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The β- emitter, rhenium-188 (188Re), has long been recognized as an attractive candidate for targeted cancer radionuclide therapy (TRNT). This transition metal shares chemical similarities with its congener element technetium, whose nuclear isomer technetium-99m (99mTc) is the current workhorse of diagnostic nuclear medicine. The differences between these two elements have a significant impact on the radiolabelling methods and should always receive critical attention. This review aims to highlight what needs to be considered to design a successful radiopharmaceutical incorporating 118Re. Some of the most effective strategies for preparing therapeutic radiopharmaceuticals with 188Re are illustrated and rationalized using the concept of the inorganic functional group (core) and a simple ligand field theoretical model combined with a qualitative definition of frontiers orbitals. Of special interest are the Re(V) oxo and Re(V) nitrido functional groups. Suitable ligands for binding to these cores are discussed, successful clinical applications are summarized, and a prediction of viable future applications is presented. Rhenium-188 decays through the emission of a high energy beta particle (2.12 MeV max energy) and a half-life of 16.9 h. An ideal biological target would therefore be a high-capacity target site (transporters, potential gradients, tumour microenvironment) with less emphasis on saturable targets such as overexpressed receptors on smaller metastases. ispartof: MOLECULES vol:28 issue:3 ispartof: location:Switzerland status: published

Rapid imaging acquisition, high spatial resolution and sensitivity, powered by advancements in solid-state detector technology, are significantly changing the perspective of single photon emission tomography (SPECT). In particular, this evolutionary step is fueling a rediscovery of technetium-99m, a still unique radionuclide within the nuclear medicine scenario because of its ideal nuclear properties and easy preparation of its radiopharmaceuticals that does not require a costly infrastructure and complex procedures. Scope of this review is to show that the arsenal of technetium-99m radiopharmaceuticals is already equipped with imaging agents that may complement and integrate the role played by analogous tracers developed for positron emission tomography (PET). These include, in particular, somatostatin (SST) and prostate-specific membrane antigen (PSMA) receptor targeting agents, and a number of peptide-derived radiopharmaceuticals. Additionally, these recent technological developments, combined with new myocardial perfusion tracers having more favorable biodistribution and pharmacokinetic properties as compared to current commercial agents, may also reinvigorate the prevailing position still hold by technetium-99m radiopharmaceuticals in nuclear cardiology.

Despite its insufficient availability, Copper-67 is currently attracting much attention for its enormous potential for cancer therapy as theranostic radionuclide. This work aims to accurately measure the unexplored cross section 70Zn(p,x)67Cu in the energy range 45–70 MeV and to evaluate its potential advantages in the case of high-intensity proton beams provided by compact cyclotrons. Thin target foils of enriched 70Zn were manufactured by lamination at the INFN-LNL and irradiated at the ARRONAX facility using the stacked-foils method. A radiochemical procedure for the separation of Cu, Ga and Zn contaminants and the isolation of 67Cu from the irradiated material was developed. The efficiency of the chemical processing was determined for each foil by monitoring the activity of selected tracer radionuclides (61Cu, 66Ga and 69mZn) through γ-spectrometry. Experimental data of the 70Zn(p,x)67Cu, 64Cu, 67Ga, 66Ga, 69mZn, 65Zn cross sections were measured for the first time in the energy range 45–70 MeV and compared with the theoretical results obtained by using the TALYS code. The 67Cu production yield by using enriched 70Zn thick targets was compared with the results obtained by using 68Zn targets in the same irradiation conditions.

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.

Background The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development. Main Body This selection of highlights provides commentary on 21 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first-in-human application of novel radiopharmaceuticals. Conclusion Trends in radiochemistry and radiopharmacy are highlighted. Hot topics cover the entire scope of EJNMMI Radiopharmacy and Chemistry, demonstrating the progress in the research field, and include new PET-labelling methods for 11C and 18F, the importance of choosing the proper chelator for a given radioactive metal ion, implications of total body PET on use of radiopharmaceuticals, legislation issues and radionuclide therapy including the emerging role of 161Tb.

Infrared and Raman spectroscopy are effective techniques that allow collecting information about secondary structure of proteins, including antibodies. Trastuzumab, antibody used in our study was in a freeze-dried form, conjugated with different bifunctional chelators and linked with the stable isotopes of lutetium and yttrium. The characterization of the final immunoconjugates showed no significant changes in the structure demonstrated by the presence of the amide bands characteristic for a α-helices and β-sheets structures. These methods could be applied during the production of the antibody freeze-dried kit formulations for the labeling with the radioactive isotopes.

The preparation, characterization, and molecular properties of technetium-99m (99mTc) radiopharmaceuticals have been reviewed within a simplified theoretical framework based on a few fundamental concepts of coordination chemistry. The properties of various categories of 99mTc complexes have been classified according to a set of characteristic metallic functional groups, also called 99mTc cores or 99mTc fragments. These metallic fragments exhibit a selective reactivity toward specific classes of ligands and, thus, completely determine the chemical and structural characteristics of the resulting 99mTc complexes. On this ground, radiolabeling procedures and analytical methods employed for the production and chemical characterization of the most important 99mTc radiopharmaceuticals have been discussed. After a brief description of the key principles of the so-called bifunctional approach, the structural features of some relevant examples of 99mTc diagnostic agents already introduced into the clinical use or currently under preliminary clinical evaluation were reported.

Along with other novel metallic radionuclides, copper-64 (64Cu) is currently being investigated as an alternative option to the gallium-68 (68Ga) and lutetium-177 (177Lu) radiopharmaceuticals widely used for targeting somatostatin receptors, expressed by neuroendocrine tumors (NETs), and recently prostate specific membrane antigen (PSMA), expressed by prostate cancer cells. This interest is mostly driven by the peculiar nuclear properties of 64Cu that make it an almost ideal example of theranostic radionuclide. In fact, 64Cu emits both low-energy positrons, β- particles and a swarm of Auger electrons. This combination of different emissions may allow to collect high-resolution PET images, but also to use the same radiopharmaceutical for eliciting a therapeutic effect. Another unique behavior of 64Cu originates from the fundamental biological role played in organisms by the ionic forms of the copper element, which is naturally involved in a multitude of cellular processes including cell replication. These intrinsic biological characteristics has led to the discovery that 64Cu, under its simplest dicationic form Cu2+, is able to specifically target a variety of cancerous cells and to detect the onset of a metastatic process in its initial stage. This short review reports an outline of the status of 64Cu radiopharmaceuticals and of the most relevant results that are constantly disclosed by preclinical and investigational clinical studies.

Copper-64 is a very attractive radioisotope with unique nuclear properties that allow using it as both a diagnostic and therapeutic agent, thus providing an almost ideal example of a theranostic radionuclide. A characteristic of Cu-64 stems from the intrinsic biological nature of copper ions that play a fundamental role in a large number of cellular processes. Cu-64 is a radionuclide that reflects the natural biochemical pathways of Cu-64 ions, therefore, can be exploited for the detection and therapy of certain malignancies and metabolic diseases. Beside these applications of Cu-64 ions, this radionuclide can be also used for radiolabelling bifunctional chelators carrying a variety of pharmacophores for targeting different biological substrates. These include peptide-based substrates and immunoconjugates as well as small-molecule bioactive moieties. Fueled by the growing interest of Member States (MS) belonging to the International Atomic Energy Agency (IAEA) community, a dedicated Coordinated Research Project (CRP) was initiated in 2016, which recruited thirteen participating MS from four continents. Research activities and collaborations between the participating countries allowed for collection of an impressive series of results, particularly on the production, preclinical evaluation and, in a few cases, clinical evaluation of various 64Cu-radiopharmaceuticals that may have potential impact on future development of the field. Since this CRP was finalized at the beginning of 2020, this short review summarizes outcomes, outputs and results of this project with the purpose to propagate to other MS and to the whole scientific community, some of the most recent achievements on this novel class of theranostic 64Cu-radiopharmaceticals.

Rapid imaging acquisition, high spatial resolution and sensitivity, powered by advancements in solid-state detector technology, are significantly changing the perspective of single photon emission tomography (SPECT). In particular, this evolutionary step is fueling a rediscovery of technetium-99m, a still unique radionuclide within the nuclear medicine scenario because of its ideal nuclear properties and easy preparation of its radiopharmaceuticals that does not require a costly infrastructure and complex procedures. Scope of this review is to show that the arsenal of technetium-99m radiopharmaceuticals is already equipped with imaging agents that may complement and integrate the role played by analogous tracers developed for positron emission tomography (PET). These include, in particular, somatostatin (SST) and prostate-specific membrane antigen (PSMA) receptor targeting agents, and a number of peptide-derived radiopharmaceuticals. Additionally, these recent technological developments, combined with new myocardial perfusion tracers having more favorable biodistribution and pharmacokinetic properties as compared to current commercial agents, may also reinvigorate the prevailing position still hold by technetium-99m radiopharmaceuticals in nuclear cardiology.

The LARAMED project, acronym for LAboratory of RAdioisotopes for MEDicine, is the new research infrastructure being established at the Legnaro National Laboratories (LNL), focused on the production of novel medical radionuclides, actually unavailable for the scientific community. This work presents the recent advancements of the LARAMED laboratories and bunkers in the SPES facility, where the 70-MeV high current proton cyclotron was installed in 2015 to perform not only fundamental nuclear physics studies but also research activities related to medical applications. The latest research outcomes on the production of the theranostic 67Cu and 47Sc radionuclides, obtained thanks to the Italian and international LARAMED network, are also summarized.

(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.

The purpose of this work was to further expand the chemistry of mixed technetium nitrido-peroxo complexes, a still poorly explored class of compounds containing the Tc(VII) moiety, [99gTc][Tc(N)(O2)2]. A number of novel complexes of the formula [99gTc][Tc(N)(O2)2(L)] with bidentate ligands (L) (where L = deprotonated alanine, glycine, proline) were prepared by reacting a solution of nitrido-technetic(VI) acid with L in the presence of a source of H2O2. Alternatively, the complex [99gTc][Tc(N)(O2)2X]&minus, (X = Cl, Br) was used as a precursor for substitution reactions where the halogenide ion was replaced by the bidentate ligand. The new complexes were characterized by elemental analysis and mass spectroscopy. The preparation of the analogous [99mTc][Tc(N)(O2)2] moiety, radiolabeled with the metastable isomer Tc-99m, was also studied at a no-carrier-added level, using S-methyl-N-methyl-dithiocarbazate as the donor of the nitrido nitrogen atoms.

International audience; The goal of PASTA project (acronym for production with accelerator of$^{47}$Sc for theranostic applications) is the determination of excitation functions associated to several nuclear reactions, aimed at yielding the theranostic radionuclide$^{47}$Sc. This work reports the main results obtained by irradiating natural vanadium targets with proton beams up to 70 MeV. Particular care is also given to the co-production of$^{46}$Sc, the only isotopic contaminant with half-life longer than$^{47}$Sc. Experimental results are compared with theoretical studies by means of known nuclear reaction software tools that are publicly available.

Conventional agents for diagnostic single-photon emission imaging and for radionuclide therapy are mostly associated with radiopharmaceuticals labeled with technetium-99m and iodine radioisotopes. This category of radiopharmaceuticals still determines, to a great extent, the usual operations inside a conventional hospital radiopharmacy. Although this description is not universally accepted and can be certainly subjected to some revision, for the purpose of the present chapter, by “conventional radiopharmacy” is meant a laboratory for the preparation and quality control of radiopharmaceuticals that are produced using either commercial, lyophilized kit formulations or supplied as ready-to-use pharmaceutical preparations. It is implicitly assumed that radiopharmaceutical products belonging to this class of licensed drugs have been always approved by some regulatory authority and intended for a specific clinical application. Obviously, radiopharmaceuticals labeled with radionuclides other than technetium-99m or iodine radioisotopes, but that can be obtained through a kit formulation or as ready-to-use preparations, e.g., indium-111 pentetreotide (Octreoscan®), radium-223 chloride (Xofigo®), yttrium-90 ibritumomab tiuxetan (Zevalin®), or rhenium-188 hydroxyethylidene diphosphonate (188Re-HEDP), can be conveniently included into this category. Conversely, both diagnostic single-photon emitting and therapeutic radiopharmaceuticals that are produced in-house following an extemporaneous, unlicensed procedure (galenic or magistral preparations) will not be considered in this chapter. From the point of view of radiopharmacy requirements, this ensemble of radiolabeling reactions is fully equivalent to those employed for preparing tracers for positron emission tomography (PET) using cyclotron-produced radionuclides. In particular, according to still predominant regulations, extemporaneous therapeutic radiopharmaceuticals should be obtained strictly following the rules of good manufacturing practice (GMP).

Copper radionuclides are rapidly emerging as potential diagnostic and therapeutic tools in oncology, particularly 64Cu-radiopharmaceuticals for targeting neuroendocrine, prostate, and hypoxic tumors. Unexpectedly, experimental results are also revealing the impressive biological behavior of simple [64Cu2+] ions. For example, it has been demonstrated that administration of ionic [64Cu2+] in physiological solution allows the selective targeting of a variety of malignancies. These remarkable biological properties appear to be crucially linked to the natural role of copper ions in cell proliferation. Here, we review the current status of 64Cu-radiopharmaceuticals in molecular imaging and cancer therapy.

Background: New approaches based on the receptor-targeted molecular interaction have been recently developed with the aim to investigate specific probes for sentinel lymph nodes. In particular, the mannose receptors expressed by lymph node macrophages became an attractive target and different multifunctional mannose derivate ligands for the labeling with 99mTc have been developed. In this study, we report the synthesis of a specific class of dextran-based, macromolecular, multifunctional ligands specially designed for labeling with the highly stable [99mTc&equiv, N]2+ core. Methods: The ligands have been obtained by appending to a macromolecular dextran scaffold pendant arms bearing a chelating moiety for the metallic group and a mannosyl residue for allowing the interaction of the resulting macromolecular 99mTc conjugate with specific receptors on the external membrane of macrophages. Two different chelating systems have been selected, S-methyl dithiocarbazate [H2N‒NH‒C(=S)SCH3=HDTCZ] and a sequence of two cysteine residues, that in combination with a monophosphine coligand, are able to bind the [99mTc&equiv, N]2+ core. Conclusions: High-specific-activity labeling has been obtained by simple mixing and heating of the [99mTc&equiv, N]2+ group with the new mannose-dextran derivatives.

In the last years, the technology for producing the important medical radionuclide technetium-99m by cyclotrons has become sufficiently mature to justify its introduction as an alternative source of the starting precursor [99mTc][TcO4]- ubiquitously employed for the production of 99mTc-radiopharmaceuticals in hospitals. These technologies make use almost exclusively of the nuclear reaction 100Mo(p,2n)99mTc that allows direct production of Tc-99m. In this study, it is conjectured that this alternative production route will not replace the current supply chain based on the distribution of 99Mo/99mTc generators, but could become a convenient emergency source of Tc-99m only for in-house hospitals equipped with a conventional, low-energy, medical cyclotron. On this ground, an outline of the essential steps that should be implemented for setting up a hospital radiopharmacy aimed at the occasional production of Tc-99m by a small cyclotron is discussed. These include (1) target production, (2) irradiation conditions, (3) separation/purification procedures, (4) terminal sterilization, (5) quality control, and (6) Mo-100 recovery. To address these issues, a comprehensive technology for cyclotron-production of Tc-99m, developed at the Legnaro National Laboratories of the Italian National Institute of Nuclear Physics (LNL-INFN), will be used as a reference example.

A short overview of fundamental chemistry of lutetium and of structural characteristics of lutetium coordination complexes, as relevant for understanding the properties of lutetium-177 radiopharmaceuticals, is presented. This includes basic concepts on lutetium electronic structure, lanthanide contraction, coordination geometries, behavior in aqueous solution and thermodynamic stability. An illustration of the structure and binding properties of the most important chelating agents for the Lu(3+) ion in aqueous solution is also reported with specific focus on coordination complexes formed with linear and macrocyclic polydentate amino-carboxylate donor ligands.

BACKGROUND Diagnosis of implant-associated infection is challenging. Several radiopharmaceuticals have been described but direct comparisons are limited. Here we compared in vitro and in an animal model 99mTc-UBI, 99mTc-ciprofloxacin, 99mTcN-CiproCS2 and 111In-DTPA-biotin for targeting E. coli (ATCC 25922) and S. aureus (ATCC 43335). METHODS Stability controls were performed with the labelled radiopharmaceuticals during 6 hours in saline and serum. The in vitro binding to viable or killed bacteria was evaluated at 37 °C and 4 °C. For in vivo studies, Teflon cages were subcutaneously implanted in mice, followed by percutaneous infection. Biodistribution of i.v. injected radiolabelled radiopharmaceuticals were evaluated during 24 h in cages and dissected tissues. RESULTS Labelling efficiency of all radiopharmaceuticals ranged between 94% and 98%, with high stability both in saline and in human serum. In vitro binding assays displayed a rapid but poor bacterial binding for all tested agents. Similar binding kinetic occurred also with heat-killed and ethanol-killed bacteria. In the tissue cage model, infection was detected at different time points: 99mTc-UBI and 99mTcN-CiproCS2 showed higher infected cage/sterile cage ratio at 24 hours for both E. coli and S. aureus; 99mTc-Ciprofloxacin at 24 hours for both E. coli and at 4 hours for S. aureus; 111In-DTPA-biotin accumulates faster in both E. coli and S. aureus infected cages. CONCLUSIONS 99mTc-UBI, 99mTcN-CiproCS2 showed poor in vitro binding but good in vivo binding to E. coli only. 111In-DTPA-biotin showed poor in vitro binding but good in vivo binding to S. aureus and poor to E. coli. 99mTc-Ciprofloxacin showed poor in vitro binding but good in vivo binding to all tested bacteria. The mechanism of accumulation in infected sites remains to be elucidated.

A new molecular metallic fragment for labeling biologically active molecules with 99mTc and 188Re is described. This system is composed of a combination of tridentate π-donor and monodentate π-acceptor ligands bound to a [M Ξ N]2+ group (M = (99m)Tc, 188Re) in a pseudo square-pyramidal geometry. A simple structural model of the new metallic fragment was obtained by reacting the ligand 2, 2'-iminodiethanethiol [H2NS2 = NH(CH2CH2SH)2] and monodentate tertiary phosphines with the [M Ξ N]2+ group (M = (99m)Tc, (188)Re). In the resulting complexes (dubbed3+1complexes), the tridentate ligand binds the [M Ξ N]2+ core through the two deprotonated, negatively charged, thiol sulfur atoms and the neutral, protonated, amine nitrogen atom. The residual fourth position of the five-coordinated arrangement is occupied by a phosphine ligand. The chemical identity of these model (99m)Tc and (188)Re compounds was established by comparison with the chromatographic properties of the corresponding complexes obtained at the macroscopic level with the long-lived (99)Tc and natural Re isotopes. The investigation was further extended to comprise a series of ligands formed by simple combinations of two basic amino acids or pseudo-amino acids to yield potential tridentate chelating systems having [S, N, S] and [N, N, S] as sets of π-donor atoms. Labeling yields and in vitro stability were investigated using different ancillary ligands. Results showed that SNS-type ligands afforded the highest labeling yields and the most robust 3+1 nitrido complexes with both (99m)Tc and (188)Re. Thus, the new chelating system can be conveniently employed for labeling peptides and other biomolecules with the [M Ξ N]2+ group.

Technetium-99m (Tc-99m) has long been a mainstay in clinical nuclear medicine, primarily monitoring biological processes in the heart, kidney, liver, and brain. More recently, Tc-99m chelates have been used as the reporter in targeted nuclear medicine probes that monitor changes in specific protein expression products. The strengths remain the inexpensive source of Tc-99m from the Mo-99/Tc-99m generator, its rich chemistry, high-yield kit formulation, and its widespread availability. Hardware and software advances, such as OSEM reconstructions with scatter and attenuation corrections, have led to quantitation of the injected radioactivity in terms of kBq/cm.