Development and Evaluation of the Magnetic Properties of a New Manganese (II) Complex: A Potential MRI Contrast Agent.

Magnetic resonance imaging (MRI) is a non-invasive powerful modern clinical technique that is extensively used for the high-resolution imaging of soft tissues. To obtain high-definition pictures of tissues or of the whole organism this technique is enhanced by the use of contrast agents. Gadolinium-based contrast agents have an excellent safety profile. However, over the last two decades, some specific concerns have surfaced. Mn(II) has different favorable physicochemical characteristics and a good toxicity profile, which makes it a good alternative to the Gd(III)-based MRI contrast agents currently used in clinics. Mn(II)-disubstituted symmetrical complexes containing dithiocarbamates ligands were prepared under a nitrogen atmosphere. The magnetic measurements on Mn complexes were carried out with MRI phantom measurements at 1.5 T with a clinical magnetic resonance. Relaxivity values, contrast, and stability were evaluated by appropriate sequences. Studies conducted to evaluate the properties of paramagnetic imaging in water using a clinical magnetic resonance showed that the contrast, produced by the complex [Mn(II)(L')2] × 2H2O (L' = 1.4-dioxa-8-azaspiro[4.5]decane-8-carbodithioate), is comparable to that produced by gadolinium complexes currently used in medicine as a paramagnetic contrast agent.

Highly Efficient Micro-Scale Liquid-Liquid In-Flow Extraction of 99mTc from Molybdenum.

The trend to achieve even more compact-sized systems is leading to the development of micro-scale reactors (lab-on-chip) in the field of radiochemical separation and radiopharmaceutical production. Technetium-99m extraction from both high and low specific activity molybdenum could be simply performed by MEK-driven solvent extraction if it were not for unpractical automation. The aim of this work is to develop a solvent extraction and separation process of technetium from molybdenum in a micro-scale in-flow chemistry regime with the aid of a capillary loop and a membrane-based separator, respectively. The developed system is able to extract and separate quantitatively and selectively (91.0 ± 1.8% decay corrected) the [99mTc]TcO4Na in about 20 min, by using a ZAIPUT separator device. In conclusion, we demonstrated for the first time in our knowledge the high efficiency of a MEK-based solvent extraction process of 99mTc from a molybdenum-based liquid phased in an in-flow micro-scale regime.

A Universal Cassette-Based System for the Dissolution of Solid Targets.

Cyclotron-based radionuclides production by using solid targets has become important in the last years due to the growing demand of radiometals, e.g., 68Ga, 89Zr, 43/47Sc, and 52/54Mn. This shifted the focus on solid target management, where the first fundamental step of the radiochemical processing is the target dissolution. Currently, this step is generally performed with commercial or home-made modules separated from the following purification/radiolabelling modules. The aim of this work is the realization of a flexible solid target dissolution system to be easily installed on commercial cassette-based synthesis modules. This would offer a complete target processing and radiopharmaceutical synthesis performable in a single module continuously. The presented solid target dissolution system concept relies on an open-bottomed vial positioned upon a target coin. In particular, the idea is to use the movement mechanism of a syringe pump to position the vial up and down on the target, and to exploit the heater/cooler reactor of the module as a target holder. All the steps can be remotely controlled and are incorporated in the cassette manifold together with the purification and radiolabelling steps. The performance of the device was tested by processing three different irradiated targets under different dissolution conditions.

Synthesis and Characterization of Manganese Dithiocarbamate Complexes: New Evidence of Dioxygen Activation.

(1) Background: Metal dithiocarbamate compounds have long been the subject of research due to their ease of formation, excellent properties and potential applications. However, manganese complexes with dithiocarbamates, to our knowledge, have never been used for medical imaging applications. With the aim of developing a new class of mononuclear manganese(II)-based agents for molecular imaging applications, we performed a specific investigation into the synthesis of mononuclear bis-substituted Mn(II) complexes with dithiocarbamate ligands. (2) Methods: Synthesis in either open or inert atmosphere at different Mn(II) to diethyldithiocarbamate molar ratios were performed and the products characterized by IR, EA, ESI-MS and XRD analysis. (3) Results: We found that only under oxygen-free atmospheric conditions the Mn(II) complex MnL2, where L = diethyldithiocarbamate ligand, is obtained, which was further observed to react with dioxygen in the solid state to form the intermediate superoxo Mn(III) complex [MnL2(η2-O2)]. The existence of the superoxo complex was revealed by mass spectroscopy, and this species was interpreted as an intermediate step in the reaction that led the bis-substituted Mn(II) complex, MnL2, to transform into the tris-substituted Mn(III) complex, MnL3. A similar result was found with the ligand L' (= bis(N-ethoxyethyl)dithiocarbamate). (4) Conclusions: We found that in open atmosphere and in aqueous solution, only manganese(III) diethyldithiocarbamate complexes can be prepared. We report here a new example of a small-molecule Mn(II) complex that efficiently activates dioxygen in the solid state through the formation of an intermediate superoxide adduct.

LARAMED: A Laboratory for Radioisotopes of Medical Interest.

The widespread availability of novel radioactive isotopes showing nuclear characteristics suitable for diagnostic and therapeutic applications in nuclear medicine (NM) has experienced a great development in the last years, particularly as a result of key advancements of cyclotron-based radioisotope production technologies. At Legnaro National Laboratories of the National Institute of Nuclear Physics (LNL-INFN), Italy, a 70-MeV high current cyclotron has been recently installed. This cyclotron will be dedicated not only to pursuing fundamental nuclear physics studies, but also to research related to other scientific fields with an emphasis on medical applications. LARAMED project was established a few years ago at LNL-INFN as a new research line aimed at exploiting the scientific power of nuclear physics for developing innovative applications to medicine. The goal of this program is to elect LNL as a worldwide recognized hub for the development of production methods of novel medical radionuclides, still unavailable for the scientific and clinical community. Although the research facility is yet to become fully operative, the LARAMED team has already started working on the cyclotron production of conventional medical radionuclides, such as Tc-99m, and on emerging radionuclides of high potential medical interest, such as Cu-67, Sc-47, and Mn-52.

Cyclotron production of manganese-52: a promising avenue for multimodal PET/MRI imaging.

BACKGROUND: The integration of positron emission tomography (PET) and magnetic resonance imaging (MRI) holds promise for advancing diagnostic imaging capabilities. The METRICS project aims to develop cyclotron-driven production of 52Mn for PET/MRI imaging. RESULTS: Using the 52Cr(p,n)52Mn reaction, we designed chromium metal targets via Spark Plasma Sintering and developed a separation procedure for isolating 52Mn. Labeling tests were conducted with traditional chelators (i.e. S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid) and the 1.4-dioxa-8-azaspiro[4.5]decane-8- carbodithioate ligand to produce radioactive complexes suitable for PET/MRI applications. Our methodology yielded high-quality 52Mn suitable for PET radiopharmaceuticals and PET/MRI imaging. Preliminary studies on phantom imaging using microPET and clinical MRI demonstrated the efficacy of our approach. CONCLUSIONS: The developed technology offers a promising avenue for producing 52Mn and enhancing PET/MRI imaging capabilities. Further in vivo investigations are warranted to evaluate the potential advantages of this hybrid imaging technique.

Cryomilling of Isotope-Enriched Ti Powders for HIVIPP Deposition to Manufacture Targets for Nuclear Cross Section Measurement.

The realization of isotopically enriched Ti targets for nuclear cross-section measurements requires particular attention, from the starting material preparation up to the deposition technique. In this work, a cryomilling process was developed and optimized, aimed at reducing the size of 49,50Ti metal sponge as provided by the supplier (size up to 3 mm), to the optimal size of 10 µm, to fit the High Energy Vibrational Powder Plating technique used for target manufacturing. The optimization of the cryomilling protocol and the HIVIPP deposition using natTi material was thus performed. The scarce amount of the enriched material to be treated (about 150 mg), the need to obtain a non-contaminated final powder and a uniform target thickness of about 500 µg/cm2 were taken into account. The 49,50Ti materials were then processed and 20 targets of each isotope were manufactured. Both powders and the final Ti targets produced were characterized by SEM-EDS analysis. The amount of Ti deposited was measured by weighing, indicating reproducible and homogeneous targets, with an areal density of 468 ± 110 µg/cm2 for 49Ti (n = 20) and 638 ± 200 µg/cm2 for 50Ti (n = 20). The uniformity of the deposited layer was also confirmed by the metallurgical interface analysis. The final targets were used for the cross section measurements of the 49Ti(p,x)47Sc and 50Ti(p,x)47Sc nuclear reaction routes aimed at the production of the theranostic radionuclide 47Sc.

First Results on Zinc Oxide Thick Film Deposition by Inverted Magnetron Sputtering for Cyclotron Solid Targets Production.

The magnetron sputtering technique has been investigated in recent years with ever-growing interest as a verifiable solid target manufacturing technology aimed at the production of medical radionuclides by using low-energy cyclotron accelerators. However, the possible loss of high-cost materials prevents access to work with isotopically enriched metals. The need for expensive materials for the supply of the growing demand for theranostic radionuclides makes the material-saving approach and recovery essential for the radiopharmaceutical field. To overcome the main magnetron sputtering drawback, an alternative configuration is proposed. In this work, an inverted magnetron prototype for the deposition of tens of µm film onto different substrates is developed. Such configuration for solid target manufacturing has been proposed for the first time. Two ZnO depositions (20-30 µm) onto Nb backing were carried out and analysed by SEM (Scanning Electron Microscopy) and XRD (X-ray Diffractogram). Their thermomechanical stability under the proton beam of a medical cyclotron was tested as well. A possible improvement of the prototype and the perspective of its utilisation were discussed.

Nuclear Cross-Section of Proton-Induced Reactions on Enriched 48Ti Targets for the Production of Theranostic 47Sc Radionuclide, 46cSc, 44mSc, 44gSc, 43Sc, and 48V.

The cross-sections of the 48Ti(p,x)47Sc, 46cSc, 44mSc, 44gSc, 43Sc, and 48V nuclear reactions were measured from 18 to 70 MeV, with particular attention to 47Sc production. Enriched 48Ti powder was deposited on an aluminum backing and the obtained targets were characterized via elastic backscattering spectroscopy at the INFN-LNL. Targets were exposed to low-intensity proton irradiation using the stacked-foils technique at the ARRONAX facility. Activated samples were measured using γ-spectrometry; the results were compared with the data int he literature and the theoretical TALYS-based values. A regular trend in the new values obtained from the different irradiation runs was noted, as well as a good agreement with the literature data, for all the radionuclides of interest: 47Sc, 46cSc, 44mSc, 44gSc, 43Sc, and 48V. 47Sc production was also discussed, considering yield and radionuclidic purity, for different 47Sc production scenarios.

A feasibility study of the therapeutic application of a mixture of 67/64 Cu radioisotopes produced by cyclotrons with proton irradiation.

PURPOSE: 64 Cu and 67 Cu radioisotopes have nuclear characteristics suitable for nuclear medicine applications. The production of 64 Cu is already well established. However, the production of 67 Cu in quantities suitable to conduct clinical trials is more challenging as it leads to the coproduction of other Cu isotopes, in particular 64 Cu. The aim of this study is to investigate the possibility of using a CuCl2 solution with a mixture of 67/64 Cu radioisotopes for therapeutic purposes, providing an alternative solution for the cyclotron production problem. METHODS: Copper radioisotopes activities were calculated by considering proton beam irradiation of the following targets: (i) 70 Zn in the energy range 70-45 MeV; (ii) 68 Zn in the energy range 70-35 MeV; (iii) a combination of 70 Zn (70-55 MeV) and 68 Zn (55-35 MeV). The contribution of each copper radioisotope to the human-absorbed dose was estimated with OLINDA/EXM software using the biokinetic model for CuCl2 published by ICRP 53. The total absorbed dose generated by the 67/64 CuCl2 mixture, obtained through different production routes, was calculated at different times after the end of the bombardment (EOB). A simple spherical model was used to simulate tumors of different sizes containing uniformly distributed 67/64 Cu mixture and to calculate the absorbed dose of self-irradiation. The biological damage produced by 67 Cu and 64 Cu was also evaluated through cellular dosimetry and cell surviving fraction assessment using the MIRDcell code, considering two prostate cancer cell lines with different radiosensitivity. RESULTS: The absorbed dose to healthy organs and the effective dose (ED) per unit of administered activity of 67 CuCl2 are higher than those of 64 CuCl2 . Absorbed dose values per unit of administered activity of 67/64 CuCl2 mixture increase with time after the EOB because the amount of 67 Cu in the mixture increases. Survival data showed that the biological damage caused per each decay of 67 Cu is greater than that of 64 Cu, assuming that radionuclides remain accumulated in the cell cytoplasm. Sphere model calculations demonstrated that 64 Cu administered activity must be about five times higher than that of 67 Cu to obtain the same absorbed dose for tumor mass between 0.01 and 10 g and about 10 times higher for very small spheres. Consequently, the 64 CuCl2 -absorbed dose to healthy organs will reach higher values than those of 67 CuCl2 . The supplemental activity of the 67/64 CuCl2 mixture, required to get the same tumor-absorbed dose produced by 67 CuCl2 , triggers a dose increment (DI) in healthy organs. The waiting time post-EOB necessary to keep this DI below 10% (t10% ) depends on the irradiation methods employed for the production of the 67/64 CuCl2 mixture. CONCLUSIONS: A mixture of cyclotron produced 67/64 Cu radioisotopes proved to be an alternative solution for the therapeutic use of CuCl2 with minimal DI to healthy organs compared with pure 67 Cu. Irradiation of a 70 Zn+68 Zn target in the 70-35 MeV proton energy range for 185 h appears to be the best option from among all the production routes investigated, as it gives the maximum amount of activity, the shortest t10% (10 h), and less than 1% of 61 Cu and 60 Cu impurities.

Radiation effective dose assessment of [51Mn]- and [52Mn]-chloride.

In order to establish the potential of [51/52Mn]Cl2 as safe PET brain tracers, the radiation effective dose (ED) of [51Mn]- and [52Mn]-chloride has been assessed by using biokinetic models in anthropomorphic phantoms. Results showed that [52Mn]-chloride releases one hundred thirty times more radiation dose (ED = 1.35 mSv/MBq) than [51Mn]-chloride (ED = 1.02E-02 mSv/MBq). Although the maximum positron energy of 52Mn allows a PET image resolution similar to that of 18F, activities below 15 MBq should be administered.

Internal radiation dose assessment of radiopharmaceuticals prepared with cyclotron-produced 99m Tc.

PURPOSE: Technetium-99m (99m Tc) is the radioisotope most widely used in diagnostic nuclear medicine. It is readily available from 99 Mo/99m Tc generators as the ß- decay product of the 99 Mo (T½  = 66 h) parent nuclide. This latter is obtained as a fission product in nuclear reactors by neutron-induced reactions on highly enriched uranium. Alternative production routes, such as direct reactions using proton beams on specific target materials [100 Mo(p,2n)99m Tc], have the potential to be both reliable and relatively cost-effective. However, results showed that the 99m Tc extracted from proton-bombarded 100 Mo-enriched targets contains small quantities of several Tc radioisotopes (93m Tc, 93 Tc, 94 Tc, 94m Tc, 95 Tc, 95m Tc, 96 Tc, and 97m Tc). The aim of this work was to estimate the dose increase (DI) due to the contribution of Tc radioisotopes generated as impurities, after the intravenous injection of four radiopharmaceuticals prepared with cyclotron-produced 99m Tc (CP-99m Tc) using 99.05% 100 Mo-enriched metallic targets. METHODS: Four 99m Tc radiopharmaceuticals (pertechnetate, sestamibi (MIBI), hexamethylpropylene-amine oxime (HMPAO) and disodium etidronate (HEDP)) were considered in this study. The biokinetic models reported by the International Commission on Radiological Protection (ICRP) for each radiopharmaceutical were used to define the main source organs and to calculate the number of disintegrations per MBq that occurred in each source organ (Nsource ) for each Tc radioisotope present in the CP-99m Tc solution. Then, target organ equivalent doses and effective dose were calculated for each Tc radioisotope with the OLINDA/EXM software versions 1.1 and 2.0, using the calculated Nsource values and the adult male phantom as program inputs. Total effective dose produced by all Tc isotopes impurities present in the CP-99m Tc solution was calculated using the fraction of total activity corresponding to each radioisotope and compared with the effective dose delivered by the generator-produced 99m Tc. RESULTS: In all cases, the total effective DI of CP-99m Tc radiopharmaceuticals calculated with either versions of the OLINDA software was less than 10% from 6 up to 12 h after EOB. 94m Tc and 93m Tc are the Tc radioisotopes with the highest concentration in the CP-99m Tc solution at EOB. However, their contribution to DI 6 h after EOB is minimal, due to their short half-lives. The radioisotopes with the largest contribution to the effective DI are 96 Tc, followed by 95 Tc and 94 Tc. This is due to the types of their emissions and relatively long half-lives, although their concentration in the CP-99m Tc solution is five times lower than that of 94m Tc and 93m Tc at the EOB. CONCLUSIONS: The increase in the radiation dose caused by other Tc radioisotopes contained in CP-99m Tc produced as described here is quite low. Even though the concentrations of the 94 Tc and 95 Tc radioisotopes in the CP-99m Tc solution exceed the limits established by the European Pharmacopoeia, CP-99m Tc radiopharmaceuticals could be used in routine nuclear medicine diagnostic studies if administered from 6 to 12 h after the EOB, thus maintaining the effective DI within the 10% limit.

In-house cyclotron production of high-purity Tc-99m and Tc-99m radiopharmaceuticals.

In the last years, the technology for producing the important medical radionuclide technetium-99m by cyclotrons has become sufficiently mature to justify its introduction as an alternative source of the starting precursor [99mTc][TcO4]- ubiquitously employed for the production of 99mTc-radiopharmaceuticals in hospitals. These technologies make use almost exclusively of the nuclear reaction 100Mo(p,2n)99mTc that allows direct production of Tc-99m. In this study, it is conjectured that this alternative production route will not replace the current supply chain based on the distribution of 99Mo/99mTc generators, but could become a convenient emergency source of Tc-99m only for in-house hospitals equipped with a conventional, low-energy, medical cyclotron. On this ground, an outline of the essential steps that should be implemented for setting up a hospital radiopharmacy aimed at the occasional production of Tc-99m by a small cyclotron is discussed. These include (1) target production, (2) irradiation conditions, (3) separation/purification procedures, (4) terminal sterilization, (5) quality control, and (6) Mo-100 recovery. To address these issues, a comprehensive technology for cyclotron-production of Tc-99m, developed at the Legnaro National Laboratories of the Italian National Institute of Nuclear Physics (LNL-INFN), will be used as a reference example.

Tumour-localizing and -photosensitising properties of meso-tetra(4-nido-carboranylphenyl)porphyrin (H2TCP).

A water-soluble meso-substituted porphyrin (H(2)TCP) bearing 36 boron atoms, which appeared to be an efficient photodynamic sensitiser (singlet oxygen quantum yield=0.44), was studied for its accumulation by murine melanotic melanoma cells (B16F1). The amount of H(2)TCP in the cells increased with the porphyrin dose in the incubation medium up to, and at least, 100 microM concentrations with no significant cytotoxic effect in the dark. Moreover, the H(2)TCP uptake increased with the incubation time reaching a plateau value corresponding with the recovery of 0.4 nmol of H(2)TCP per mg of cell proteins after 24h incubation. Fluorescence microscopy observations showed that the porphyrin was largely localized intracellularly, exhibiting a discrete distribution in the cytoplasm with a pattern which was closely similar to that observed for the endosomal probe Lucifer yellow. The photosensitising efficiency of the H(2)TCP toward B16F1 cells was studied for different irradiation (1-15 min) and incubation (1-24 h) times. Nearly complete (>95%) cell mortality was obtained upon incubation with 20 microM H(2)TCP and 10 min irradiation with red light (600-700 nm, 20 mW/cm(2)). The porphyrin was also accumulated in appreciable amounts by the tumour tissue after intravenous injection to C57BL/6 mice bearing a subcutaneously transplanted melanotic melanoma. Maximum accumulation in the tumour was achieved by administration of H(2)TCP dissolved in the ternary mixture 20% dimethylsulfoxide (DMSO)-30% polyethyleneglycol (PEG 400)-50% water. Thus, this porphyrin could act as both a photodynamic therapy agent and a radiosensitising agent for boron neutron capture therapy.

A solvent-extraction module for cyclotron production of high-purity technetium-99m.

The design and fabrication of a fully-automated, remotely controlled module for the extraction and purification of technetium-99m (Tc-99m), produced by proton bombardment of enriched Mo-100 molybdenum metallic targets in a low-energy medical cyclotron, is here described. After dissolution of the irradiated solid target in hydrogen peroxide, Tc-99m was obtained under the chemical form of 99mTcO4-, in high radionuclidic and radiochemical purity, by solvent extraction with methyl ethyl ketone (MEK). The extraction process was accomplished inside a glass column-shaped vial especially designed to allow for an easy automation of the whole procedure. Recovery yields were always >90% of the loaded activity. The final pertechnetate saline solution Na99mTcO4, purified using the automated module here described, is within the Pharmacopoeia quality control parameters and is therefore a valid alternative to generator-produced 99mTc. The resulting automated module is cost-effective and easily replicable for in-house production of high-purity Tc-99m by cyclotrons.

The excitation functions of (100)Mo(p,x)(99)Mo and (100)Mo(p,2n)(99m)Tc.

Proton-induced nuclear reactions for generation of (99)Mo and (99m)Tc radionuclides were investigated using the stacked-foil activation technique on 99.05% enriched (100)Mo targets at energies up to Ep=21MeV. Excitation functions of the reactions (100)Mo(p,x)(99)Mo and (100)Mo(p,2n)(99m)Tc have been measured.

The modeling of the reaction cross sections in the production of teranositic radionuclides / La modelación de las secciones eficaces de reacción en la producción de radionúclidos teranosíticos

Abstract We utilize various nuclear reaction codes with the aim to guide, interpret, and support the experiments in the proton-induced production measurements of radionuclides for the development of innovative radio-pharmaceuticals. The understanding of reaction cross sections at low-intermediate energies is crucial in this context and requires the knowledge of nuclear models available in different codes, such as EMPIRE, TALYS, and FLUKA. These nuclear reaction codes serve as tool to interpret the measurement of production cross-sections and to complete the measurements with estimates of production of contaminants and/or stable isotopes that are difficult to measure. We illustrate different model calculations to simulate isotope production useful in experiments devoted to the measurement of proton-induced production of the two theranostic radio-isotopes 67Cu and 47Sc.

Resumen Utilizamos varios códigos de reacción nuclear con el objetivo de guiar, interpretar y respaldar los experimentos en las mediciones de producción de radionúclidos inducidas por protones para el desarrollo de productos radio-farmacéuticos innovadores. La comprensión de las secciones eficaces de reacción en energías intermedias bajas es crucial en este contexto y requiere el conocimiento de modelos nucleares disponibles en diferentes códigos, como EMPIRE, TALYS y FLUKA. Estos códigos de reacción nuclear sirven como herramienta para interpretar la medición de secciones eficaces de producción y para completar las mediciones con estimaciones de producción de contaminantes y / o isótopos estables que son difíciles de medir. Ilustramos diferentes cálculos de modelos para simular la producción de isótopos útiles en experimentos dedicados a la medición de la producción inducida por protones de los dos isótopos teranósticos 67Cu y 47Sc.

Cyclotron production of 67Cu: A new measurement of the 68Zn(p,2p)67Cu, 68Zn(p,2n)67Ga and 68Zn(p,3n)66Ga nuclear cross sections

The cross sections of the 68Zn(p,2p)67Cu,68Zn(p,2n)67Ga and 68Zn(p,3n)66Ga reactions were measured at the ARRONAX facility by using the 70 MeV cyclotron, with particular attention to the production of the theranostic radionuclide 67Cu. Enriched 68Zn material was electroplated on silver backing and exposed to alow-intensity proton beam by using the stacked-foils target method. Since 67Cu and 67Ga radionuclides have similar half-lives and same γ-lines (they both decay to 67Zn), a radiochemical process aimed at Cu/Ga separation was mandatory to avoid interferences in γ-spectrometry measurements. A simple chemical procedure having a high separation efficiency (>99%)was developed and monitored during each foil processing, thanks to the tracer isotopes 61Cu and 66Ga.Nuclear cross sections were measured in the energy range 35-70 MeV by using reference reactions recommended by the International Atomic Energy Agency (IAEA) to monitor beam flux. In comparison with literature data a general good agreement on the trend of the nuclear reactions was noted, especially with latest measurements, but slightly lower values were obtained in case of 67Cu. Experimental results of the 68Zn(p,2p)67Cu,68Zn(p,2n)67Ga and 68Zn(p,3n)66Ga reactions were also compared with the theoretical values estimated by using the nuclear reaction code TALYS. The production yield of the theranostic radionuclide 67Cu was estimated considering the results obtained in this work.

Las secciones eficaces de las reacciones 68Zn (p, 2p) 67Cu, 68Zn (p, 2n) 67Ga y 68Zn (p, 3n) 66Ga se midieron en la instalación ARRONAX utilizando el ciclotrón 70 MeV, con especial atención a la producción del radionucleidos teranóstico 67Cu. El material enriquecido 68Zn se galvanizó sobre soporte de plata y se expuso a un haz de protones de baja intensidad utilizando un blanco de láminas apiladas. Como los radionucleidos 67Cu y 67Ga tienen periodos de semidesintegración y líneas γ similares (ambos se desintegran a 67Zn), un proceso radioquímico dirigido a la separación Cu / Ga fue obligatorio para evitar interferencias en las mediciones de espectrometría γ. Se desarrolló un procedimiento químico simple con una alta eficiencia de separación (> 99%) durante cada procesamiento de la lámina, gracias a los isótopos trazadores 61Cu y 66Ga. Las secciones eficaces nucleares se midieron en el rango de energía de 35-70 MeV utilizando reacciones de referencia recomendadas por el Organismo Internacional de Energía Atómica (OIEA) para monitorear el flujo del haz. Al comparar con los datos de la literatura, se observó una buena concordancia en general con la tendencia de las reacciones nucleares, particularmente con las últimas mediciones, pero se obtuvieron valores ligeramente inferiores en el caso de 67Cu. Los resultados experimentales de las reacciones 68Zn (p, 2p) 67Cu, 68Zn (p, 2n) 67Ga y 68Zn (p, 3n) 66Ga también se compararon con los valores teóricos estimados usando el código de reacción nuclear TALYS. El rendimiento de producción del radionucleido teranóstico 67Cu se estimó considerando los resultados obtenidos en este trabajo.

Cyclotron production of 67Cu: A new measurement of the 68Zn(p,2p)67Cu, 68Zn(p,2n)67Ga and 68Zn(p,3n)66Ga nuclear cross sections / Producción de 67Cu en ciclotrón: una nueva medición de secciones eficaces nucleares de 68Zn(p,2p)67Cu, 68Zn(p,2n)67Ga and 68Zn(p,3n)66Ga

Abstract The cross sections of the 68Zn(p,2p)67Cu,68Zn(p,2n)67Ga and 68Zn(p,3n)66Ga reactions were measured at the ARRONAX facility by using the 70 MeV cyclotron, with particular attention to the production of the theranostic radionuclide 67Cu. Enriched 68Zn material was electroplated on silver backing and exposed to alow-intensity proton beam by using the stacked-foils target method. Since 67Cu and 67Ga radionuclides have similar half-lives and same γ-lines (they both decay to 67Zn), a radiochemical process aimed at Cu/Ga separation was mandatory to avoid interferences in γ-spectrometry measurements. A simple chemical procedure having a high separation efficiency (>99%)was developed and monitored during each foil processing, thanks to the tracer isotopes 61Cu and 66Ga.Nuclear cross sections were measured in the energy range 35-70 MeV by using reference reactions recommended by the International Atomic Energy Agency (IAEA) to monitor beam flux. In comparison with literature data a general good agreement on the trend of the nuclear reactions was noted, especially with latest measurements, but slightly lower values were obtained in case of 67Cu. Experimental results of the 68Zn(p,2p)67Cu,68Zn(p,2n)67Ga and 68Zn(p,3n)66Ga reactions were also compared with the theoretical values estimated by using the nuclear reaction code TALYS. The production yield of the theranostic radionuclide 67Cu was estimated considering the results obtained in this work.

Resumen Las secciones eficaces de las reacciones 68Zn (p, 2p) 67Cu, 68Zn (p, 2n) 67Ga y 68Zn (p, 3n) 66Ga se midieron en la instalación ARRONAX utilizando el ciclotrón 70 MeV, con especial atención a la producción del radionucleidos teranóstico 67Cu. El material enriquecido 68Zn se galvanizó sobre soporte de plata y se expuso a un haz de protones de baja intensidad utilizando un blanco de láminas apiladas. Como los radionucleidos 67Cu y 67Ga tienen periodos de semidesintegración y líneas γ similares (ambos se desintegran a 67Zn), un proceso radioquímico dirigido a la separación Cu / Ga fue obligatorio para evitar interferencias en las mediciones de espectrometría γ. Se desarrolló un procedimiento químico simple con una alta eficiencia de separación (> 99%) durante cada procesamiento de la lámina, gracias a los isótopos trazadores 61Cu y 66Ga. Las secciones eficaces nucleares se midieron en el rango de energía de 35-70 MeV utilizando reacciones de referencia recomendadas por el Organismo Internacional de Energía Atómica (OIEA) para monitorear el flujo del haz. Al comparar con los datos de la literatura, se observó una buena concordancia en general con la tendencia de las reacciones nucleares, particularmente con las últimas mediciones, pero se obtuvieron valores ligeramente inferiores en el caso de 67Cu. Los resultados experimentales de las reacciones 68Zn (p, 2p) 67Cu, 68Zn (p, 2n) 67Ga y 68Zn (p, 3n) 66Ga también se compararon con los valores teóricos estimados usando el código de reacción nuclear TALYS. El rendimiento de producción del radionucleido teranóstico 67Cu se estimó considerando los resultados obtenidos en este trabajo.

A novel 10B-enriched carboranyl-containing phthalocyanine as a radio- and photo-sensitising agent for boron neutron capture therapy and photodynamic therapy of tumours: in vitro and in vivo studies.

The synthesis of a Zn(ii)-phthalocyanine derivative bearing four 10B-enriched o-carboranyl units (10B-ZnB4Pc) and its natural isotopic abundance analogue (ZnB4Pc) in the peripheral positions of the tetraazaisoindole macrocycle is presented. The photophysical properties of ZnB4Pc, as tested against model biological systems, were found to be similar with those typical of other photodynamically active porphyrin-type photosensitisers, including a singlet oxygen quantum yield of 0.67. The carboranyl-carrying phthalocyanine was efficiently accumulated by B16F1 melanotic melanoma cells in vitro, appeared to be partitioned in at least some subcellular organelles and, upon red light irradiation, induced extensive cell mortality. Moreover, ZnB4Pc, once i.v.-injected to C57BL/6 mice bearing a subcutaneously transplanted pigmented melanoma, photosensitised an important tumour response, provided that the irradiation at 600-700 nm was performed 3 h after the phthalocyanine administration, when appreciable concentrations of ZnB4Pc were still present in the serum. Analogously, irradiation of the 10B-ZnB4Pc-loaded pigmented melanoma with thermal neutrons 24 h after injection led to a 4 day delay in tumour growth as compared with control untreated mice. These results open the possibility to use one chemical compound as both a photosensitising and a radiosensitising agent for the treatment of tumours by the combined application of photodynamic therapy and boron neutron capture therapy.