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Abstract 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 in many aspects.

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.

Abstract 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.

Abstract Background The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to update the readership on trends in the field of radiopharmaceutical development. Results This 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. Conclusion Trends in radiochemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry.

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.

The cross sections of the 68Zn(p,2p)67Cu,68Zn(p,2n)67Ga and 68Zn(p,3n)66Ga reactions were measured at the ARRONAX facility by using the 70 MeV cyclotron, with particular attention to the production of the theranostic radionuclide 67Cu. Enriched 68Zn material was electroplated on silver backing and exposed to alow-intensity proton beam by using the stacked-foils target method. Since 67Cu and 67Ga radionuclides have similar half-lives and same γ-lines (they both decay to 67Zn), a radiochemical process aimed at Cu/Ga separation was mandatory to avoid interferences in γ-spectrometry measurements. A simple chemical procedure having a high separation efficiency (>99%)was developed and monitored during each foil processing, thanks to the tracer isotopes 61Cu and 66Ga.Nuclear cross sections were measured in the energy range 35-70 MeV by using reference reactions recommended by the International Atomic Energy Agency (IAEA) to monitor beam flux. In comparison with literature data a general good agreement on the trend of the nuclear reactions was noted, especially with latest measurements, but slightly lower values were obtained in case of 67Cu. Experimental results of the 68Zn(p,2p)67Cu,68Zn(p,2n)67Ga and 68Zn(p,3n)66Ga reactions were also compared with the theoretical values estimated by using the nuclear reaction code TALYS. The production yield of the theranostic radionuclide 67Cu was estimated considering the results obtained in this work.

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.

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.

(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 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.

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.

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≡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≡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.

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.

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.Uma nova classe de complexos de Tc-99m capazes de atravessar a barreira hemato-encefálica foi investigada e descrita neste trabalho. Estes compostos são formados reagindo os precursores bissubstituídos do nitrido [99mTc(N)(PS)2] (PS = phosphino-tiol ligante) com trietillborano (BEt3) sob restritas condições anidras e usando solventes não aquosos. A estrutura molecular desses traçadores não foi totalmente estabelecida, mas evidências experimentais preliminares sugerem que eles resultam da interação da base de Lewis [99mTc(N)(PS)2] com o ácido de Lewis BEt3, levando a formação do novo aducto -B-Nº Tc-. Após purificação e recuperação em uma solução fisiológica, os novos derivados borano-nitrido-Tc-99m foram injetados em ratos para avaliação de seu comportamento biológico in vivo. Os resultados mostraram uma acumulação significativa no tecido cerebral, indicando que estes complexos são capazes de atravessar a barreira hemato-encefálica íntegra. A captação pelo sistema nervosa central foi confirmada pela imagem da distribuição de atividade em animais vivos, usando um scanner para animais pequenos (YAP(S)SPECT).

The chemical methods for the production of technetium-99m radiopharmaceuticals containing a terminal TcºN triple bond have been established more than a decade ago. From that time, the chemistry of nitrido Tc-99m complexes has provided a highly efficient tool for the design and preparation of novel classes of diagnostic agents, and a number of potentially useful radiopharmaceuticals have been discovered. In particular, nitrido technetium-99m tracers have been developed for heart perfusion imaging. In this short review, the chemical and biological properties of the neutral myocardial perfusion tracer bis(N-ethoxy, N-ethyl-dithiocarbamato) nitrido Tc-99m (TcN-NOEt) will be summarized along with the preparation and preliminary biological evaluation of the first class of monocationic nitrido technetium-99m radiopharmaceuticals exhibiting improved biodistribution properties closer to those expected for an ideal perfusion imaging agent.Os métodos químicos para produção de radiofármacos marcados com tecnécio-99m contendo a ligação tripla terminal TcºN foram estabelecidos há mais de uma década. Desde esta época, a química dos complexos nitridos marcados com 99mTc tem sido uma ferramenta altamente eficiente para o desenho e preparo de novas classes de agentes para diagnóstico e, foi descoberto um número de radiofarmacos potencialmente úteis. Nesta pequena revisão, as propriedades biológicas e químicas do traçador para perfusão miocárdica neutra, o bis(N-etoxi, N-etil-ditiocarbamato) nitrido 99mTc (TcN-NOEt), serão resumidas junto com o preparo e avaliação biológica preliminar da primeira classe de radiofármacos nitrido monocatiônico marcado com tecnécio-99m que exibe melhores propriedades em relação à biodistribuição, mais próximas daquelas esperadas para um agente perfusor ideal para imagens.

Despite the advances associated with the introduction of PET technology, reasons to consider that SPECT, particularly with radiopharmaceuticals will continue playing an important role in Nuclear Medicine, are presented. The details examined are the following ones. An improvement of the technology SPECT is appreciated with the development of new detection systems and the advantages of the appearance of the hybrid systems SPECT / TAC. The biggest half-life of the main SPECT radionuclides like and in comparison with PET radionuclides, facilitates its transportation at larger distances, allow the realization of studies with radiopharmaceuticals with different radionuclides in the same patient, and the possibility of the detection of lesions of low tracer accumulation. Finally the main base core for complex formation with different ligands are reviewed, as a background that assure the appearance of new radiopharmaceuticals of practical interest. The oncological and cardiological potential applications are examined with emphasis in these last ones. It is clear that radiopharmacy will continue playing an important role in nuclear medicine.