Background
Terbium-155 T
1/2
= 5.32 d, Eγ = 87 keV (32%) 105 keV (25%) is an interesting radionuclide suitable for single photon emission computed tomography (SPECT) imaging with potential ...application in the diagnosis of oncological disease. It shows similar decay characteristics to the clinically established indium-111 and would be a useful substitute for the diagnosis and prospective dosimetry with biomolecules that are afterwards labeled with therapeutic radiolanthanides and pseudo-radiolanthanides, such as lutetium-177 and yttrium-90. Moreover, terbium-155 could form part of the perfect “matched pair” with the therapeutic radionuclide terbium-161, making the concept of true radiotheragnostics a reality. The aim of this study was the investigation of the production of terbium-155 via the
155
Gd(p,n)
155
Tb and
156
Gd(p,2n)
155
Tb nuclear reactions and its subsequent purification, in order to obtain a final product in quantity and quality sufficient for preclinical application. The
156
Gd(p,2n)
155
Tb nuclear reaction was performed with 72 MeV protons (degraded to ~ 23 MeV), while the
155
Gd(p,n)
155
Tb reaction was degraded further to ~ 10 MeV, as well as performed at an 18 MeV medical cyclotron, to demonstrate its feasibility of production.
Result
The
156
Gd(p,2n)
155
Tb nuclear reaction demonstrated higher production yields of up to 1.7 GBq, however, lower radionuclidic purity when compared to the final product (~ 200 MBq) of the
155
Gd(p,n)
155
Tb nuclear reaction. In particular, other radioisotopes of terbium were produced as side products. The radiochemical purification of terbium-155 from the target material was developed to provide up to 1.0 GBq product in a small volume (~ 1 mL 0.05 M HCl), suitable for radiolabeling purposes. The high chemical purity of terbium-155 was proven by radiolabeling experiments at molar activities up to 100 MBq/nmol. SPECT/CT experiments were performed in tumor-bearing mice using
155
TbTb-DOTATOC.
Conclusion
This study demonstrated two possible production routes for high activities of terbium-155 using a cyclotron, indicating that the radionuclide is more accessible than the exclusive mass-separated method previously demonstrated. The developed radiochemical purification of terbium-155 from the target material yielded
155
TbTbCl
3
in high chemical purity. As a result, initial cell uptake investigations, as well as SPECT/CT in vivo studies with
155
TbTb-DOTATOC, were successfully performed, indicating that the chemical separation produced a product with suitable quality for preclinical studies.
The Isotope Separation On-Line (ISOL) method for the production of Radioactive Ion Beams (RIB) is attracting significant interest in the worldwide nuclear physics community. Within this context the ...SPES (Selective Production of Exotic Species) RIB facility is now under construction at INFN LNL (Istituto Nazionale di Fisica Nucleare Laboratori Nazionali di Legnaro). This technique is established as one of the main techniques for high intensity and high quality beams production. The SPES facility will produce n-rich isotopes by means of a 40 MeV proton beam, emitted by a cyclotron, impinging on a uranium carbide multi-foil fission target. The aim of this work is to describe the most important results obtained by the study of the on-line behavior of the SPES production target assembly. This target system will produce RIBs at a rate of about 1013 fissions per second, it will be able to dissipate a total power of up to 10 kW, and it is planned to work continuously for 2 week-runs of irradiation. ISOL beams of 24 different elements will be produced, therefore a target and ion source development is ongoing to ensure a great variety of produced isotopes and to improve the beam intensity and purity.
Radionuclides for radiopharmaceuticals can be produced in cyclotrons or nuclear reactors. Each of these production modes has serious issues, such as high target costs, production of long-lived wastes ...and contaminants, expensive separation. For this reason, new methods are under consideration for the production of highly pure radionuclides. The ISOL (Isotope Separation On-Line) method is the major technique for the production of radioactive ion beams for nuclear physics applications. The SPES-ISOLPHARM project at INFN-LNL (Istituto Nazionale di Fisica Nucleare-Laboratori Nazionali di Legnaro) is a feasibility study for the production of medical isotopes exploiting the ISOL method. The ongoing activities concerning a recent experiment focused on
111
Ag, a study performed in collaboration with Padova and Trento Universities, is presented.
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•Theory of pH-static titrations for metal + ligand complexation kinetics was given.•pH static titrations represent a kinetic method alternative to spectrophotometry.•The kinetics of ...Sr2++DOTA reaction at various pH and temperatures was studied.•Other used methods for kinetic measurements can give wrong results.
The theory of pH-static (or pH-stat) titrations in kinetic measurements of metal ion + ligand complex formation was resumed, and equations required to fit the experimental data were derived. This method was applied to study the kinetics of Sr2++DOTA reaction (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). pH-static titrations were performed at various pH (from 4.00 to 6.00) and temperatures (5, 15, and 25 °C) and at a constant ionic strength of (Na)Cl 0.15 mol/L. The complex formation involved either a rapidly formed intermediate species which then gave the final complex, or the direct metal + ligand reaction. The corresponding equilibrium constant βos and kinetic constants kos (first order) and k (second order) were obtained. Both k and kos increased by increasing pH and temperature. Kinetic data were recorded by pH-static titrations also for Ni2++DOTA reaction, and other kinetic results were obtained by using a more commonly employed method, proposed by Kasprzyk and Wilkins S. P. Kasprzyk and R. G. Wilkins, Inorg. Chem., 1982, 21, 3349, which however appears to be theoretically incorrect. The comparison between the kinetic results for Sr2++DOTA and Ni2++DOTA reactions obtained by pH-static titrations, by the Kasprzyk/Wilkins method, and by the well-established spectrophotometric method (literature data), indicated that the Kasprzyk/Wilkins method should be used with caution as sometimes its systematic errors can be statistically relevant with respect to the typical precision of kinetic data.
Accelerator-based techniques with electromagnetic mass separation are considered among the most innovative and promising strategies to produce non-conventional radionuclides for nuclear medicine. ...Such approach was successfully used at CERN, where the dedicated MEDICIS facility was built, and at TRIUMF, where the ISAC radioactive beam facility was used to produce unconventional α-emitters. In such framework, the Legnaro National Laboratories of the Italian Institute of Nuclear Physics (INFN-LNL) proposed the ISOLPHARM project (ISOL technique for radioPHARMaceuticals), which will exploit radionuclides producible with the SPES (Selective Production of Exotic Species) ISOL (Isotope Separation On-Line) facility to develop novel radiopharmaceuticals. The ISOL technique utilizes the irradiation with a primary beam of particles/nuclei of a production target where radionuclides are produced. A radioactive ion beam is subsequently extracted from the production target unit, and transported up to an analyzing magnet, where non-isobaric contaminants are filtered out. The so-obtained purified radioactive beam is dumped onto an implantation substrate, referred as collection target. Then, the desired nuclides can be chemically harvested from the collected isobars, and the isotopically pure atom collection can be employed to radiolabel high specific activity radiopharmaceuticals. Metallic deposition targets in the form of coated metal foils were mostly used at TRIUMF and CERN. At ISOLPHARM, a different approach is under investigation which foresees the use of soluble cold-pressed collection targets, possibly facilitating the chemical purification process of the collected radionuclides. In this study, the production and characterization of some of the ISOLPHARM collection targets is presented, in particular, soluble salts (NaCl and NaNO3) and organic materials widely used for pharmaceutical tablets production are considered. All such materials proved to be potentially suitable as collection targets, since solid samples were easily produced and resulted compatible with the vacuum conditions required for the ion implantation process. Furthermore, some of the selected substrates were used for proof-of-concept deposition tests with stable silver, to prove their suitability as ISOLPHARM deposition substrates for silver-111, a promising candidate for radiotherapy. Such tests highlighted possible scenarios useful for the development of new alternative materials, as the use of insoluble organic targets.
•ISOL based techniques for the production of medical radionuclides require the use of an implantation target.•Generally, implantation targets are metallic foil, ISOLPHARM at INFN-LNL proposes saline or organic substrates.•NaCl, NaNO3, cellulosic and dextrates substrates were produced by direct compression.•All samples were characterized in terms of density, mechanical strength, disaggregation and vacuum compatibility.•Implantation depth calculations and tests with the deposition of Ag + ions were performed.
Worldwide efforts to tackle the nature of exotic nuclei comprise the construction of new-generation Radioactive Ion Beam facilities. The Italian community is deeply involved in the process and the ...construction of SPES at Legnaro National Laboratories (INFN) is progressing. This contribution describes the layout of SPES in all its flavours, from Nuclear Physics to Applications in Nuclear Medicine and Neutron Physics. In particular, the status of the SPES-β ISOL facility, together with some of the relevant physics cases and the associated equipment are described.
Radiopharmaceuticals represent a fundamental tool for nuclear medicine procedures, both for diagnostic and therapeutic purposes. The present work aims to explore the Isotope Separation On-Line (ISOL) ...technique for the production of carrier-free radionuclides for nuclear medicine at SPES, a nuclear physics facility under construction at INFN-LNL. Stable ion beams of strontium, yttrium and iodine were produced using the SPES test bench (Front-End) to simulate the production of 89Sr, 90Y, 125I and 131I and collected with good efficiency on suitable targets.
•The use of ISOL method for radionuclides production is proposed.•ISOL method allows to produce carrier-free radionuclides for nuclear medicine.•Tests with stable ion beams were produced as a proof of concept.•Sodium Chloride is suitable as material for targets for Sr and Y beams.•Activated Carbon can be compacted with PVA to have a solid target for I2 beams.
The ISOLPHARM project explores the feasibility of exploiting an innovative technology to produce extremely high specific activity beta-emitting radionuclides as radiopharmaceutical precursors. This ...technique is expected to produce radiopharmaceuticals that are virtually mainly impossible to obtain in standard production facilities, at lower cost and with less environmental impact than traditional techniques. The groundbreaking ISOLPHARM method investigated in this project has been granted an international patent (INFN). As a component of the SPES (Selective Production of Exotic Species) project at the Istituto Nazionale di Fisica Nucleare–Laboratori Nazionali di Legnaro (INFN–LNL), a new facility will produce radioactive ion beams of neutron-rich nuclei with high purity and a mass range of 80–160 amu. The radioactive isotopes will result from nuclear reactions induced by accelerating 40 MeV protons in a cyclotron to collide on a target of UC
x
. The uranium in the target material will be
238
U, yielding radioactive isotopes that belong to elements with an atomic number between 28 and 57. Isotope separation on line (ISOL) is adopted in the ISOLPHARM project to obtain pure isobaric beams for radiopharmaceutical applications, with no isotopic contaminations in the beam or subsequent trapping substrate. Isobaric contaminations may potentially affect radiochemical and radionuclide purity, but proper methods to separate chemically different elements can be developed.
The concept of using ibuprofen as an albumin-binding entity was recently demonstrated by the development of
LuLu-Ibu-PSMA-01. In the present study, we designed a novel ibuprofen-containing ...radioligand (Ibu-PSMA-02) with subtle structural changes regarding the linker entity in order to investigate a potential impact on the in vitro and in vivo properties. Ibu-PSMA-02 was prepared using solid-phase synthesis techniques and labeled with lutetium-177.
LuLu-Ibu-PSMA-02 was evaluated in vitro with regard to its plasma protein-binding properties, PSMA affinity and uptake into PSMA-expressing PC-3 PIP tumor cells. The tissue distribution profile of
LuLu-Ibu-PSMA-02 was assessed in tumor-bearing mice and dose estimations were performed. The in vitro characteristics of
LuLu-Ibu-PSMA-02 were similar to those previously obtained for
LuLu-Ibu-PSMA-01 with respect to plasma protein-binding, PSMA affinity and tumor cell uptake. The in vivo studies revealed, however, an unprecedentedly high uptake of
LuLu-Ibu-PSMA-02 in PC-3 PIP tumors, resulting in an increased absorbed tumor dose of 7.7 Gy/MBq as compared to 5.1 Gy/MBq calculated for
LuLu-Ibu-PSMA-01. As a consequence of the high tumor accumulation,
LuLu-Ibu-PSMA-02 showed higher tumor-to-background ratios than
LuLu-Ibu-PSMA-01. This study exemplified that smallest structural changes in the linker entity of PSMA radioligands may have a significant impact on their pharmacokinetic profiles and, thus, may be applied as a means for ligand design optimization.
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