Radiopharmaceutical Research Research Articles

The development of technology of Fludeoxyglucose (18F) for injection, laboratory analysis methods

18F-Fluorodeoxyglucose has optimal characteristics for use in nuclear medicine and is a priority among radiopharmaceuticals for the diagnosis of cancer by positron emission tomography (PET). 18F-Fluorodeoxyglucose has the longest half-life with the lowest energy of radiation, it allows to obtain PET images of high contrast at low dose loading on the patient. Low energy positron radiation provides high spatial resolution of PET images. However, the half-life of 18F-Fluorodeoxyglucose is large enough to allow the transportation of radiopharmaceuticals from the centralized production site to diagnostic centers with PET scanners (the so-called PET satellite concept), and to extend the time limits of PET research and synthesis of radiopharmaceuticals [1].
 The study is the development of technology and quality control methods to ensure quality at all stages of the production of radiopharmaceuticals 18F-Fluorodeoxyglucose, injection.
 There was justified 18F-Fluorodeoxyglucose production technology and quality control at all stages of production, based on complex research in the department producing radiopharmaceuticals Ukrainian Center of radiosurgery consisting Clinical Hospital «Feofaniya».
 Object of study – 18F-Fluorodeoxyglucose, injection, injection is used in nuclear medicine for PET diagnosis of cancer.
 We used the biopharmaceutical and pharmaceutical methods.
 For the first time based pharmaceutical research was the rational technology of diagnostic radiopharmaceuticals 18F-Fluorodeoxyglucose, injection for use in PET diagnosis of cancer patients. Methods of controlling drug 18F-Fluorodeoxyglucose, injection according monographs of the State Pharmacopoeia of Ukraine. On the basis of the analysis developed by established methods of control performance specifications and shelf life of radiopharmaceuticals 18F-Fluorodeoxyglucose, injection.

Calibration of the LDI/CDTN Whole Body Counter us-ing two physical phantoms

The Laboratory of Internal Dosimetry of the Center for Development of Nuclear Technology (LDI/CDTN) is responsible for routine monitoring of internal contamination of the Individuals Occupationally Exposed (IOEs) at the Unit for Research and Production of Radiopharmaceuticals (UPPR/CDTN), the Research Reactor TRIGA-IPR-R1/CDTN and other workplaces of the institute where there is a risk of accidental intakes. Additionally, LDI supports the Institute of Radiation Protection and Dosimetry (IRD/CNEN) to attend radiological emergencies. The determination of photon emitting radionuclides in the human body requires the use of calibration techniques in different counting geometries for converting the count rates into activity in organs and tissues. This paper presents and discusses the calibration of the LDI/CDTN Whole Body Counter (WBC) using a standard BOMAB phantom (Bottle Mannequin Absorber) compared to a home-made phantom produced with Polyethylene Terephthalate bottles (PET). Initially, the BOMAB was filled with a cocktail containing 60 Co, 137 Cs and 133 Ba. The phantom was counted at the LDI whole body counter and an Efficiency x Energy curve was obtained. Subsequently the PET-BOMAB was filled with the same standard source and a second curve was determined. The efficiency values in each region of interest as well as the shape of both curves were found to be equivalent. The results validate the use of the PET-BOMAB for the calibration of whole body geometry applied to the measurement of high energy radionuclides in the energy region evaluated in this work.

Conceptual Proposal of a Facility Design for Accommodating Minipigs for Pharmaceutical and Radiopharmaceutical Research

Conceptual Proposal of a Facility Design for Accommodating Minipigs for Pharmaceutical and Radiopharmaceutical Research

CALCULATION STUDIES OF SPATIAL DISTRIBUTION OF THE ABSORBED DOSE RATE FOR VARIOUS SEEDS

Purpose . Conducting computational studies of dosimetric characteristics of microsources with the radionuclide I‑125, pilot production of which is established in the research and production complex of isotope and radiopharmaceuticals, JSC “State Scientific Centre of the Russian Federation — Institute for Physics and Power Engineering named after A. I. Leypunsky” (SSC RF IPPE). Sources of production IPPE are similar to the model 6711 of the company Nicomed Amersham, dosimetric characteristics of which are standardized in accordance with the TG43 AAPM formalism. Materials and methods. Microsourse «SEED No. 6711» (model of the company Nicomed Amersham) is hermetically sealed in a titanium capsule silver rod covered with a thin layer of radioactive I‑125. The half-life of iodine‑125 is 59,43 days. In the process of decay of I‑125 is converted into the Te‑125. Calculation of parameters of microsources and their comparison with the standard model 6711 is carried out with use of the computer code MCNP. Results . The method of calculation of the basic dosimetric characteristics of the microsourse SSC RF-IPPE in accordance with the TG43 formalism is developed. A comparative analysis of experimental data and calculated results by MCNP code, which allowed to identify possible reasons for differences, is performed. The estimated dose characteristics and recommended standard data for dose characteristics of micro «SEED No. 6711» are compared. Conclusions . There are two possible reasons for the differences between experimental and calculated results. The first one may be the roughness of the surface of a silver rod or diffusion of radioactive iodine in silver. The second reason might be the difference of the cross sections of the characteristic radiation of silver used in MCNP code. In the comparison of calculated dose characteristics and recommended standard the role of the application activity is very important. In compliance with the standard conditions on the composition of the environment, water phantom and air with 40% humidity, the results obtained are outside the acceptable difference of 3% from the recommended data. While the variation of only the thickness of the deposition of radioactive material in the 0–10 mkm change dosimetric characteristics in the range of 15–20%.

Chemical, radiochemical and biological studies of new gallium(III) complexes with hexadentate chelators.

New N4O2-donor acyclic chelators 2-[[2-[2-(3,5-dimethylpyrazol-1-yl)ethyl-[2-[(2-hydroxyphenyl)methylamino]ethyl]amino]ethylamino]methyl]phenol (H2L(pz*,NH)) and 2-[[2-[2-[(2-hydroxyphenyl)methylamino]ethyl-(2-pyridylmethyl)amino]ethylamino]methyl]phenol (H2L(py,NH)) were obtained upon introduction of pyridyl or pyrazolyl coordinating units at the central nitrogen atom of diethylenetriamine (dien) and by functionalization of its terminal amines with phenol groups. The coordination behavior of H2L(pz*,NH) and H2L(py,NH) was evaluated towards (nat)Ga/(67)Ga, aiming to assess their suitability to obtain Ga(iii) chelates relevant for biomedical applications. Single crystal X-ray diffraction analysis of the complexes [GaL(pz*,NH)](ClO4) and [GaL(py,NH)](ClO4) confirmed the presence of N4O2-hexadentate chelators with the phenoxide groups coordinated cis relatively to the pyridyl/pyrazolyl arms. Unlike [GaL(pz*,NH)](ClO4), [GaL(py,NH)](ClO4) exists in solution as a mixture of isomers, as confirmed by several NMR techniques. The corresponding radiocomplex [(67)GaL(py,NH)](+) was obtained smoothly in almost quantitative radiochemical yield, contrary to [(67)GaL(pz*,NH)](+) that seems to be (hemi)labile under the same conditions. [(67)GaL(py,NH)](+) presents a high in vivo stability and a favourable biodistribution profile in mice. The imine congeners 2-[(E)-2-[2-(3,5-dimethylpyrazol-1-yl)ethyl-[2-[(E)-(2-hydroxyphenyl)methyleneamino]ethyl]amino]ethyliminomethyl]phenol (H2L(pz*,C[double bond, length as m-dash]N)) and 2-[(E)-2-[2-[(E)-(2-hydroxyphenyl)methyleneamino]ethyl-(2-pyridylmethyl)amino]ethyliminomethyl]phenol (H2L(py,C[double bond, length as m-dash]N)) were also evaluated but they did not form complexes compatible for biomedical applications owing to their high reactivity.

Radiochemistry course in the undergraduate nuclear science program at Universiti Kebangsaan Malaysia

Universiti Kebangsaan Malaysia offered an undergraduate degree program in Nuclear Science since 1980 and the programme has undergone several modifications due to changes in national policy and priority. The programme covers nuclear sub-disciplines such as nuclear physic, radiobiology, radiochemistry, radiation chemistry and radiation safety. The radiochemistry component consists of radiochemistry, chemistry in nuclear industry, radiochemical analysis laboratory, radiopharmaceutical chemistry subjects and mini research project in radiochemistry.

A PET-Compatible Tissue Bioreactor for Research, Discovery, and Validation of Imaging Biomarkers and Radiopharmaceuticals: System Design and Proof-of-Concept Studies

Research and discovery of novel radiopharmaceuticals and targets thereof generally involves initial studies in cell cultures, followed by animal studies, both of which present several inherent limitations. The objective of this work was to develop a tissue bioreactor (TBR) enabling modulation of the microenvironment and to integrate the TBR with a small-animal PET scanner to facilitate imaging biomarker research and discovery and validation of radiopharmaceuticals. The TBR chamber is a custom-blown, water-jacketed, glass vessel enclosed in a circulating perfusion bath powered by a peristaltic pump, which is integrated within the field of view of the PET scanner. The chamber is in series with a gas exchanger and a vessel for degassing the system during filling. Dissolved oxygen/temperature probes and septa for injection or sampling are located at the inlet and outlet of the cell chamber. A pH probe is located at the chamber outlet. Effluent is collected in the fraction collector as mixed-cup samples. In addition, both medium and tissue chamber can be sampled to investigate tissue and secretory products through multiscale analysis. As a proof of concept, we studied the effects of lipids on glucose uptake using HepG2 cells. To that end, we varied the nutrient substrate environment over a period of approximately 27 d, before and after the addition of lipids, and studied the effects of pioglitazone, a peroxisome proliferator-activated receptor γ agonist, on lipid and glucose uptake. In parallel, the TBR was imaged by PET in conjunction with (11)C-palmitate in the presence and absence of lipids to characterize (11)C-palmitate uptake. The O2 consumption, glucose consumption, lactate production, and free fatty acid consumption and production rates were consistent in demonstrating the effects of lipids on glucose uptake. Pioglitazone exhibited improved glucose uptake within 3 d of treatment. Semiquantitative analysis suggested that lipids induced greater (11)C-palmitate uptake. The integrated TBR offers a platform to monitor and modulate the tissue microenvironment, thus facilitating tissue-specific imaging and therapeutic biomarkers of disease, identification of molecular diagnostic markers, and validation of radiopharmaceuticals in both rodent and human cell lines.

Clinical and Translational Imaging: reviews in nuclear medicine and molecular imaging

Clinical and Translational Imaging is the new official organ of the Italian Association of Nuclear Medicine and Molecular Imaging (AIMN). This association, long committed to consistently raising the standard and impact of its scientific publications, and feeling that the time is ripe for a qualitative leap forward, is embarking on this exciting project strengthened by the support and experience of a prestigious partner, Springer, whose vision and priorities are very much in line with its own. Clinical and Translational Imaging is an international peer-reviewed journal specifically devoted to review articles on translational and clinical imaging in the field of nuclear medicine and molecular imaging. The journal aims to offer this fast-evolving field a new perspective and a new kind of publication. Indeed, the intention, in launching this journal, is not to compete with existing ones, but rather to complement them. Traditional imaging journals tend to devote most of their space to original scientific papers, but these, by definition, often present highly specific and sometimes controversial data and, therefore, fail to convey a clear message to the more clinically oriented reader. These valuable data urgently need to be translated, compiled and delivered to the reader in a readily comprehensible and applicable format, thereby increasing their diffusion and impact. Furthermore, the increasingly large volume of scientific papers published in the field of imaging has created a real need for a more systematic appreciation and overview of the different currents of thought and future directions that are stemming from specific research findings, and thus for in-depth critical reviews that provide methodologically sound and clinically useful analyses of these data. In short, Clinical and Translational Imaging intends, through its targeted review articles, to draw attention to on going efforts to translate basic science into clinical application. To this end, our policy is to publish papers that present, in a descriptive manner, evidence-based diagnostic and therapeutic strategies and best practices, but we will also be looking for papers that are visionary and anticipate new developments, including policy recommendations designed to advance the field of medical imaging worldwide. The journal will welcome timely and updated summaries on clinical practice and translational research and clinical applications of approved and experimental radiopharmaceuticals for diagnostic and therapeutic use. Papers dealing with advanced preclinical evidence in the fields of physics, dosimetry, radiation biology and radiopharmacy with relevance to upcoming applications in human subjects are also within the scope of the journal. Thanks to the support of expert peer-reviewers and a distinguished editorial board, which includes internationally renowned experts, Clinical and Translational Imaging is expected to rapidly establish itself as a valuable, authoritative and selective reference tool. The journal will appear bimonthly and will be made available through Springer’s online platform SpringerLink, thereby guaranteeing articles rapid international exposure. All manuscripts will undergo the rigorous peer-review process that is required by any international journal aiming to furnish a reliable body of research data and knowledge. The editorial board has decided to publish a limited number of monographic issues, each of which will have a guest editor or editors and feature contributions from invited authors. These invited papers will be peerreviewed. G. Lucignani (&) Universita degli Studi di Milano, A.O. San Paolo, Milan, Italy e-mail: giovanni.lucignani@unimi.it

An overview of translational (radio)pharmaceutical research related to certain oncological and non-oncological applications.

Translational medicine pursues the conversion of scientific discovery into human health improvement. It aims to establish strategies for diagnosis and treatment of diseases. Cancer treatment is difficult. Radio-pharmaceutical research has played an important role in multiple disciplines, particularly in translational oncology. Based on the natural phenomenon of necrosis avidity, OncoCiDia has emerged as a novel generic approach for treating solid malignancies. Under this systemic dual targeting strategy, a vascular disrupting agent first selectively causes massive tumor necrosis that is followed by iodine-131 labeled-hypericin ((123)I-Hyp), a necrosis-avid compound that kills the residual cancer cells by crossfire effect of beta radiation. In this review, by emphasizing the potential clinical applicability of OncoCiDia, we summarize our research activities including optimization of radioiodinated hypericin Hyp preparations and recent studies on the biodistribution, dosimetry, pharmacokinetic and, chemical and radiochemical toxicities of the preparations. Myocardial infarction is a global health problem. Although cardiac scintigraphy using radioactive perfusion tracers is used in the assessment of myocardial viability, searching for diagnostic imaging agents with authentic necrosis avidity is pursued. Therefore, a comparative study on the biological profiles of the necrosis avid (123)I-Hyp and the commercially available (99m)Tc-Sestamibi was conducted and the results are demonstrated. Cholelithiasis or gallstone disease may cause gallbladder inflammation, infection and other severe complications. While studying the mechanisms underlying the necrosis avidity of Hyp and derivatives, their naturally occurring fluorophore property was exploited for targeting cholesterol as a main component of gallstones. The usefulness of Hyp as an optical imaging agent for cholelithiasis was studied and the results are presented. Multiple uses of automatic contrast injectors may reduce costs and save resources. However, cross-contaminations with blood-borne pathogens of infectious diseases may occur. We developed a radioactive method for safety evaluation of a new replaceable patient-delivery system. By mimicking pathogens with a radiotracer, we assessed the feasibility of using the system repeatedly without septic risks. This overview is deemed to be interesting to those involved in the related fields for translational research.

Radiochemistry on chip: towards dose-on-demand synthesis of PET radiopharmaceuticals

We have developed an integrated microfluidic platform for producing 2-[(18)F]-fluoro-2-deoxy-D-glucose ((18)F-FDG) in continuous flow from a single bolus of radioactive isotope solution, with constant product yields achieved throughout the operation that were comparable to those reported for commercially available vessel-based synthesisers (40-80%). The system would allow researchers to obtain radiopharmaceuticals in a dose-on-demand setting within a few minutes. The flexible architecture of the platform, based on a modular design, can potentially be applied to the synthesis of other radiotracers that require a two-step synthetic approach, and may be adaptable to more complex synthetic routes by implementing additional modules. It can therefore be employed for standard synthesis protocols as well as for research and development of new radiopharmaceuticals.

Group 7 transition metal complexes with N-heterocyclic carbenes

This tutorial review summarizes all works and highlights recent advances published in the growing field of group 7 N-heterocyclic carbene (NHC) complexes. It provides a valuable source for all scientists that are interested in conducting research with new compounds bearing these metals. The article provides an overview of all manganese NHC complexes that are known to date. There are a lot of examples where manganese NHC complexes show unpredicted behaviour during synthesis, very different from other transition metal NHC complexes and their higher homologues rhenium and technetium. These differences are depicted and discussed. Furthermore, the chemistry of technetium NHC compounds and their chemical behaviour are discussed. To date published work on technetium NHC chemistry has been restricted to the oxidation state +v. It was found that such compounds are very reactive but show great stability in dry air. Their radioactivity makes such compounds interesting candidates for radiochemical applications. Since most group 7 NHC chemistry was conducted on rhenium NHC complexes, this tutorial review highlights the chemical behaviour of such compounds. Rhenium(i) complexes reveal luminescent properties, making them interesting candidates for applications ranging from biological markers to organic light-emitting diodes (OLEDs). Another interesting feature is the radioactivity of some compounds, which makes them excellent candidates for radiopharmaceutical research; hence their synthesis and reactivity are discussed.

Synthesis, in vitro and in vivo characterization of two novel 68Ga-labelled 5-nitroimidazole derivatives as potential agents for imaging hypoxia

Hypoxia imaging is an important field in radiopharmaceutical research since hypoxic cells are very resistant to radiation treatment and diffusional limitations restrict the efficacy of chemotherapy. Gallium-68 is a widely used radionuclide for positron emission tomography (PET) due to the availability of the (68)Ge/(68)Ga-generator. With the aim to develop new potential [(68)Ga]-radiopharmaceuticals for imaging hypoxia, we have synthesized and evaluated two novel (68)Ga-labelled 5-nitroimidazole derivatives. Two 5-nitroimidazole derivatives, and were synthesized. Preparation of [(68)Ga]complexes [(68)Ga]-Nit1 and [(68)Ga]-Nit2 was performed at pH 4.5 and 95 °C during 15 minutes and radiochemical purity (RP) was evaluated by reverse phase HPLC. Stability, lipophilicity and plasma protein binding were studied. Biological behaviour in HCT-15 cells both in normoxia and hypoxia has been assessed. Biodistribution in animals bearing induced 3LL Lewis murine lung carcinoma was studied. Comparison with [(18)F]FMISO is also presented. Nit1 and Nit2 have been successfully synthesized. Labelling in high radiochemical purity was achieved for both ligands. Complexes are stable in labelling milieu for at least four hours and in human plasma or in the presence of an excess of DTPA for at least two hours. Both compounds showed high uptake in hypoxic cells in vitro and a very favourable biodistribution profile in mice bearing induced tumours. Results are comparable to those obtained for [(18)F]FMISO. Selective uptake and retention in tumour together with favourable tumour/muscle ratio make these compounds promising candidates for further evaluation as potential hypoxia imaging agents.

Synthesis, in vitro and in vivo characterization of novel 99mTc-‘4+1’-labeled 5-nitroimidazole derivatives as potential agents for imaging hypoxia

The evaluation of oxygenation status of solid tumors is an important field of radiopharmaceutical research. With the aim to develop new potential 99mTc-radiopharmaceuticals for imaging hypoxia, we have synthesized two novel isocyanide derivatives of metronidazole, which has demonstrated high affinity for hypoxic tumors in vitro and in vivo. Metronidazole derivatives 4-isocyano-N-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]butanamide (M1) and 1-(4-isocyanobutanoyl)-4-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]piperazine (M2) were synthesized, and labeling was performed through preparation of their corresponding 99mTc-(4+1) complexes, 99mTc-NS3M1 and 99mTc-NS3M2. The structure of the technetium complexes was corroborated by preparation and characterization of the corresponding rhenium complexes. We have studied the main physicochemical properties (stability, lipophilicity and plasma protein binding). Biological behavior in HCT-15 cells both in oxia and in hypoxia was assessed. Biodistribution in normal mice and in animals bearing induced 3LL Lewis murine lung carcinoma was also studied. Metronidazole derivatives were successfully synthesized. Labeling with high radiochemical purity was achieved for both ligands. 99mTc complexes were stable in labeling milieu and human plasma. However, presence of the piperazine linker in M2 resulted in higher lipophilicity and protein binding. Although cell uptake in hypoxic conditions was observed for both radiotracers, 99mTc-NS3M2 biodistribution was considered unsuitable for a potential radiopharmaceutical due to high liver uptake and poor blood clearance. However, 99mTc-NS3M1 demonstrated a very favorable in vivo profile both in normal mice and in mice bearing induced tumors. Selective uptake and retention in tumor together with favorable tumor/muscle ratio make 99mTc-NS3M1 a promising candidate for further evaluation as potential hypoxia imaging agent in tumors.

Subtype-Selective Dopamine Receptor Radioligands for PET Imaging: Current Status and Recent Developments

This review presents a general overview of the subtype-selective dopamine receptor radioligands for in vivo imaging of dopamine receptor expression by positron emission tomography (PET). Besides the (11)C- and (18)F-labeled radioligands which are already in clinical use, a summary of subtype-selective radioligands which had been studied in vitro and in vivo is provided, which shines light onto the current status and recent developments in this field of radiopharmaceutical research.

The Unrealized Potential of 34mCl for Radiopharmaceutical Research with PET

The unstable isotopes of chlorine have a brief history limited largely to production from sulphur isotopes. Recent improvements in accelerator targetry have made radiochlorine available from small cyclotrons, and concurrent research into labeling chemistry suggests both electrophilic and nucleophilic avenues for the synthesis of novel imaging probes. The prevalence of chlorine compounds from anthropogenic and natural sources offers varied and fertile ground for future scientific explanation with their radiolabeled counterparts.

Dose-on-demand of diverse 18F-fluorocholine derivatives through a two-step microfluidic approach

The validation and confirmation of clinical usefulness of new and known positron emission tomography (PET) tracers require stable production routes and simple and robust radiochemical procedures. Microfluidic technologies are regarded as an approach that could allow an unprecedented flexibility and productivity in PET radiopharmaceutical research. In this work, we will show how a commercially available microfluidic system can be used for a sequential and repeatable radiosynthesis of three different fluorocholine analogues currently under investigation as tumor tracers. Advion microfluidic system was used for performing the synthesis and purification of [(18)F]fluoromethyl, [(18)F]fluoroethyl or [(18)F]fluoropropyl choline employing a two-step approach, starting from the corresponding alkyl-ditosylate and reacting the [(18)F]fluorotosylate obtained in the first step with neat dimethylethanolamine. The purification was obtained using a recyclable SPE cartridge set. The three products, fluoromethylcholine, fluoroethylcholine and fluoropropylcholine, were obtained in good to optimum yields (22%-54% decay corrected) with a 15-min procedure. The production could be restarted several times for producing each one of the tracers without decrease in yields and purities, in accordance with a dose-on-demand (DOD) approach. The final products were formulated in isotonic saline solution. The described approach gives a proof of principle of the enhanced productivity obtainable using a microfluidic approach; in particular, the possibility to produce the reported tracers in a DOD fashion following a homogeneous synthetic and purification approach will foster further studies on the clinical evaluation of the best fluorocholine analogue for prostate cancer imaging without biasing for differences in radiochemical approach.

99mTc-centered one-pot synthesis for preparation of 99mTc radiotracers

Nuclear medicine relies on two main imaging modalities: single photon emission computed tomography (SPECT) and positron emission tomography (PET). Radiopharmaceuticals (or radiotracers) are the blood stream of nuclear medicine for the diagnosis or therapy of diseases. Diagnostic radiotracers that are small molecules labelled with a gamma-emitter for SPECT or positron-emitter for PET provide a non-invasive method to assess the disease or disease states and monitor the therapeutic efficacy of a specific treatment regime. Over the past four decades, radiopharmaceutical research has been practising one-pot synthesis at the tracer level (10(-7)-10(-6) M). Many (99m)Tc radiotracers currently used in nuclear medicine are routinely prepared by following the basic principles of one-pot synthesis. Unlike traditional organic one-pot synthesis, which often involves the formation of multiple C-C and C-heteroatom bonds in a single step, the (99m)Tc-centered one-pot synthesis requires the formation of multiple coordination bonds between Tc and various donor atoms, such as N, O, S and P. This review will illustrate how the (99m)Tc-centered one-pot synthesis is utilized for routine preparations of different (99m)Tc radiotracers.

Re and Tc Complexes with Pyrazolyl-Containing Chelators: from Coordination Chemistry to Target-Specific Delivery of Radioactivity

The design of novel target-specific imaging agents based on 99mTc requires a considerable development of its coordination chemistry. Among all oxidation states available for technetium (-I to VII), the V oxidation state has been the most extensively studied in radiopharmaceutical chemistry, and the majority of the 99mTc-radiopharmaceuticals in clinical use contain the core [99mTc(O)]3+. More recently, the remarkable features of the organometallic precursor fac- [M(CO)3(H2O)3]+ (M = Re, Tc), introduced by Alberto et al., brought renewed interest in the design of innovative lowoxidation 99mTc-based radiopharmaceuticals. Owing to our interest on the design of innovative target-specific radioactive probes, we have been recently involved in the study of the chemistry of [M(O)]3+ and fac-[M(CO)3]+ (M = Re, Tc) with chelators combining a pyrazolyl unit with aliphatic amines and/or carboxylic acids or thioethers. Such research efforts are reviewed herein, where we present an overview of the chemistry, radiochemistry and biological properties of Re and 99mTc complexes anchored by those pyrazolyl-containing chelators with relevance in radiopharmaceutical research. The revised work focuses mainly on tricarbonyl M(I) complexes but M(V) oxocomplexes are also covered. This contribution intends to highlight the potential of pyrazolyl-containing chelators for the labeling of biologically active molecules with 99mTc(I), being presented a variety of examples which include peptides, peptide nucleic acids, inhibitors/substrates of enzymes and DNA-binders.

Blood plasma model predictions for the proposed bone-seeking radiopharmaceutical [117mSn]Sn(IV)-N,N′,N′-trimethylenephosphonate-poly(ethyleneimine)

In an attempt to elucidate the in vivo stability of the prospective radiopharmaceutical [(117m)Sn]Sn(IV)-PEI-MP, where PEI-MP stands for N,N',N'-trimethylenephosphonate-polyethyleneimine, glass electrode potentiometry was used to determine the stability constants of the Sn(4+) ion as complexed with a variety of physiological amino acids. In addition, linear free energy relationship (LFER) correlation plots were used to extrapolate the constants of the major blood plasma ligands, based on data from Cu(2+), Pb(2+), and Zn(2+). In so doing, a thermodynamic model of blood plasma was established for Sn(4+) from which the complexation tendencies of Sn(4+) were predicted in the event of the intravenous administration of such a drug. It was found that the Sn(IV)-PEI-MP could succumb to competition by the glutamine amino acid, which forms more stable complex(es), whilst the PEI-MP gets taken up largely by Ca(2+). Also, this study shows the value of the in vitro experiments and modeling performed for radiopharmaceutical research and for attempts to reduce the number of animal experiments.

The Chemistry of Technetium–Water Complexes within the Manganese Triad: Challenges and Perspectives

AbstractThe chemistry of technetium is essentially driven by radiopharmaceutical applications. These comprise the syntheses of novel complexes but, moreover, the combination of targeting biomolecules with metal complexes. Aqua ions are especially convenient for facilitatating the introduction of metal cations into biomolecules, but are nonexistent for Tc and Re in the Mn triad. This microreview will discuss the chemistry of those Tc complexes that contain H2O as ligands. Special attention will be payed to organometallic aqua ions, i.e. complexes that are typically organometallic with water as ligand. Of particular interest is the coordination chemistry of [M(OH2)3(CO)3]+ (M = Mn, Tc, Re) complexes in water since it is the origin of the widely applied radiopharmaceutical research with 99mTc and 188Re. The chemistry of organometallic aqua ions is not confined to Werner‐type ligands, hence, a further emphasis will be placed on pure organometallic chemistry in water.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)