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.

Metal-Based Radiopharmaceuticals in Inorganic Chemistry.

The field of radiopharmaceuticals is constantly evolving thanks to the great contribution of specialists coming from different disciplines such as inorganic chemistry, radiochemistry, organic and biochemistry, pharmacology, nuclear medicine, physics, etc [...].

Technetium-99m Radiopharmaceuticals for Ideal Myocardial Perfusion Imaging: Lost and Found Opportunities.

The favorable nuclear properties in combination with the rich coordination chemistry make technetium-99m the radioisotope of choice for the development of myocardial perfusion tracers. In the early 1980s, [99mTc]Tc-Sestamibi, [99mTc]Tc-Tetrofosmin, and [99mTc]Tc-Teboroxime were approved as commercial radiopharmaceuticals for myocardial perfusion imaging in nuclear cardiology. Despite its peculiar properties, the clinical use of [99mTc]Tc-Teboroxime was quickly abandoned due to its rapid myocardial washout. Despite their widespread clinical applications, both [99mTc]Tc-Sestamibi and [99mTc]Tc-Tetrofosmin do not meet the requirements of an ideal perfusion imaging agent due to their relatively low first-pass extraction fraction and high liver absorption. An ideal radiotracer for myocardial perfusion imaging should have a high myocardial uptake; a high and stable target-to-background ratio with low uptake in the lungs, liver, stomach during the image acquisition period; a high first-pass myocardial extraction fraction and very rapid blood clearance; and a linear relationship between radiotracer myocardial uptake and coronary blood flow. Although it is difficult to reconcile all these properties in a single tracer, scientific research in the field has always channeled its efforts in the development of molecules that are able to meet the characteristics of ideality as much as possible. This short review summarizes the developments in 99mTc myocardial perfusion tracers, which are able to fulfill hitherto unmet medical needs and serve a large population of patients with heart disease, and underlines their strengths and weaknesses, the lost and found opportunities thanks to the developments of the new ultrafast SPECT technologies.

Synthetic and Nanotechnological Approaches for a Diagnostic Use of Manganese.

The development of multimodal imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) allows the contemporary obtaining of metabolic and morphological information. To fully exploit the complementarity of the two imaging modalities, the design of probes displaying radioactive and magnetic properties at the same time could be very beneficial. In this regard, transition metals offer appealing options, with manganese representing an ideal candidate. As nanosized imaging probes have demonstrated great value for designing advanced diagnostic/theranostic procedures, this work focuses on the potential of liposomal formulations loaded with a new synthesized paramagnetic Mn(II) chelates. Negatively charged liposomes were produced by thin-layer hydration method and extrusion. The obtained formulations were characterized in terms of size, surface charge, efficiency of encapsulation, stability over time, relaxivity, effective magnetic moment, and in vitro antiproliferative effect on human cells by means of the MTT assay. The negatively charged paramagnetic liposomes were monodisperse, with an average hydrodynamic diameter not exceeding 200 nm, and they displayed good stability and no cytotoxicity. As determined by optical emission spectroscopy, manganese complexes are loaded almost completely on liposomes maintaining their paramagnetic properties.

Rhenium Radioisotopes for Medicine, a Focus on Production and Applications.

In recent decades, the use of alpha; pure beta; or beta/gamma emitters in oncology, endocrinology, and interventional cardiology rheumatology, has proved to be an important alternative to the most common therapeutic regimens. Among radionuclides used for therapy in nuclear medicine, two rhenium radioisotopes are of particular relevance: rhenium-186 and rhenium-188. The first is routinely produced in nuclear reactors by direct neutron activation of rhenium-186 via 185Re(n,γ)186Re nuclear reaction. Rhenium-188 is produced by the decay of the parent tungsten-188. Separation of rhenium-188 is mainly performed using a chromatographic 188W/188Re generator in which tungsten-188 is adsorbed on the alumina column, similar to the 99Mo/99mTc generator system, and the radionuclide eluted in saline solution. The application of rhenium-186 and rhenium-188 depends on their specific activity. Rhenium-186 is produced in low specific activity and is mainly used for labeling particles or diphosphonates for bone pain palliation. Whereas, rhenium-188 of high specific activity can be used for labeling peptides or bioactive molecules. One of the advantages of rhenium is its chemical similarity with technetium. So, diagnostic technetium analogs labeled with radiorhenium can be developed for therapeutic applications. Clinical trials promoting the use of 186/188Re-radiopharmaceuticals is, in particular, are discussed.

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.

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.

Copper-64 based radiopharmaceuticals for brain tumors and hypoxia imaging.

INTRODUCTION: The most common and aggressive primary malignancy of the central nervous system is Glioblastoma that, as a wide range of malignant solid tumor, is characterized by extensive hypoxic regions. A great number of PET radiopharmaceuticals have been developed for the identification of hypoxia in solid tumors, among these, we find copper-based tracers. The aim of the current review paper was to provide an overview of radiocopper compounds applied for preclinical and clinical research in brain tumors and hypoxia imaging or therapy. EVIDENCE ACQUISITION: Copper offers a wide variety of isotopes, useful for nuclear medicine applications, but only 64Cu and 67Cu are under the spotlight of the scientific community since being good candidates for theranostic applications. Between the two, 64Cu availability and production cost have attracted more interest of the scientific community. EVIDENCE SYNTHESIS: In order to better understand the application of copper-bis thiosemicarbazones in hypoxia imaging, an overview of the role of hypoxia in cancer, existing non-imaging and imaging techniques for hypoxia identification and promising future avenues regarding hypoxia is necessary. Different proposed uptake mechanisms of [64Cu][Cu(ATSM)] inside the cell will be discussed and other 64Cu-based tracers for brain tumors described. CONCLUSIONS: Among radio copper compounds [64Cu][Cu(ATSM)] is the most studied radiopharmaceutical for imaging and treatment of brain tumors. Experimental evidence suggested that [64Cu][Cu(ATSM)] could be more appropriately considered as a marker of over-reduced intracellular state rather than a pure hypoxia agent. Moreover, preliminary clinical data suggested that [64Cu]CuCl2 can be a potentially useful diagnostic agent for malignancies of the central nervous system (CNS).

Interdisciplinary Tasks in the Cyclotron Production of Radiometals for Medical Applications. The Case of 47Sc as Example.

The growing number of cyclotrons of different sizes installed in the territory has given a strong impulse to the production of conventional and emerging radionuclides for medical applications. In particular, the great advantage of using medical cyclotrons is the possibility to produce on-site, when needed (on-demand), with medical radionuclides of interest encouraging the personalized medicine approach. Radiometals satisfy the ideal characteristics that radionuclides should have for routine employment in nuclear medicine, especially since they have a robust chemistry suitable to synthetize stable in vivo radiopharmaceuticals with high radiochemical yields. In this letter several interdisciplinary aspects involved in the radiometals cyclotron production cycle are summarized focusing the attention on cyclotron production facilities, target material, and chemical processing available for medical applications. As an example, the current status and recent development in the production of the theranostic radionuclide scandium-47 have been reported.

Therapeutic Radiometals: Worldwide Scientific Literature Trend Analysis (2008⁻2018).

Academic journals have published a large number of papers in the therapeutic nuclear medicine (NM) research field in the last 10 years. Despite this, a literature analysis has never before been made to point out the research interest in therapeutic radionuclides (RNs). For this reason, the present study aims specifically to analyze the research output on therapeutic radiometals from 2008 to 2018, with intent to quantify and identify global trends in scientific literature and emphasize the interdisciplinary nature of this research field. The data search targeted conventional (131I, 90Y, 177Lu, 188Re, 186Re, 153Sm, 89Sr, 186Er) and emergent (67Cu, 47Sc, 223Ra, 166Ho, 161Tb, 149Tb, 212Pb/212Bi, 225Ac, 213Bi, 211At, 117mSn) RNs. Starting from this time frame, authors have analyzed and interpreted this scientific trend quantitatively first, and qualitatively after.

Perspectives on the Use of Liquid Extraction for Radioisotope Purification.

The reliable and efficient production of radioisotopes for diagnosis and therapy is becoming an increasingly important capability, due to their demonstrated utility in Nuclear Medicine applications. Starting from the first processes involving the separation of 99mTc from irradiated materials, several methods and concepts have been developed to selectively extract the radioisotopes of interest. Even though the initial methods were based on liquid-liquid extraction (LLE) approaches, the perceived difficulty in automating such processes has slowly moved the focus towards resin separation methods, whose basic chemical principles are often similar to the LLE ones in terms of chelators and phases. However, the emerging field of flow chemistry allows LLE to be easily automated and operated in a continuous manner, resulting in an even improved efficiency and reliability. In this contribution, we will outline the fundamentals of LLE processes and their translation into flow-based apparatuses; in addition, we will provide examples of radioisotope separations that have been achieved using LLE methods. This article is intended to offer insights about the future potential of LLE to purify medically relevant radioisotopes.

Correction: Uccelli, L., et al. Therapeutic Radiometals: Worldwide Scientific Literature Trend Analysis (2008⁻2018). Molecules 2019, 24, 640.

The authors wish to make the following corrections to their paper [...].

Technetium Complexes and Radiopharmaceuticals with Scorpionate Ligands.

Scorpionate ligands have played a crucial role in the development of technetium chemistry and, recently, they have also fueled important advancements in the discovery of novel diagnostic imaging agents based on the γ-emitting radionuclide technetium-99m. The purpose of this short review is to provide an illustration of the most general and relevant results in this field, however without being concerned with the details of the analytical features of the various compounds. Thus, emphasis will be given to the description of the general features of technetium complexes with scorpionate ligands including coordination modes, structural properties and an elementary bonding description. Similarly, the most relevant examples of technetium-99m radiopharmaceuticals derived from scorpionate ligands and their potential interest for nuclear imaging will be summarized.

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.

Influence of Storage Temperature on Radiochemical Purity of 99mTc-Radiopharmaceuticals.

The influence of effective room temperature on the radiochemical purity of 99mTc-radiopharmaceuticals was reported. This study was born from the observation that in the isolators used for the preparation of the 99mTc-radiopharmaceuticals the temperatures can be higher than those reported in the commercial illustrative leaflets of the kits. This is due, in particular, to the small size of the work area, the presence of instruments for heating, the continuous activation of air filtration, in addition to the fact that the environment of the isolator used for the 99mTc-radiopharmaceuticals preparation and storage is completely isolated and not conditioned. A total of 244 99mTc-radiopharmaceutical preparations (seven different types) have been tested and the radiochemical purity was checked at the end of preparation and until the expiry time. Moreover, we found that the mean temperature into the isolator was significantly higher than 25 °C, the temperature, in general, required for the preparation and storage of 99mTc-radiopharmaceuticals. Results confirmed the radiochemical stability of radiopharmaceutical products. However, as required in the field of quality assurance, the impact that different conditions than those required by the manufacturer on the radiopharmaceuticals quality have to be verified before human administration.

14 MeV Neutrons for 99Mo/99mTc Production: Experiments, Simulations and Perspectives.

BACKGROUND: the gamma-emitting radionuclide Technetium-99m (99mTc) is still the workhorse of Single Photon Emission Computed Tomography (SPECT) as it is used worldwide for the diagnosis of a variety of phatological conditions. 99mTc is obtained from 99Mo/99mTc generators as pertechnetate ion, which is the ubiquitous starting material for the preparation of 99mTc radiopharmaceuticals. 99Mo in such generators is currently produced in nuclear fission reactors as a by-product of 235U fission. Here we investigated an alternative route for the production of 99Mo by irradiating a natural metallic molybdenum powder using a 14-MeV accelerator-driven neutron source. METHODS: after irradiation, an efficient isolation and purification of the final 99mTc-pertechnetate was carried out by means of solvent extraction. Monte Carlo simulations allowed reliable predictions of 99Mo production rates for a newly designed 14-MeV neutron source (New Sorgentina Fusion Source). RESULTS: in traceable metrological conditions, a level of radionuclidic purity consistent with accepted pharmaceutical quality standards, was achieved. CONCLUSIONS: we showed that this source, featuring a nominal neutron emission rate of about 1015 s-1, may potentially supply an appreciable fraction of the current 99Mo global demand. This study highlights that a robust and viable solution, alternative to nuclear fission reactors, can be accomplished to secure the long-term supply of 99Mo.

Recent achievements in Tc-99m radiopharmaceutical direct production by medical cyclotrons.

99mTc is the most commonly used radionuclide in the field of diagnostic imaging, a noninvasive method intended to diagnose a disease, assess the disease state and monitor the effects of treatments. Annually, the use of 99mTc, covers about 85% of nuclear medicine applications. This isotope releases gamma rays at about the same wavelength as conventional X-ray diagnostic equipment, and owing to its short half-life (t½ = 6 h) is ideal for diagnostic nuclear imaging. A patient can be injected with a small amount of 99mTc and within 24 h almost 94% of the injected radionuclide would have decayed and left the body, limiting the patient's radiation exposure. 99mTc is usually supplied to hospitals through a 99Mo/99mTc radionuclide generator system where it is produced from the ß decay of the parent nuclide 99Mo (t½ = 66 h), which is produced in nuclear reactors via neutron fission. Recently, the interruption of the global supply chain of reactor-produced 99Mo, has forced the scientific community to investigate alternative production routes for 99mTc. One solution was to consider cyclotron-based methods as potential replacement of reactor-based technology and the nuclear reaction 100Mo(p,2n)99mTc emerged as the most worthwhile approach. This review reports some achievements about 99mTc produced by medical cyclotrons. In particular, the available technologies for target design, the most efficient extraction and separation procedure developed for the purification of 99mTc from the irradiated targets, the preparation of high purity 99mTc radiopharmaceuticals and the first clinical studies carried out with cyclotron produced 99mTc are described.

A dry powder formulation from silk fibroin microspheres as a topical auto-gelling device.

With the aim of establishing the formulation of a new hydrophilic auto-gelling medical device for biomedical applications, fibroin-based microspheres were prepared. The proposed microspheres were produced by a cost-effective and industrially scalable technique, such as the spray-drying. Spray-dried silk fibroin microspheres were obtained and the effects of different hydrophilic polymer on the process yield, microsphere morphology and conformation transition of fibroin were evaluated. The final auto-gelling formulations were obtained by adding calcium gluconate (as a calcium source for alginate crosslinking) to the prepared microspheres and tested by an in vitro gelling test. This study showed that the combination of fibroin with sodium alginate and poloxamer produced the most promising auto-gelling formulation for specific biomedical applications, such as the treatment of pressure ulcers.

99mTc-labeled FAPI compounds for cancer and inflammation: from radiochemistry to the first clinical applications.

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.

Oldie but Goodie: Is Technetium-99m Still a Treasure Trove of Innovation for Medicine? A Patents Analysis (2000-2022).

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.