Metal Radionuclides Research Articles

Bispidine-based Ligands as Bifunctional Chelators for Radiopharmaceuticals

Abstract: Novel bispidine skeleton has been extensively designed as bifunctional chelators (BFCs) for their special stereochemical structure and variable dentate numbers. Bispidine-based ligands (BBLs) as BFCs generally integrate the benefits of conventional acyclic and macrocyclic BFCs, demonstrating exceptional radiolabeling kinetics, thermodynamic stability and kinetic inertness for their metal complexes. The accessible inherent spatial asymmetry in bispidine skeleton is well-suited for Jahn-Teller active metal ions, notably Cu(II). Currently, BBLs have already been studied to coordinate with radionuclides such as 52Mn, 64/67Cu, 68Ga, 111In, 133La, 177Lu, 212Pb, 212/213Bi, and 225Ac for radiopharmaceuticals application. Among them, the 64Cu, 52Mn, 111In, 177Lu, and 225Ac complexes with BBLs have particularly made significant research progress. In this review, we introduce the synthesis of BBLs and their applications in chelating the above five metallic radionuclides for the development of radiopharmaceuticals are discussed.

Decontamination performance of metallic radionuclides in irradiated graphite via a fluidized bed reactor

Metallic radionuclides in irradiated graphite waste are extremely hazardous to the biosphere. In consideration of its simple process, the chlorination roasting could be a promising option for the decontamination of metallic radionuclides from irradiated graphite waste. A novel numerical model for the removal of metallic radionuclides in irradiated graphite via a bubbling fluidized bed reactor was built up to evaluate the decontamination performance of chlorination roasting in large-scale treatment. The gas-solid flow was coupled with the reaction kinetics determined by experimental results and quantum chemistry calculation. A bubbling fluidized bed reactor with treatment capacity of 36–360 kg h−1 was designed, which was in terms of the effects of temperature, carrier gas velocity, HCl content and feed rate on the decontamination efficiency (DE). Temperature and HCl content had significant effects on DE. DE increased from 12 % to 100 % with rising temperature from 1173 to 1573 K. DE grew from 62 % to 99 % with increasing HCl content from 10 % to 20 %. Machine learning model was applied to directly determine the decontamination performance of the fluidized bed reactor, which provided reliable assessment in the chlorination roasting process. This study would be beneficial to large-scale treatment of metallic radionuclides in irradiated graphite via a fluidized bed reactor.

Uranium contamination of bivalve Mytilus galloprovincialis, speciation and localization

Uranium is a natural radioelement (also a model for heavier actinides), but may be released through anthropogenic activities. In order to assess its environmental impact in a given ecosystem, such as the marine system, it is essential to understand its distribution and speciation, and also to quantify its bioaccumulation. Our objective was to improve our understanding of the transfer and accumulation of uranium in marine biota with mussels taken here as sentinel species because of their sedentary nature and ability to filter seawater.We report here on the investigation of uranium accumulation, speciation, and localization in Mytilus galloprovincialis using a combination of several analytical (Inductively Coupled Plasma Mass Spectrometry, ICP-MS), spectroscopic (X ray Absorption Spectroscopy, XAS, Time Resolved Laser Induced Fluorescence Spectroscopy, TRLIFS), and imaging (Transmission Electron Microscopy, TEM, μ-XAS, Secondary Ion Mass Spectrometry, SIMS) techniques. Two cohorts of mussels from the Toulon Naval Base and the Villefranche-sur-Mer location were studied. The measurement of uranium Concentration Factor (CF) values show a clear trend in the organs of M. galloprovincialis: hepatopancreas ≫ gill > body ≥ mantle > foot. Although CF values for the entire mussel are comparable for TNB and VFM, hepatopancreas values show a significant increase in those from Toulon versus Villefranche-sur-Mer.Two organs of interest were selected for further spectroscopic investigations: the byssus and the hepatopancreas. In both cases, U(VI) (uranyl) is accumulated in a diffuse pattern, most probably linked to protein complexing functions, with the absence of a condensed phase.While such speciation studies on marine organisms can be challenging, they are an essential step for deciphering the impact of metallic radionuclides on the marine biota in the case of accidental release. Following our assumptions on uranyl speciation in both byssus and hepatopancreas, further steps will include the inventory and identification of the proteins or metabolites involved.

Chlorination mechanism of typical metallic radionuclides by HCl on irradiated graphite surface from first principles

Radioactive activity of metallic radionuclides accounts for a considerable proportion in irradiated graphite from nuclear reactors. Chlorination roasting is a promising method to remove metallic radionuclides in decommissioned irradiated graphite. The decontamination effect and chlorination mechanism of 90Sr and 60Co by HCl over an irradiated graphite surface were estimated by density functional theory. 90Sr and 60Co could be chlorinated via X(signifying metallic radionuclide)→XCl→XCl2 reaction pathway. The rate-determining step appeared where metallic radionuclides desorbed from the irradiated graphite surface. The chlorination energy barriers of 90Sr and 60Co were 236 and 575 kJ/mol, respectively, implying that chlorination roasting method for decontaminate of 90Sr and 60Co in the irradiated graphite was feasible. This work is beneficial to the application of chlorination roasting for removal of metallic radionuclides in irradiated graphite.

Metallic radionuclide-labeled tetrameric 2,6-diisopropylphenyl azides for cancer treatment.

This study proposes a new method for radionuclide therapy that involves the use of oligomeric 2,6-diisopropylphenyl azides and a chelator to form stable complexes with metallic radionuclides. The technique works by taking advantage of the endogenous acrolein produced by cancer cells. The azides react with the acrolein to give a diazo derivative that immediately attaches to the nearest organelle, effectively anchoring the radionuclide within the tumor. Preliminary in vivo experiments were conducted on a human lung carcinoma xenograft model, demonstrating the feasibility of this approach for cancer treatment.

Investigation on decontamination kinetics of metallic radionuclides in irradiated graphite by chlorination roasting

Irradiated graphite used as moderator and reflector material in reactor core in nuclear industry is an important radioactive waste after reactor decommissioning. Treatment of irradiated graphite waste has been a challenge for IAEA member states. Chlorination roasting was proposed in order to remove the metallic radionuclides in irradiated graphite waste. The promising advantages of the proposed method include that the category of graphite waste can be reduced with near-zero carbon emission, and it can lead to potentially the recycling of irradiated graphite and metallic radionuclides. The decontamination kinetics of metallic radionuclides was evaluated based on a lab-scale tube furnace combined with density functional theory (DFT). 56Fe ions were implanted into nuclear graphite to simulate metallic radionuclides derived by neutron radiation. Decontamination efficiencies of Fe at 900, 1000, 1100, and 1200 °C for the retention time of 210 min were 42.6%, 81.6%, 94.4%, and 96.7%, respectively. Fe could volatilize from graphite in the form of complex metal chloride with retaining a large amount of graphite inert matrix. The decontamination process was described by the second order reaction model. Through DFT evaluation, Fe was chlorinated via Fe → FeCl → FeCl2 reaction pathway. This decontamination process is efficient, cost-effective, and reliable, which provide a valuable contribution to managing irradiated graphite.

Theranostic Nuclear Medicine with Gallium-68, Lutetium-177, Copper-64/67, Actinium-225, and Lead-212/203 Radionuclides.

Molecular changes in malignant tissue can lead to an increase in the expression levels of various proteins or receptors that can be used to target the disease. In oncology, diagnostic imaging and radiotherapy of tumors is possible by attaching an appropriate radionuclide to molecules that selectively bind to these target proteins. The term "theranostics" describes the use of a diagnostic tool to predict the efficacy of a therapeutic option. Molecules radiolabeled with γ-emitting or β+-emitting radionuclides can be used for diagnostic imaging using single photon emission computed tomography or positron emission tomography. Radionuclide therapy of disease sites is possible with either α-, β-, or Auger-emitting radionuclides that induce irreversible damage to DNA. This Focus Review centers on the chemistry of theranostic approaches using metal radionuclides for imaging and therapy. The use of tracers that contain β+-emitting gallium-68 and β-emitting lutetium-177 will be discussed in the context of agents in clinical use for the diagnostic imaging and therapy of neuroendocrine tumors and prostate cancer. A particular emphasis is then placed on the chemistry involved in the development of theranostic approaches that use copper-64 for imaging and copper-67 for therapy with functionalized sarcophagine cage amine ligands. Targeted therapy with radionuclides that emit α particles has potential to be of particular use in late-stage disease where there are limited options, and the role of actinium-225 and lead-212 in this area is also discussed. Finally, we highlight the challenges that impede further adoption of radiotheranostic concepts while highlighting exciting opportunities and prospects.

Synthesis of novel DOTA-/AAZTA-based bifunctional chelators: Solution thermodynamics, peptidomimetic conjugation, and radiopharmaceutical evaluation

Bifunctional chelators (BFCs), which link metallic radionuclide and a targeting vector, are some of the most crucial components of metallic radionuclide-based radiopharmaceuticals for positron-emission computed tomography (PET) imaging. In this study, we designed and synthesized two versatile BFCs, p-NCS-Ph-DE4TA and p-NCS-Ph-AAZ4TA, and we conjugated them with a prostate-specific membrane antigen (PSMA) inhibitor. These two chelators showed high affinity for Ga (III) according to a study of the thermodynamics and kinetics and DFT calculations. The labeled PSMA targeted probes, [68Ga]Ga-p-NCS-Ph-DE4TA-PSMA and [68Ga]Ga-p-NCS-Ph-AAZ4TA-PSMA, maintained excellent stability in vitro, and they exhibited high specific activity when binding to PSMA. A PET/CT imaging study in mice bearing SMMC-7721 hepatocellular carcinoma xenografts demonstrated clear visualization of tumors with a high tumor uptake and low background level, indicating the excellent performance in vivo and specific activity when targeting hepatocellular carcinomas. In summary, p-NCS-Ph-DE4TA and p-NCS-Ph-AAZ4TA are leading developmental candidates for PET imaging for tumor diagnosis.

Dual MVK cleavable linkers effectively reduce renal retention of 111In-fibronectin-binding peptides

BackgroundPreviously, we have exploited bacterial adhesins-derived fibronectin-binding peptides (FnBPs) for targeting mechanically altered fibronectin (Fn) fibrils within the cancer-associated extra-cellular matrix (ECM). However, despite the ability of FnBP probes to visualize pathological lesions, when labeled with metallic radionuclides and administered for targeted imaging, they exhibit high and persistent retention of radioactivity within the kidneys. Intending to overcome this issue towards a future translation of FnBPs to the clinic, the goal of the present study was to reduce the renal retention of 111In-labelled FnBPs employing dual renal brush border membrane (BBM) enzyme-sensitive Met-Val-Lys-based linkers, enabling a rapid washout of radioactivity from the kidneys. MethodsThree maleimide-activated NOTA-conjugated brush border-enzyme cleavable linkers equipped with either single or dual consecutive MVK-based cleavable moieties were designed and synthesized. Their respective NOTA-MVK-based FnBPA5.1 conjugates were obtained by means of maleimide-thiol mediated conjugation at the N-terminus of the Fn-binding sequence, radiolabeled with indium-111, and further evaluated in vitro and in vivo in comparison to the control [111In]In-FnBPA5.1. ResultsThe linker equipped with two MVK sites displayed a two-fold more effective cleavage rate than the single MVK featuring linker in vitro, as revealed by the quantification of the released Met-containing radiometabolites. SPECT/CT imaging and biodistribution studies of the series of FnBPA5.1 radioconjugates performed at 24 h post-injection (p.i.) confirmed the in vitro results, indicating that the renal retention of 111In-labelled FnBPs can be significantly lowered through the interposition of a single MVK-based sequence between the Fn-targeting moiety and the chelating unit (52.75 ± 9.79 vs 92.88 ± 4.85 % iA/g, P < 0.001), and even further reduced by the addition of a second one (down to 34.82 ± 6.04, P < 0.001), with minor influence on the biodistribution in other organs, such as tumors. ConclusionsIn summary, we report here promising 111In-labelled FnBP radiotracers equipped with dual MVK-based cleavable linkers leading to a more effective reduction of renal retention and improved tumor-to-kidney ratios compared to the single MVK-featuring derivative. Our dual MVK strategy is a crucial step towards the clinical translation of mechano-sensory FnBPs and might as well be adopted for other radiopharmaceuticals suffering from persistent renal retention of radioactivity.

Possible Impurities in Radiopharmaceuticals and Corresponding Test Methods

The main quality attributes of radiopharmaceuticals that ensure their effectiveness and safety and are unique to their specifications are activity, radionuclide identity, radionuclide purity, and radiochemical purity. The aim of this study was to analyse the possibility of formation and methods for determination of various impurities in radiopharmaceuticals based on radionuclides of several groups: technetium-99m and rhenium-188; iodine and fluorine-18 isotopes; and gallium-68 and some other metallic radionuclides used in theranostic schemes combining radionuclide diagnostics and radionuclide therapy. The article analyses the sources for the formation of radionuclide, radiochemical, and chemical impurities; the influence of these impurities on visualisation quality and dosimetric characteristics of radiopharmaceuticals; various approaches to the methods of impurity detection and quantification; compendial requirements to the quality of radiopharmaceuticals; and research results reported in publications. The article demonstrates the need for the development and certification of Russian reference standards for testing quality attributes of radiopharmaceuticals as part of harmonisation of the State Pharmacopoeia of the Russian Federation with the Pharmacopoeia of the Eurasian Economic Union and the European Pharmacopoeia.

Porphyrins as Chelating Agents for Molecular Imaging in Nuclear Medicine.

Porphyrin ligands, showing a significant affinity for cancer cells, also have the ability to chelate metallic radioisotopes to form potential diagnostic radiopharmaceuticals. They can be applied in single-photon emission computed tomography (SPECT) and positron emission tomography (PET) to evaluate metabolic changes in the human body for tumor diagnostics. The aim of this paper is to present a short overview of the main metallic radionuclides complexed by porphyrin ligands and used in these techniques. These chelation reactions are discussed in terms of the complexation conditions and kinetics and the complex stability.

Concentrations and fluxes of suspended particulate matter and associated contaminants in the Rhône River from Lake Geneva to the Mediterranean Sea

Abstract. The Rhône River is among the main rivers of western Europe and the biggest by freshwater discharge and sediment delivery to the Mediterranean Sea. Its catchment is characterized by distinct hydrological regimes that may produce annual sediment deliveries ranging from 1.4 to 18.0 Mt yr−1. Its course meets numerous dams, hydro and nuclear power plants as well as agricultural, urban and industrial areas. Moreover, with the climatic crisis we are currently facing, it is proven that the occurrence and the intensity of extreme events (floods or droughts) will increase. Therefore, it is crucial to monitor the concentrations and fluxes of suspended particulate matter (SPM) and associated contaminants to study the current trends and their evolution. In the Rhône River (from Lake Geneva to the Mediterranean Sea), a monitoring network of 15 stations (3 on the Rhône River and 12 on tributaries) has been set up in the past decade by the Rhône Sediment Observatory (OSR) to investigate the concentrations and the fluxes of SPM and associated contaminants as well as their sources. The main purpose of the OSR is to assess the long-term trend of the main contaminant concentrations and fluxes, and to understand their behavior during extreme events, such as floods or dam flushing operations. The dataset presented in this paper contains the concentrations and fluxes of SPM as well as the concentrations and fluxes of several particle-bound contaminants of concern, e.g., polychlorinated biphenyl (PCB), trace metal elements (TME) and radionuclides, the particle size distribution and the particulate organic carbon of SPM. Sediment traps or continuous flow centrifuges were used to collect sufficient amount of SPM in order to conduct the measurements, and data completion was applied to reconstruct missing values. This observatory is on-going since 2011 and the database is regularly updated. All the data are made publicly available in French and English through the BDOH OSR database at https://doi.org/10.15454/RJCQZ7 (Lepage et al., 2021).

A concept for the extraction of the most refractory elements at CERN-ISOLDE as carbonyl complex ions

We introduce a novel thick-target concept tailored to the extraction of refractory 4d and 5d transition metal radionuclides of molybdenum, technetium, ruthenium and tungsten for radioactive ion beam production. Despite the more than 60-year old history of thick-target ISOL mass-separation facilities like ISOLDE, the extraction of these most refractory elements as radioactive ion beam has so far not been successful. In ordinary thick ISOL targets, their radioisotopes produced in the target are stopped within the condensed target material. Here, we present a concept which overcomes limitations associated with this method. We exploit the recoil momentum of nuclear reaction products for their release from the solid target material. They are thermalized in a carbon monoxide-containing atmosphere, in which volatile carbonyl complexes form readily at ambient temperature and pressure. This compound serves as volatile carrier for transport to the ion source. Excess carbon monoxide is removed by cryogenic gas separation to enable low pressures in the source region, in which the species are ionized and hence made available for radioactive ion beam formation. The setup is operated in batch mode. Initially, we investigate the feasibility of the approach with isotopes of more than 35s half-life. At the cost of reduced efficiency, the concept could also be applied to isotopes with half-lives of at least one to 10s. We report parameter studies of the key processes of the method, which validate this concept and which define the parameters for the setup. This would allow for the first time the extraction of radioactive molybdenum, tungsten and several other transition metals at thick-target ISOL facilities.

Accumulation and Speciation of Cobalt in Paracentrotus lividus.

Since the first human release of radionuclides on Earth at the end of the Second World War, impact assessments have been implemented. Radionuclides are now ubiquitous, and the impact of local accidental release on human activities, although of low probability, is of tremendous social and economic consequences. Although radionuclide inventories (at various scales) are essential as input data for impact assessment, crucial information on physicochemical speciation is lacking. Among the metallic radionuclides of interest, cobalt-60 is one of the most important activation products generated in the nuclear industry. In this work, a marine model ecosystem has been defined because seawater and more generally marine ecosystems are final receptacles of metal pollution. A multistep approach from quantitative uptake to understanding of the accumulation mechanism has been implemented with the sea urchin Paracentrotus lividus. In a well-controlled aquarium, the day-by-day uptake of cobalt and its quantification in different compartments of the sea urchin were monitored with various conditions of exposure by combining ICP-OES analysis and γ spectrometry. Cobalt is mainly distributed following the rating intestinal tract ≫ gonads > shell spines. Cobalt speciation in seawater and inside the gonads and the intestinal tract was determined using extended X-ray absorption fine structure (EXAFS). The cobalt inside the gonads and the intestinal tract is mainly complexed by the toposome, the main protein in the sea urchin P. lividus. Complexation with purified toposome was characterized and a complexation site combining EXAFS and AIMD (ab initio molecular dynamics) was proposed implying monodentate carboxylates.

Cover Feature: Recent Advances in Radiometals for Combined Imaging and Therapy in Cancer (ChemMedChem 19/2021)

The Cover Feature illustrates the possible applications of different types of radioactive decay in cancer imaging and therapy. Metal radionuclides delivered to the cancer site can be utilized in various ways. The upper half of the image highlights the diagnostic modalities Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT). The emission of alpha particles and electrons in tumors and their metastases—as shown in the lower half—leads to irreparable damage and eventually cell death making them powerful options for targeted cancer treatment. Cover graphic design by Susan D. Weil, from MSK and used with permission from MSK, © 2021 Memorial Sloan Kettering Cancer Center. All rights reserved. More information can be found in the Review by Jason S. Lewis et al.

Harnessing α-Emitting Radionuclides for Therapy: Radiolabeling Method Review.

Targeted α-therapy (TAT) is an emerging powerful tool treating late-stage cancers for which therapeutic options are limited. At the core of TAT are targeted radiopharmaceuticals, where isotopes are paired with targeting vectors to enable tissue- or cell-specific delivery of α-emitters. DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and DTPA (diethylenetriamine pentaacetic acid) are commonly used to chelate metallic radionuclides but have limitations. Significant efforts are underway to develop effective stable chelators for α-emitters and are at various stages of development and community adoption. Isotopes such as 149Tb, 212/213Bi, 212Pb (for 212Bi), 225Ac, and 226/227Th have found suitable chelators, although further studies, especially invivo studies, are required. For others, including 223Ra, 230U, and, arguably 211At, the ideal chemistry remains elusive. This review summarizes the methods reported to date for the incorporation of 149Tb, 211At, 212/213Bi, 212Pb (for 212Bi), 223Ra, 225Ac, 226/227Th, and 230U into radiopharmaceuticals, with a focus on new discoveries and remaining challenges.

The Race for Hydroxamate-Based Zirconium-89 Chelators.

Metallic radionuclides conjugated to biological vectors via an appropriate chelator are employed in nuclear medicine for the diagnosis (imaging) and radiotherapy of diseases. For the application of radiolabeled antibodies using positron emission tomography (immunoPET), zirconium-89 has gained increasing interest over the last decades as its physical properties (t1/2 = 78.4 h, 22.6% β+ decay) match well with the slow pharmacokinetics of antibodies (tbiol. = days to weeks) allowing for late time point imaging. The most commonly used chelator for 89Zr in this context is desferrioxamine (DFO). However, it has been shown in preclinical studies that the hexadentate DFO ligand does not provide 89Zr-complexes of sufficient stability in vivo and unspecific uptake of the osteophilic radiometal in bones is observed. For clinical applications, this might be of concern not only because of an unnecessary dose to the patient but also an increased background signal. As a consequence, next generation chelators based on hydroxamate scaffolds for more stable coordination of 89Zr have been developed by different research groups. In this review, we describe the progress in this research field until end of 2020, including promising examples of new candidates of chelators currently in advanced stages for clinical translation that outrun the performance of the current gold standard DFO.

Applications of Radiolabelled Curcumin and Its Derivatives in Medicinal Chemistry.

Curcumin is a natural occurring molecule that has aroused much interest among researchers over the years due to its pleiotropic set of biological properties. In the nuclear medicine field, radiolabelled curcumin and curcumin derivatives have been studied as potential radiotracers for the early diagnosis of Alzheimer’s disease and cancer. In the present review, the synthetic pathways, labelling methods and the preclinical investigations involving these radioactive compounds are treated. The studies entailed chemical modifications for enhancing curcumin stability, as well as its functionalisation for the labelling with several radiohalogens or metal radionuclides (fluorine-18, technetium-99m, gallium-68, etc.). Although some drawbacks have yet to be addressed, and none of the radiolabelled curcuminoids have so far achieved clinical application, the studies performed hitherto provide useful insights and lay the foundation for further developments.

Emerging Radionuclides in a Regulatory Framework for Medicinal Products - How Do They Fit?

Recent years have seen the establishment of several radionuclides as medicinal products in particular in the setting of theranostics and PET. [177Lu]Lutetium Chloride or [64Cu]Copper Chloride have received marketing authorization as radionuclide precursor, [68Ga]Gallium Chloride has received regulatory approval in the form of different 68Ge/68Ga generators. This is a formal requirement by the EU directive 2001/83, even though for some of these radionuclide precursors no licensed kit is available that can be combined to obtain a final radiopharmaceuticals, as it is the case for Technetium-99m. In view of several highly promising, especially metallic radionuclides for theranostic applications in a wider sense, the strict regulatory environment poses the risk of slowing down development, in particular for radionuclide producers that want to provide innovative radionuclides for clinical research purposes, which is the basis for their further establishment. In this paper we address the regulatory framework for novel radionuclides within the EU, the current challenges in particular related to clinical translation and potential options to support translational development within Europe and worldwide.

Advances in Development of Radiometal Labeled Amino Acid-Based Compounds for Cancer Imaging and Diagnostics.

Radiolabeled biomolecules targeted at tumor-specific enzymes, receptors, and transporters in cancer cells represent an intensively investigated and promising class of molecular tools for the cancer diagnosis and therapy. High specificity of such biomolecules is a prerequisite for the treatment with a lower burden to normal cells and for the effective and targeted imaging and diagnosis. Undoubtedly, early detection is a key factor in efficient dealing with many severe tumor types. This review provides an overview and critical evaluation of novel approaches in the designing of target-specific probes labeled with metal radionuclides for the diagnosis of most common death-causing cancers, published mainly within the last three years. Advances are discussed such traditional peptide radiolabeling approaches, and click and nanoparticle chemistry. The progress of radiolabeled peptide based ligands as potential radiopharmaceuticals is illustrated via novel structure and application studies, showing how the molecular modifications reflect their binding selectivity to significant onco-receptors, toxicity, and, by that, practical utilization. The most impressive outputs in categories of newly developed structures, as well as imaging and diagnosis approaches, and the most intensively studied oncological diseases in this context, are emphasized in order to show future perspectives of radiometal labeled amino acid-based compounds in nuclear medicine.