Technetium Nitrido-Peroxo Complexes: An Unexplored Class of Coordination Compounds

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]− (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

Novel Tc-99m radiotracers for brain imaging

A novel class of Tc-99m complexes able to cross the blood brain barrier has been investigated and described here. These compounds are formed by reacting the bis-substituted nitrido precusors [99mTc(N)(PS)2] (PS = phosphino-thiol ligand) with triethylborane (BEt3) under strictly anhydrous conditions and using non-aqueous solvents. The molecular structure of these tracers was not fully established, but preliminary experimental evidence suggests that they result from the interaction of the Lewis base [99mTc(N)(PS)2] with the Lewis acid BEt3, which leads to the formation of the novel -B-Nº Tc- adduct. After purification and recovery in a physiological solution, the new borane-nitrido Tc-99m derivatives were injected in rats for evaluating their in vivo biological behavior. Results showed a significant accumulation in brain tissue, thus indicating that these complexes are capable of penetrating the intact blood brain barrier. Uptake in the central nervous system was confirmed by imaging the distribution of activity on the integrated living animal using a YAP(S)SPECT small animal scanner

Design and synthesis of99mTcN-labeled dextran-mannose derivatives for sentinel lymph node detection

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 with99mTc 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≡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 macromolecular99mTc 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≡N]2+core. Conclusions: High-specific-activity labeling has been obtained by simple mixing and heating of the [99mTc≡N]2+group with the new mannose-dextran derivatives

Preparation and frst biological evaluation of novel Re-188/Tc-99m peptide conjugates with substance-P

Introduction: New 188Re and 99mTc peptide conjugates with substance- P (SP) were prepared and biologically evaluated. The radiopharmaceuticals have been labelled with the [M=N]2+ (M=99mTc, 188Re) core using a combination of pi-donor tridentate and pi-acceptor monodentate ancillary ligands. Methods: The new radiopharmaceuticals have been prepared through a two-step reaction by simultaneous addition of the tridentate and monodentate ligands to a vial containing a preformed [M=N]2+ core. The tridentate ligand was formed by linking two cysteine residues to the terminal arginine of the undecapeptide SP, whereas the monodentate ligand was a tertiary phosphine. The preparation of the corresponding Re-188 derivative required developing a more complex chemical procedure to obtain the [Re=N]2+ core in satisfactory yields. Characterization of the resulting products was obtained by chromatographic methods. Biological evaluation was performed for both Tc-99m and Re-188 derivatives by in-vitro studies on isolated cells expressing NK1-receptors. In-vivo imaging in mice was carried out using a small-animal YAP(S)PET tomograph. Conclusion: New Tc-99m and Re-188 peptide radiopharmaceuticals with SP have been prepared in high yield and with high-specifc activity. Both Tc-99m and Re-188 peptide radioconjugates exhibit high affnity for NK1 receptors, thus giving further evidence to the empirical rule that structurally related Tc-99m and Re-188 radiopharmaceuticals exhibit identical biological properties

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 from99Mo/99mTc generators as pertechnetate ion, which is the ubiquitous starting material for the preparation of99mTc radiopharmaceuticals.99Mo in such generators is currently produced in nuclear fission reactors as a by-product of235U fission. Here we investigated an alternative route for the production of99Mo 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 final99mTc-pertechnetate was carried out by means of solvent extraction. Monte Carlo simulations allowed reliable predictions of99Mo 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 1015s−1, may potentially supply an appreciable fraction of the current99Mo 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 of99Mo

Highlight selection of radiochemistry and radiopharmacy developments by editorial board

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 commentary of highlights has resulted in 21 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals. Conclusion: Trends in radiochemistry and radiopharmacy are highlighted demonstrating the progress in the research field in various topics including new PET-labelling methods, FAPI-tracers and imaging, and radionuclide therapy being the scope of EJNMMI Radiopharmacy and Chemistry

IAEA Contribution to Nanosized Targeted Radiopharmaceuticals for Drug Delivery

The rapidly growing interest in the application of nanoscience in the future design of radiopharmaceuticals and the development of nanosized radiopharmaceuticals in the late 2000 ' s, resulted in the creation of a Coordinated Research Project (CRP) by the International Atomic Energy Agency (IAEA) in 2014. This CRP entitled 'Nanosized delivery systems for radiopharmaceuticals' involved a team of expert scientist from various member states. This team of scientists worked on a number of cutting-edge areas of nanoscience with a focus on developing well-defined, highly effective and site-specific delivery systems of radiopharmaceuticals. Specifically, focus areas of various teams of scientists comprised of the development of nanoparticles (NPs) based on metals, polymers, and gels, and their conjugation/encapsulation or decoration with various tumor avid ligands such as peptides, folates, and small molecule phytochemicals. The research and development efforts also comprised of developing optimum radiolabeling methods of various nano vectors using diagnostic and therapeutic radionuclides including Tc-99m, Ga-68, Lu-177 and Au-198. Concerted efforts of teams of scientists within this CRP has resulted in the development of various protocols and guidelines on delivery systems of nanoradiopharmaceuticals, training of numerous graduate students/post-doctoral fellows and publications in peer reviewed journals while establishing numerous productive scientific networks in various participating member states. Some of the innovative nanoconstructs were chosen for further preclinical applications-all aimed at ultimate clinical translation for treating human cancer patients. This review article summarizes outcomes of this major international scientific endeavor

Highlight selection of radiochemistry and radiopharmacy developments by editorial board

BackgroundThe Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to update the readership on trends in the field of radiopharmaceutical development.ResultsThis commentary of highlights has resulted in 23 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals.ConclusionTrends in radiochemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry

Highlight selection of radiochemistry and radiopharmacy developments by editorial board

BackgroundThe Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to update the readership on trends in the field of radiopharmaceutical development.ResultsThis commentary of highlights has resulted in 23 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals.ConclusionTrends in radiochemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry.</p

The DOTA macrocyclic cavity in metallic radiopharmaceuticals: Mythology or reality?

Abstract Background The hypothetical concept of ‘macrocyclic cavity’ is largely employed as useful model to interpret the affinity of metal ions for the macrocyclic chelating ligand 2,2′,2′′,2′′′-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (H4DOTA). It Is hypothesized that a close matching between the size of the macrocyclic cavity and that of the metallic ion is a key parameter to ensure the high-yield formation of stable coordination metal-DOTA complex. This approach has become popular in the design of radiopharmaceuticals containing radiometals and H4DOTA as chelating group. Results Based on X-ray structural data of metallic complexes formed by the ligand H4DOTA upon coordination with a variety of metals, an elementary argument based on Euclidean geometry is presented here that questions the existence of the hypothetical ‘macrocyclic cavity’ within the chelator macrocycle. The geometrical analysis was applied to the complex formed by a Ga3+ ion coordinated to H4DOTA as model compound. Conclusions Application of Euclidean geometry to calculate bond angles in the coordination complex of the ligand H4DOTA with the Ga+3 ion, supposed to incorporate a hypothetical ‘macrocyclic cavity’, revealed that this conceptual entity has no physical reality and, therefore, cannot be considered a meaningful description of a stable structural arrangement for metallic radiopharmaceuticals