In vivo biodistribution and tumor uptake of [64Cu]-FAU nanozeolite via positron emission tomography Imaging.

Nanoparticles have emerged as promising theranostic tools for biomedical applications, notably in the treatment of cancers. However, to fully exploit their potential, a thorough understanding of their biodistribution is imperative. In this context, we prepared radioactive [64Cu]-exchanged faujasite nanosized zeolite ([64Cu]-FAU) to conduct positron emission tomography (PET) imaging tracking in preclinical glioblastoma models. In vivo results revealed a rapid and gradual accumulation over time of intravenously injected [64Cu]-FAU zeolite nanocrystals within the brain tumor, while no uptake in the healthy brain was observed. Although a specific tumor targeting was observed in the brain, the kinetics of uptake into tumor tissue was found to be dependent on the glioblastoma model. Indeed, our results showed a rapid uptake in U87-MG model while in U251-MG glioblastoma model tumor uptake was gradual over the time. Interestingly, a [64Cu] activity, decreasing over time, was also observed in organs of elimination such as kidney and liver without showing a difference in activity between both glioblastoma models. Ex vivo analyses confirmed the presence of zeolite nanocrystals in brain tumor with detection of both Si and Al elements originated from them. This radiolabelling strategy, performed for the first time using nanozeolites, enables precise tracking through PET imaging and confirms their accumulation within the glioblastoma. These findings further bolster the potential use of zeolite nanocrystals as valuable theranostic tools.

Methodology for small animals targeted irradiations at conventional and ultra-high dose rates 65 MeV proton beam.

As part of translational research projects, mice may be irradiated on radiobiology platforms such as the one at the ARRONAX cyclotron. Generally, these platforms do not feature an integrated imaging system. Moreover, in the context of ultra-high dose-rate radiotherapy (FLASH-RT), treatment planning should consider potential changes in the beam characteristics and internal movements in the animal. A patient-like set-up and methodology has been implemented to ensure target coverage during conformal irradiations of the brain, lungs and intestines. In addition, respiratory cycle amplitudes were quantified by fluoroscopic acquisitions on a mouse, to ensure organ coverage and to assess the impact of respiration during FLASH-RT using the 4D digital phantom MOBY. Furthermore, beam incidence direction was studied from mice µCBCT and Monte Carlo simulations. Finally,in vivodosimetry with dose-rate independent radiochromic films (OC-1) and their LET dependency were investigated. The immobilization system ensures that the animal is held in a safe and suitable position. The geometrical evaluation of organ coverage, after the addition of the margins around the organs, was satisfactory. Moreover, no measured differences were found between CONV and FLASH beams enabling a single model of the beamline for all planning studies. Finally, the LET-dependency of the OC-1 film was determined and experimentally verified with phantoms, as well as the feasibility of using these filmsin vivoto validate the targeting. The methodology developed ensures accurate and reproducible preclinical irradiations in CONV and FLASH-RT without in-room image guidance in terms of positioning, dose calculation andin vivodosimetry.

Production of 203Pb from enriched 205Tl using deuteron beams.

Lead-203 is a SPECT emitter that can be used in theranostic applications as an imaging counterpart of lead-212 which is intended to be used for alpha therapy as lead-212/bismuth-212 in-vivo generator. In our study, we explore the production of lead-203 using enriched thallium-205 target irradiated by a deuteron beam. Excitation functions of deuteron induced reactions leading to the formation of 204m,203m2+m1+g,202m,201m+gPb, 202Tl and 203m+gHg isotopes were determined experimentally in the energy range from 21 MeV to 34 MeV. Cross sections were measured using the stacked foils technique and a set of two monitor foils, natNi and natTi for beam intensity evaluation. The experimental excitation functions of the investigated reactions were compared with the published data and also with the TENDL-2021 nuclear database. From our experimental data, we calculated lead-203 thick target yield in the energy range between 30 MeV and 32.5 MeV to be 56.7 MBq/µAh ±6.1 MBq/µAh. This value is compatible with large batch production showing that deuteron beams can be used for a routine production process. However, special attention must be paid to 203Hg and other lead contaminants.

Can we reach suitable 161Tb purity for medical applications using the 160Gd(d,n) reaction?

Terbium is a chemical element that has several radioactive isotopes with suitable physical characteristics to be used in medical applications either for imaging or for therapy. This makes terbium a promising element to implement the theranostic approach. For therapeutic applications, 161Tb (T1/2 = 6.89 d) is suitable for targeted ß-therapy. The main production route is through neutron capture reaction in nuclear reactors. In this work, we explored an alternative production route, the 160Gd(d,n)161Tb reaction. We have measured its production cross-section as well as those of possible co-produced contaminants, with a special focus on 160Tb (T1/2 = 72.3 d). To achieve this, cross-section measurements were made from natural gadolinium target. Production yields of 10.3 MBq/µA/h for the 161Tb and 1.5 MBq/µA/h for the 160Tb were obtained at 20 MeV. A161Tb radionuclidic purity of 86% was achieved over the 8 MeV-20 MeV energy range. The co-production of other terbium isotopes limits the interest of using higher energies. Based on the limited purity of 161Tb using the 160Gd(d,n)161Tb reaction, we conclude that it is not a production route suitable for medical applications. Although, this may be reconsidered when mass separation technique with high efficiency will be available.

Preclinical Evaluation of a 64Cu-Based Theranostic Approach in a Murine Model of Multiple Myeloma.

Although the concept of theranostics is neither new nor exclusive to nuclear medicine, it is a particularly promising approach for the future of nuclear oncology. This approach is based on the use of molecules targeting specific biomarkers in the tumour or its microenvironment, associated with optimal radionuclides which, depending on their emission properties, allow the combination of diagnosis by molecular imaging and targeted radionuclide therapy (TRT). Copper-64 has suitable decay properties (both ß+ and ß- decays) for PET imaging and potentially for TRT, making it both an imaging and therapy agent. We developed and evaluated a theranostic approach using a copper-64 radiolabelled anti-CD138 antibody, [64Cu]Cu-TE1PA-9E7.4 in a MOPC315.BM mouse model of multiple myeloma. PET imaging using [64Cu]Cu-TE1PA-9E7.4 allows for high-resolution PET images. Dosimetric estimation from ex vivo biodistribution data revealed acceptable delivered doses to healthy organs and tissues, and a very encouraging tumour absorbed dose for TRT applications. Therapeutic efficacy resulting in delayed tumour growth and increased survival without inducing major or irreversible toxicity has been observed with 2 doses of 35 MBq administered at a 2-week interval. Repeated injections of [64Cu]Cu-TE1PA-9E7.4 are safe and can be effective for TRT application in this syngeneic preclinical model of MM.

First evidence of in vivo effect of FLASH radiotherapy with helium ions in zebrafish embryos.

The ability to reduce toxicity of ultra-high dose rate (UHDR) helium ion irradiation has not been reported in vivo. Here, we tested UHDR helium ion irradiation in an embryonic zebrafish model. Our results show that UHDR helium ions spare body development and reduce spine curvature, compared to conventional dose rate.

Ultrahigh-Dose-Rate Proton Irradiation Elicits Reduced Toxicity in Zebrafish Embryos.

Purpose: Recently, ultrahigh-dose-rate radiation therapy (UHDR-RT) has emerged as a promising strategy to increase the benefit/risk ratio of external RT. Extensive work is on the way to characterize the physical and biological parameters that control the so-called "Flash" effect. However, this healthy/tumor differential effect is observable in in vivo models, which thereby drastically limits the amount of work that is achievable in a timely manner. Methods and Materials: In this study, zebrafish embryos were used to compare the effect of UHDR irradiation (8-9 kGy/s) to conventional RT dose rate (0.2 Gy/s) with a 68 MeV proton beam. Viability, body length, spine curvature, and pericardial edema were measured 4 days postirradiation. Results: We show that body length is significantly greater after UHDR-RT compared with conventional RT by 180 µm at 30 Gy and 90 µm at 40 Gy, while pericardial edema is only reduced at 30 Gy. No differences were obtained in terms of survival or spine curvature. Conclusions: Zebrafish embryo length appears as a robust endpoint, and we anticipate that this model will substantially fasten the study of UHDR proton-beam parameters necessary for "Flash."

Therapeutic efficacy of 166Holmium siloxane in microbrachytherapy of induced glioblastoma in minipig tumor model.

Glioblastoma is considered the most common malignant primary tumor of central nervous system. In spite of the current standard and multimodal treatment, the prognosis of glioblastoma is poor. For this reason, new therapeutic approaches need to be developed to improve the survival time of the glioblastoma patient. In this study, we performed a preclinical experiment to evaluate therapeutic efficacy of 166Ho microparticle suspension administered by microbrachytherapy on a minipig glioblastoma model. Twelve minipigs were divided in 3 groups. Minipigs had injections into the tumor, containing microparticle suspensions of either 166Ho (group 1; n = 6) or 165Ho (group 2; n = 3) and control group (group 3; n = 3). The survival time from treatment to euthanasia was 66 days with a good state of health of all minipigs in group 1. The median survival time from treatment to tumor related death were 8.6 and 7.3 days in groups 2 and control, respectively. Statistically, the prolonged life of group 1 was significantly different from the two other groups (p < 0.01), and no significant difference was observed between group 2 and control (p=0.09). Our trial on the therapeutic effect of the 166Ho microparticle demonstrated an excellent efficacy in tumor control. The histological and immunohistochemical analysis showed that the efficacy was related to a severe 166Ho induced necrosis combined with an immune response due to the presence of the radioactive microparticles inside the tumors. The absence of reflux following the injections confirms the safety of the injection device.

Proton Irradiations at Ultra-High Dose Rate vs. Conventional Dose Rate: Strong Impact on Hydrogen Peroxide Yield.

During ultra-high dose rate (UHDR) external radiation therapy, healthy tissues appear to be spared while tumor control remains the same compared to conventional dose rate. However, the understanding of radiochemical and biological mechanisms involved are still to be discussed. This study shows how the hydrogen peroxide (H2O2) production, one of the reactive oxygen species (ROS), could be controlled by early heterogenous radiolysis processes in water during UHDR proton-beam irradiations. Pure water was irradiated in the plateau region (track-segment) with 68 MeV protons under conventional (0.2 Gy/s) and several UHDR conditions (40 Gy/s to 60 kGy/s) at the ARRONAX cyclotron. Production of H2O2 was then monitored using the Ghormley triiodide method. New values of GTS(H2O2) were added in conventional dose rate. A substantial decrease in H2O2 production was observed from 0.2 to 1.5 kGy/s with a more dramatic decrease below 100 Gy/ s. At higher dose rate, up to 60 kGy/s, the H2O2 production stayed stable with a mean decrease of 38% ± 4%. This finding, associated to the decrease in the production of hydroxyl radical (•OH) already observed in other studies in similar conditions can be explained by the well-known spur theory in radiation chemistry. Thus, a two-step FLASH-RT mechanism can be envisioned: an early step at the microsecond scale mainly controlled by heterogenous radiolysis, and a second, slower, dominated by O2 depletion and biochemical processes. To validate this hypothesis, more measurements of radiolytic species will soon be performed, including radicals and associated lifetimes.

Technical note: Proton beam dosimetry at ultra-high dose rates (FLASH): Evaluation of GAFchromic™ (EBT3, EBT-XD) and OrthoChromic (OC-1) film performances.

PURPOSE: The ARRONAX cyclotron facility offers the possibility to deliver proton beams from low to ultra-high dose rates (UHDR). As a good control of the dosimetry is a prerequisite of UHDR experimentations, we evaluated in different conditions the usability and the dose rate dependency of several radiochromic films commonly used for dosimetry in radiotherapy. METHODS: We compared the dose rate dependency of three types of radiochromic films: GAFchromic™ EBT3 and GAFchromic™ EBT-XD (Ashland Inc., Wayne, NJ, USA), and OrthoChromic OC-1 (OrthoChrome Inc., Hillsborough, NJ, USA), after proton irradiations at various mean dose rates (0.25, 40, 1500, and 7500 Gy/s) and for 10 doses (2-130 Gy). We also evaluated the dose rate dependency of each film considering beam structures, from single pulse to multiple pulses with various frequencies. RESULTS: EBT3 and EBT-XD films showed differences of response between conventional (0.25 Gy/s) and UHDR (7500 Gy/s) conditions, above 10 Gy. On the contrary, OC-1 films did not present overall difference of response for doses except below 3 Gy. We observed an increase of the netOD with the mean dose rate for EBT3 and EBT-XD films. OC-1 films did not show any impact of the mean dose rate up to 7500 Gy/s, above 3 Gy. No difference was found based on the beam structure, for all three types of films. CONCLUSIONS: EBT3 and EBT-XD radiochromic films should be used with caution for the dosimetry of UHDR proton beams over 10 Gy. Their overresponse, which increases with mean dose rate and dose, could lead to non-negligible overestimations of the absolute dose. OC-1 films are dose rate independent up to 7500 Gy/s in proton beams. Films response is not impacted by the beam structure. A broader investigation of the usability of OC-1 films in UHDR conditions should be conducted at intermediate and higher mean dose rates and other beam energies.

CERN-MEDICIS: A Review Since Commissioning in 2017.

The CERN-MEDICIS (MEDical Isotopes Collected from ISolde) facility has delivered its first radioactive ion beam at CERN (Switzerland) in December 2017 to support the research and development in nuclear medicine using non-conventional radionuclides. Since then, fourteen institutes, including CERN, have joined the collaboration to drive the scientific program of this unique installation and evaluate the needs of the community to improve the research in imaging, diagnostics, radiation therapy and personalized medicine. The facility has been built as an extension of the ISOLDE (Isotope Separator On Line DEvice) facility at CERN. Handling of open radioisotope sources is made possible thanks to its Radiological Controlled Area and laboratory. Targets are being irradiated by the 1.4 GeV proton beam delivered by the CERN Proton Synchrotron Booster (PSB) on a station placed between the High Resolution Separator (HRS) ISOLDE target station and its beam dump. Irradiated target materials are also received from external institutes to undergo mass separation at CERN-MEDICIS. All targets are handled via a remote handling system and exploited on a dedicated isotope separator beamline. To allow for the release and collection of a specific radionuclide of medical interest, each target is heated to temperatures of up to 2,300°C. The created ions are extracted and accelerated to an energy up to 60 kV, and the beam steered through an off-line sector field magnet mass separator. This is followed by the extraction of the radionuclide of interest through mass separation and its subsequent implantation into a collection foil. In addition, the MELISSA (MEDICIS Laser Ion Source Setup At CERN) laser laboratory, in service since April 2019, helps to increase the separation efficiency and the selectivity. After collection, the implanted radionuclides are dispatched to the biomedical research centers, participating in the CERN-MEDICIS collaboration, for Research & Development in imaging or treatment. Since its commissioning, the CERN-MEDICIS facility has provided its partner institutes with non-conventional medical radionuclides such as Tb-149, Tb-152, Tb-155, Sm-153, Tm-165, Tm-167, Er-169, Yb-175, and Ac-225 with a high specific activity. This article provides a review of the achievements and milestones of CERN-MEDICIS since it has produced its first radioactive isotope in December 2017, with a special focus on its most recent operation in 2020.

A Monte Carlo Determination of Dose and Range Uncertainties for Preclinical Studies with a Proton Beam.

Proton therapy (PRT) is an irradiation technique that aims at limiting normal tissue damage while maintaining the tumor response. To study its specificities, the ARRONAX cyclotron is currently developing a preclinical structure compatible with biological experiments. A prerequisite is to identify and control uncertainties on the ARRONAX beamline, which can lead to significant biases in the observed biological results and dose-response relationships, as for any facility. This paper summarizes and quantifies the impact of uncertainty on proton range, absorbed dose, and dose homogeneity in a preclinical context of cell or small animal irradiation on the Bragg curve, using Monte Carlo simulations. All possible sources of uncertainty were investigated and discussed independently. Those with a significant impact were identified, and protocols were established to reduce their consequences. Overall, the uncertainties evaluated were similar to those from clinical practice and are considered compatible with the performance of radiobiological experiments, as well as the study of dose-response relationships on this proton beam. Another conclusion of this study is that Monte Carlo simulations can be used to help build preclinical lines in other setups.

Targeted-Alpha-Therapy Combining Astatine-211 and anti-CD138 Antibody in A Preclinical Syngeneic Mouse Model of Multiple Myeloma Minimal Residual Disease.

Despite therapeutic progress in recent years with the introduction of targeted therapies (daratumumab, elotuzumab), multiple myeloma remains an incurable cancer. The question is therefore to investigate the potential of targeted alpha therapy, combining an anti-CD138 antibody with astatine-211, to destroy the residual cells that cause relapses. A preclinical syngeneic mouse model, consisting of IV injection of 1 million of 5T33 cells in a KaLwRij C57/BL6 mouse, was treated 10 days later with an anti-mCD138 antibody, called 9E7.4, radiolabeled with astatine-211. Four activities of the 211At-9E7.4 radioimmunoconjugate were tested in two independent experiments: 370 kBq (n = 16), 555 kBq (n = 10), 740 kBq (n = 17) and 1100 kBq (n = 6). An isotype control was also tested at 555 kBq (n = 10). Biodistribution, survival rate, hematological parameters, enzymatic hepatic toxicity, histological examination and organ dosimetry were considered. The survival median of untreated mice was 45 days after engraftment. While the activity of 1100 kBq was highly toxic, the activity of 740 kBq offered the best efficacy with 65% of overall survival 150 days after the treatment with no evident sign of toxicity. This work demonstrates the pertinence of treating minimal residual disease of multiple myeloma with an anti-CD138 antibody coupled to astatine-211.

ARRONAX Cyclotron: Setting up of In-House Hospital Radiopharmacy.

Whilst radiopharmaceuticals have an important role to play in both imaging and treatment of patients, most notably cancer patients, nuclear medicine and radiopharmacy are currently facing challenges to create innovative new drugs. Traditional radiopharmaceutical manufacture can be considered as either a routine hospital production or a large-scale industrial production. The gap between these two practices has meant that there is an inability to supply innovative radiopharmaceuticals for use at the local level for mono- or multicentric clinical trials with satisfactory quality and safety specifications. This article highlights the regulatory requirements in aseptic pharmaceutical processing and in nuclear medicine to be able to locally produce radiopharmaceuticals. We validate the proof-of-concept for an "in-house" hospital-based radiopharmacy including an on-site cyclotron, that can fulfill the conflicting requirements between radiation safety and aseptic processing. The ARRONAX in-house radiopharmacy is currently able to provide sterile and pyrogenic-free injectable radiopharmaceutical compounds for both industrial and institutional clinical trials.

What is the Best Radionuclide for Immuno-PET of Multiple Myeloma? A Comparison Study Between 89Zr- and 64Cu-Labeled Anti-CD138 in a Preclinical Syngeneic Model.

Although positron emission tomography (PET) imaging with 18-Fluorodeoxyglucose (18F-FDG) is a promising technique in multiple myeloma (MM), the development of other radiopharmaceuticals seems relevant. CD138 is currently used as a standard marker for the identification of myeloma cells and could be used in phenotype tumor imaging. In this study, we used an anti-CD138 murine antibody (9E7.4) radiolabeled with copper-64 (64Cu) or zirconium-89 (89Zr) and compared them in a syngeneic mouse model to select the optimal tracers for MM PET imaging. Then, 9E7.4 was conjugated to TE2A-benzyl isothiocyanate (TE2A) and desferrioxamine (DFO) chelators for 64Cu and 89Zr labeling, respectively. 64Cu-TE2A-9E7.4 and 89Zr-DFO-9E7.4 antibodies were evaluated by PET imaging and biodistribution studies in C57BL/KaLwRij mice bearing either 5T33-MM subcutaneous tumors or bone lesions and were compared to 18F-FDG-PET imaging. In biodistribution and PET studies, 64Cu-TE2A-9E7.4 and 89Zr-DFO-9E7.4 displayed comparable good tumor uptake of subcutaneous tumors. On the bone lesions, PET imaging with 64Cu-TE2A-9E7.4 and 89Zr-DFO-9E7.4 showed higher uptake than with 18F-FDG-PET. Comparison of both 9E7.4 conjugates revealed higher nonspecific bone uptakes of 89Zr-DFO-9E7.4 than 64Cu-TE2A-9E7.4. Because of free 89Zr's tropism for bone when using 89Zr-anti-CD138, 64Cu-anti-CD138 antibody had the most optimal tumor-to-nontarget tissue ratios for translation into humans as a specific new imaging radiopharmaceutical agent in MM.

Promising Scandium Radionuclides for Nuclear Medicine: A Review on the Production and Chemistry up to In Vivo Proofs of Concept.

Scandium radionuclides have been identified in the late 1990s as promising for nuclear medicine applications, but have been set aside for about 20 years. Among the different isotopes of scandium, 43Sc and 44Sc are interesting for positron emission tomography imaging, whereas 47Sc is interesting for therapy. The 44Sc/47Sc or 43Sc/47Sc pairs could be thus envisaged as true theranostic pairs. Another interesting aspect of scandium is that its chemistry is governed by the trivalent ion, Sc3+. When combined with its hardness and its size, it gives this element a lanthanide-like behavior. It is then also possible to use it in a theranostic approach in combination with 177Lu or other lanthanides. This article aims to review the progresses that have been made over the last decade on scandium isotope production and coordination chemistry. It also reviews the radiolabeling aspects and the first (pre) clinical studies performed.

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.

Synthesis of C-functionalized TE1PA and comparison with its analogues. An example of bioconjugation on 9E7.4 mAb for multiple myeloma 64Cu-PET imaging.

In view of the excellent copper(ii) and 64-copper(ii) complexation of a TE1PA ligand, a monopicolinate cyclam, in both aqueous medium and in vivo, we looked for a way to make it bifunctional, while maintaining its chelating properties. Overcoming the already known drawback of grafting via its carboxyl group, which is essential to the overall properties of the ligand, a TE1PA bifunctional derivative bearing an additional isothiocyanate coupling function on a carbon atom of the macrocyclic ring was synthesized. This led to an architecture that is comparable to that of other commercially available bifunctional copper(ii) chelators such as p-SCN-Bn-DOTA already used in clinical trials for 64Cu-immuno-PET imaging. The C-functionalization of TE1PA on one carbon atom in the ß-N position of the cyclam backbone was successfully achieved by adapting our patented methodology to the huge challenge, allowing the regiospecific mono-N-functionalization of the unsymmetrical ligand. The obtained ligand p-SCN-Bn-TE1PA was coupled to a 9E7.4 murine antibody (mAb), an IgG2a anti CD-138 for multiple myeloma (MM) targeting. The conjugation efficiency was assessed by looking at the 64Cu radiolabeling and the radiopharmaceutical 64Cu-9E7.4-p-SCN-Bn-TE1PA immunoreactivity, and in particular by comparing with 9E7.4-p-SCN-Bn-NOTA and 9E7.4-p-SCN-Bn-DOTA obtained from commercial and presumably highly efficient chelators NOTA and DOTA, respectively. The results are quite clear, showing that p-SCN-Bn-TE1PA has a coupling rate 5 times higher and an immunoreactivity 1.5 to 2 times greater than those of its two competitors. p-SCN-Bn-TE1PA also outperforms TE1PA conjugated via its carboxylic function on the same antibody. The first 64Cu-immuno-PET preclinical study in a syngeneic model of MM was performed, confirming the good in vivo properties of 64Cu-9E7.4-p-SCN-Bn-TE1PA for PET imaging, considering the high clearance even after 24 h and the particularly important tumor-to-liver ratio that was increasing at 48 h.