga-68-, Lu-177-, and Y-90-labeled ones, including PET imaging with a phantom and in vivo PET imaging. These pre-clinical evaluations are an integral part of demonstrating the viability of the approach and of reaching the goal of developing all procedures to the point that, after completion of the project, first clinical trials with Sc-43 can be initiated at one or more nuclear medicine departments in Switzerland. The applicants have successfully demonstrated in the past that they are able to master all steps from production of a radionuclide, labeling of pharmaceuticals and pre-clinical work up to the point of first in-human application, including all the regulatory requirements imposed by the authorities. The benefits of the collaboration will be manifold and not only limited to the immediate outcome of the project: Research in nuclear medicine could profit enormously from the vast knowledge of nuclear- and particle physics and radiochemistry in producing novel, commercially unavailable radionuclides, in the desired quality and quantity and from radiopharmaceutical research providing the necessary pre-clinical evaluations. Essential for the success of such an endeavor is the interdisciplinary interaction of physicists, radiochemists and radiopharmaceutical chemists to reach the ultimate goal of bringing new diagnostic and therapeutic radiopharmaceuticals up to the point of clinical trials, which is also expressed in the catchphrase “from bench top to bedside”. The proposed activities will allow establishing a unique center of competence in Switzerland, able to produce knowledge and further technological developments beyond the duration of the proposed project. The availability of research radionuclides is, therefore, an indispensable prerequisite. With a moderate investment into a solid target at the biomedical cyclotron in Bern, this project will serve as a stepping stone to allow a future, cost-effective, year-round production of a number of essential, non-standard radionuclides for research in Switzerland, such as Sc-44g, Cu-64, and Zr-89, taking advantage of an existing modern infrastructure. Currently, University of Bern and Paul Scherrer Institute are among the few places in Switzerland that educate PhD students and postdoctoral fellows in the topics of radiochemistry, radiopharmaceutical chemistry and medical applications of nuclear- and particle physics.
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