The growing demand for medical radiometals calls for more sustainable production strategies that minimize waste and improve resource efficiency. Herein, we present a circular radiometal chemistry approach for the cyclotron-based production of copper radioisotopes using a medical cyclotron and natZnO targets. The workflow integrates irradiation, radiochemical separation, and material recovery within a closed-loop system inspired by the waste-as-resource principles. natZnO targets were produced using Spark Plasma Sintering and subsequently irradiated at 17.9 MeV, 20 μA for up to 1 h. Following proton irradiation and primary separation of the produced 61Cu (up to 969 MBq at the End Of Bombardment), co-produced gallium radioisotopes were successfully recovered from post-separation waste streams through a two-step chromatographic process, achieving 85% and 89% recovery yields for copper and gallium isotopes, respectively. Both the produced copper and gallium isotopes were successfully employed in radiolabeling and apparent molar activity (AMA) studies with radiopharmaceutical ligands, achieving AMA values of up to 3.55 GBq/μmol and 4.01 GBq/μmol for copper and gallium, respectively. In addition, targets produced from natZnO recovered via a precipitation-based method (recovery yield up to 85%) were successfully irradiated, confirming the feasibility of material reintegration into the production cycle. This work establishes a scalable proof-of-concept for a circular workflow in radiometal production by combining gallium recovery and zinc recycling. This approach reduces waste generation and improves possible utilization of enriched materials, resulting in a more sustainable access to emerging theranostic radionuclides such as copper and gallium radioisotopes.

Background/Objectives: Intrinsic genetic instability and the marked heterogeneity of malignant cell populations represent significant clinical challenges in oncology, often limiting the efficacy of conventional receptor-targeted and antigen-based therapies. To overcome these limitations, [64Cu]CuCl2 has emerged as a particularly promising theranostic agent because it combines PET imaging (β+ emission) with therapeutic effects (β- particles and Auger electrons). In particular, Auger electrons, when delivered to the cell nucleus, induce severe DNA damage due to their high linear energy transfer and very short tissue range. This work aimed to deepen existing preclinical knowledge by providing a comprehensive in vitro analysis of the interactions of [64Cu]CuCl2 with various human cancer cell lines-specifically, the breast adenocarcinoma (MDAf-MB-231) and gastric carcinoma (NCI-N87) cell lines-and a healthy control (IMR-90 normal human fetal lung fibroblasts). Methods: We focused on evaluating cellular uptake, subcellular localization, impact on metabolic activity, and induction of apoptosis. Cell lines (MDA-MB-231, NCI-N87, IMR-90) were exposed to increasing activities of [64Cu]CuCl2 (10, 100, and 250 µCi/mL). Uptake was assessed in both nuclear and cytoplasmic compartments after 4 h. Metabolic activity and apoptosis/necrosis were evaluated at 96 and 120 h post-treatment. Results: Tumor cell lines demonstrated significantly higher [64Cu]CuCl2 uptake, particularly at the nuclear level, compared to healthy controls. A marked decrease in metabolic activity and an increase in apoptosis were observed in MDA-MB-231 and NCI-N87 cells (from 50% to 90% and 5% to 60% apoptosis, respectively). In contrast, IMR-90 cells exhibited minimal cytotoxic response (≤20%), suggesting a preferential response in the malignant cell models tested. Conclusions: [64Cu]CuCl2 induced distinct patterns of intracellular accumulation and biological response among the investigated cell models, with cancer cells displaying greater nuclear uptake and apoptotic susceptibility than non-malignant cells. These findings provide a high-resolution radiobiological baseline and microdosimetric validation, supporting the rigorous design of future, dedicated in vivo preclinical investigations to evaluate the translational potential of ionic [64Cu]CuCl2.

This work reports on the successful use of the Spark Plasma Sintering (SPS) process for the densification of the zinc oxide (ZnO) powder (<5 mu m size) to manufacture solid thick targets for cyclotron-based production of radionuclides. The complete technological cycle for ZnO pellet sintering and its adhesion to the metallic backing to create a coin-shaped target structure is discussed. Different technological approaches were demonstrated, including sintering in series and parallel. To investigate the structural changes that occur during the rapid densification process, SEM and XRD analyses were performed on ZnO powder and pellets. The metallurgical interface analysis was carried out on the final target to acknowledge the adhesion quality between the different materials (metals and ceramics). The thermomechanical stability of targets was tested under different proton beam irradiation currents at the solid target station of a medical cyclotron. All the experiments were performed with natural ZnO powder to demonstrate the reproducibility of the results (relative densities higher than 95 % and low material losses of 2.5 +/- 1.9 %, n = 49). This would ensure in the future that enriched [Zn-70]ZnO material can be used to produce pure copper-67 (Cu-67) radionuclide through cyclotron irradiation. Furthermore, a strategy for the chemical recovery of ZnO pellets into their original powder form after dissolution was studied. The recovery yield of ZnO achieved an average of 84.9 +/- 4.7 % (n = 15). This result demonstrates the efficacy of the optimised precipitation method with NaOH. The recovered powder was successfully reused for the manufacture of a new target.

Endometriosis is a highly prevalent, chronic gynecological disorder characterized by the ectopic presence of endometrial-like tissue, driving significant morbidity and chronic pelvic pain. Pathologically, it is increasingly recognized as a fibro-inflammatory condition involving extensive tissue remodeling and fibrosis. Current conventional imaging modalities, including ultrasound and MRI, are primarily morphological, while standard molecular imaging using Positron Emission Tomography (PET) tracers has shown limited diagnostic utility. [18F]Fluorodeoxyglucose (FDG) suffers from high physiological uptake in pelvic organs and inconsistent detection of lesions. Receptor-based tracers like [68Ga]Ga-DOTATATE have demonstrated uncertain efficacy. In contrast, radiopharmaceuticals targeting the Fibroblast Activation Protein (FAP) offer a promising molecular approach. FAP is specifically overexpressed by activated fibroblasts present in the stroma of endometriotic lesions, correlating significantly with tissue fibrosis (collagen content) and local immune infiltration (e.g., CD68 macrophages). This comprehensive review analyzes the landscape of radiopharmaceuticals for endometriosis imaging, contrasting the specific limitations of traditional metabolic and receptor agents with the molecular rationale and emerging evidence supporting the use of FAP Inhibitors (FAPI), positioning them as crucial, non-invasive tools for the future diagnosis and management of this challenging disease.

Background/Objectives: Molecular imaging, especially PET, has advanced significantly, shifting from metabolic radiotracers like 2-deoxy-2-[18F]fluoro-D-glucose [18F]FDG to target-specific probes. Among these, αvβ6-integrin has emerged as a promising target in cancer and non-cancer diseases. This review focuses on the radiochemical properties and initial clinical applications of the [68Ga]Ga-Trivehexin PET probe. Methods: The literature review on [68Ga]Ga-Trivehexin systematically evaluated both preclinical and clinical studies, with particular emphasis on its radiochemical characteristics and preliminary clinical applications, while highlighting advancements, associated challenges, and the potential for future developments in the field. Results: This study highlights the significant advancements achieved with [68Ga]Ga-Trivehexin in the field of molecular imaging. The optimized multimeric system has substantially enhanced the radiotracer’s pharmacokinetic properties, binding affinity, and selectivity for αvβ6 integrin, demonstrating up to an 18-fold improvement compared to previous monomeric tracers. The synthesis protocol has been refined to achieve high radiochemical purity (>95%), essential for safe clinical use. Preliminary clinical applications, particularly in head and neck cancer (HNC) and pancreatic ductal adenocarcinoma (PDAC), have shown promising results, with high detection rates and improved differential diagnosis compared to [18F]FDG. Furthermore, [68Ga]Ga-Trivehexin PET/CT has shown potential in non-oncological conditions, such as idiopathic pulmonary fibrosis (IPF) and primary hyperthyroidism, suggesting broader clinical applicability. Conclusions: [68Ga]Ga-Trivehexin is a promising PET probe for imaging αvβ6-integrin in cancers and non-oncological diseases like idiopathic pulmonary fibrosis (IPF) and primary hyperparathyroidism (PHP).

64Cu is gaining recognition not only for its diagnostic capabilities in nuclear medical imaging but also for its therapeutic and theranostic potential. The simultaneous βˉ and Auger emissions of 64Cu can be utilized to induce a therapeutic effect on cancerous lesions. The finding of the exceptional biodistribution characteristics of the radionuclide 64Cu, when administered as basic copper ions, has highlighted its potential therapeutic application in cancer treatment. Preclinical and clinical research on the effectiveness of [64Cu]CuCl2 as a theranostic radiopharmaceutical has commenced only in the past decade. Current clinical studies are increasingly demonstrating the high specificity and uptake of [64Cu]Cu2+ by malignant tissues during early cancer progression, indicating its potential for early cancer diagnosis across various organs. This short review aims to present the latest preclinical studies involving [64Cu]CuCl2, offering valuable insights for researchers planning new in vitro and in vivo studies to explore the theranostic potential of [64Cu]Cu2+.

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.

The present study investigates the possible use of manganese (Mn)-based liposomal formulations for diagnostic applications in imaging techniques such as magnetic resonance imaging (MRI), with the aim of overcoming the toxicity limitations associated with the use of free Mn2+. Specifically, anionic liposomes carrying two model Mn(II)-based compounds, MnCl2 (MC) and Mn(HMTA) (MH), were prepared and characterised in terms of morphology, size, loading capacity, and in vitro activity. Homogeneous dispersions characterised mainly by unilamellar vesicles were obtained; furthermore, no differences in size and morphology were detected between unloaded and Mn-loaded vesicles. The encapsulation efficiency of MC and MH was evaluated on extruded liposomes by means of ICP-OES analysis. The obtained results showed that both MC and MH are almost completely retained by the lipid portion of liposomes (LPs), with encapsulation efficiencies of 99.7% for MC and 98.8% for MH. The magnetic imaging properties of the produced liposomal formulations were investigated for application in a potential preclinical scenario by collecting magnetic resonance images of a phantom designed to compare the paramagnetic contrast properties of free MC and MH compounds and the corresponding manganese-containing liposome dispersions. It was found that both LP-MC and LP-MH at low concentrations (0.5 mM) show better contrast (contrast-to-noise ratios of 194 and 209, respectively) than solutions containing free Mn at the same concentrations (117 and 134, respectively) and are safe to use on human cells at the selected dose. Taken together, the results of this comparative analysis suggest that these liposome-containing Mn compounds might be suitable for diagnostic purposes.

Lutathera® is the first EMA- and FDA-approved radiopharmaceutical for radioligand therapy (RLT). Currently, on the legacy of the NETTER1 trial, only adult patients with progressive unresectable somatostatin receptor (SSTR) positive gastroenteropancreatic (GEP) neuroendocrine neoplasms (NET) can be treated with Lutathera®. Conversely, patients with SSTR-positive disease arising from outside the gastroenteric region do not currently have access to Lutathera® treatment despite several papers in the literature reporting the effectiveness and safety of RLT in these settings. Moreover, patients with well-differentiated G3 GEP-NET are also still “Lutathera orphans”, and retreatment with RLT in patients with disease relapse is currently not approved. The aim of this critical review is to summarize current literature evidence assessing the role of Lutathera® outside the approved indications. Moreover, ongoing clinical trials evaluating new possible applications of Lutathera® will be considered and discussed to provide an updated picture of future investigations.

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.