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.

Molecular imaging is redefining in vivo characterization of multiple sclerosis, a demyelinating disease with complex and heterogeneous clinical profiles. Recent advances in PET tracers enable more specific detection of pathologic features beyond conventional MRI. Among them, [18F]3F4AP-a fluorinated analog of 4-aminopyridine-targets voltage-gated potassium channels that become exposed after demyelination, offering a promising tool to detect myelin loss. Similarly, [11C]PiB and [11C]MeDAS, originally developed for amyloid and myelin imaging, respectively, exhibit high affinity for myelin, allowing direct assessment of white matter integrity. In particular, [11C]MeDAS shows selective binding to intact myelin sheaths and strong correlation with histologic myelin content in preclinical models. These agents have demonstrated utility in both animal studies and early clinical investigations, supporting their translational relevance. This review focuses on the pharmacologic properties, imaging protocols, and developmental progress of PET tracers that directly or indirectly reflect demyelination, advancing personalized approaches to diagnosis, monitoring, and therapeutic evaluation in multiple sclerosis.

Nectin cell adhesion molecule 4 (Nectin-4) is specifically overexpressed in most cancers of epithelial origin but downregulated in normal tissue, representing an ideal target for positron emission tomography imaging. The development of positron emission tomography imaging probes targeting Nectin-4 has gained significant attention in recent years, especially after the approval in December 2019 by the US Food and Drug Administration of enfortumab vedotin-an antibody drug conjugate targeting Nectin-4-in patients with locally advanced or metastatic bladder cancer. This article aims to comprehensively review original research articles discussing preclinical development or early translational clinical applications of radiolabeled probes targeting Nectin-4. The main radioactive compounds investigated belong to two classes, antibody-based radiopharmaceuticals and peptide-drug conjugates, in particular novel bicyclic peptides. While monoclonal antibody-based probes have demonstrated theranostic potential in preclinical studies, their clinical application has been hindered by their slow pharmacokinetic properties. However, peptide-based positron emission tomography/computed tomography tracers offer several advantages, such as ease of handling in synthesis, a more favorable biodistribution, and lower immunogenicity and have been tested in preliminary clinical experiences.

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.

Cancer therapy has advanced with molecularly targeted approaches and immunotherapy, yet chemotherapy remains essential for many aggressive cancers, including breast, lung, ovarian, pancreatic, bladder, sarcoma, and lymphomas. A major challenge is chemoresistance, in which cancer cells evade chemotherapy's cytotoxic effects. Overexpression of adenosine triphosphate-binding cassette transporters, especially P-glycoprotein, significantly contributes to this resistance. Thus, imaging biomarkers are urgently needed to detect P-glycoprotein overexpression in vivo, identify resistant cancer cell clones, and map their distribution and heterogeneity within tumors. This article reviews the applications of SPECT, PET, and optical imaging in addressing chemoresistance. It emphasizes the potential of these modalities to enhance cancer treatment by enabling early identification of resistant clones and improving therapeutic strategies. The article outlines key steps required for the integration of molecular imaging into clinical practice, aiming to overcome chemoresistance and optimize patient outcomes.

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.

BACKGROUND:In recent years, fibroblast activating protein (FAP), a biomarker overexpressed by cancer-associated fibroblasts, has emerged as one of the most promising biomarkers in oncology. Similarly, FAP overexpression has been detected in various fibroblast-mediated inflammatory conditions such as liver cirrhosis and idiopathic pulmonary fibrosis. Along this trajectory, FAP-targeted positron emission tomography (PET), utilizing FAP inhibitors (FAPi) labeled with positron emitters, has gained traction as a powerful imaging approach in both cancer and inflammation. However, PET represents a high-cost technology, and its widespread adoption is still limited compared to the availability of gamma cameras. To address this issue, several efforts have been made to explore the potential of [99mTc]Tc-FAPi tracers as molecular probes for imaging with gamma cameras and single photon emission computed tomography (SPECT).MAIN BODY:Several approaches have been investigated for labeling FAPi-based compounds with 99mTc. Specifically, the mono-oxo, tricarbonyl, isonitrile, and HYNIC strategies have been applied to produce [99mTc]Tc-FAPi tracers, which have been tested in vitro and in animal models. Overall, these labeling approaches have demonstrated high efficiency and strong binding. The resulting [99mTc]Tc-FAPi tracers have shown high specificity for FAP-positive cells and xenografts in both in vitro and animal model studies, respectively. However, the majority of [99mTc]Tc-FAPi tracers have exhibited variable levels of lipophilicity, leading to preferential excretion through the hepatobiliary route and undesirable binding to lipoproteins. Consequently, efforts have been made to synthesize more hydrophilic FAPi-based compounds to improve pharmacokinetic properties and achieve a more favorable biodistribution, particularly in the abdominal region. SPECT imaging with [99mTc]Tc-FAPi has yielded promising results in patients with gastrointestinal tumors, demonstrating comparable or superior diagnostic performance compared to other imaging modalities. Similarly, encouraging outcomes have been observed in subjects with gliomas, lung cancer, breast cancer, and cervical cancer. Beyond oncological applications, [99mTc]Tc-FAPi-based imaging has been successfully employed in myocardial and idiopathic pulmonary fibrosis.CONCLUSIONS:This overview focuses on the various radiochemical strategies for obtaining [99mTc]Tc-FAPi tracers, highlighting the main challenges encountered and possible solutions when applying each distinct approach. Additionally, it covers the preclinical and initial clinical applications of [99mTc]Tc-FAPi in cancer and inflammation.

Technetium-99m is the workhorse of diagnostic nuclear medicine. The aim of the work is to analyze the technetium-99m patents since 2000 to photograph its innovation. QUESTEL's ORBIT Intelligence system was used for the collection of technetium inventions disclosed in patents and patent applications in more than 96 countries in the period 2000-2022; 2768 patent documents were analyzed. Patent counting and analysis have shown that SPECT imaging using technetium-99m radiopharmaceuticals is still robust. The introduction of new technetium-99m radiopharmaceuticals into clinical routine goes beyond successful trials. In eastern economies, such as China and other emerging markets, patent applications are on the rise, while those in developed western countries are stagnating, with some exceptions for the United States. But despite the difficulties, academic and industrial research on these tracers remains essential for the development of nuclear medicine.

The production of medical radionuclides is one of the research activities carried out in the framework of the SPES (Selective Production of Exotic Species) project under the completion stage at the Legnaro National Laboratories of the National Institute for Nuclear Physics (INFN-LNL). The heart of SPES is the 70-MeV proton cyclotron having a dual-beam extraction, installed and commissioned in a new building equipped with ancillary laboratories currently under construction. The SPES main goal is the realization of an advanced ISOL (Isotope Separation On-Line) facility to produce re-accelerated exotic ion beams for fundamental nuclear physics studies. The cyclotron double-beam extraction system allows to simultaneously carry out applied research, such as radionuclides production for medicine (SPES- γ ). This paper summarizes the results obtained with the interdisciplinary projects LARAMED (LAboratory of RAdionuclides for MEDicine) and ISOLPHARM (ISOL technique for radioPHARMaceuticals). The first one, based upon the direct activation method, is focused on the production of the radionuclides under the spotlight of the international community (e.g., ^99m Tc, ^67 Cu, ^52/51 Mn, ^47 Sc and Tb isotopes), from the nuclear cross-section measurements up to the preclinical studies. The other one exploits the ISOL technique for the development and production of radioisotopes with high-specific activity, such as ^111 Ag, going beyond the state of the art in the field. The most recent SPES- γ research activities and future perspective are here described, characterized by a consolidated network of collaborations with national and international institutions.

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.

The present work reports the status of the LAboratory of RAdionuclides for MEDicine facility, as part of the Selective Production of Exotic Species research infrastructure under completion, along with the main project outcomes gained during the last years, thanks to an ongoing fruitful network of collaborations. The interdisciplinary aspects of the production of medically-relevant radionuclides, such as 67 Cu, 47 Sc, 52 Mn etc., are shown, including the latest technological achievements in targetry, radiochemistry, and applied nuclear physics.

The REMIX project is focused on the cyclotron-based production of 47 Sc, 149 Tb, 152 Tb, 155 Tb and 161 Tb radionuclides, whose decay characteristics make them suitable for medical applications. This work will outline the main results achieved withing the REMIX collaboration, that is organized in the following Work Packages (WP): WP1. Target manufacturing ( 49 Ti, 50 Ti and 155 Gd 2 O 3 ) and characterization; WP2. Nuclear cross section (XS) measurements with 49 Ti and 50 Ti targets for 47 Sc production; WP3. Nuclear XS measurements with nat Dy, 159 Tb and nat Eu targets for xx Tb production; WP4. Nuclear XS modeling for 47 Sc and 155 Tb production; WP5. Dosimetric calculations for 47 Sc- and xx Tb-labelled radiopharmaceuticals; WP6. 155 Tb Thick Target Yield (TTY) measurements; WP7. Apparatus design and realization for irradiation tests with the LARAMED beamline. Since the LARAMED bunkers and ancillary laboratories are currently under completion at the INFN-LNL, the nuclear XS experiments are carried out in collaboration with the GIP ARRONAX facility (Saint-Herblain, France) and the Thick Target Yield (TTY) measurements are performed at the Sacro Cuore Don Calabria hospital (SCDCh, Negrar, Verona, Italy).