Metallic radionuclides in the development of diagnostic and therapeutic radiopharmaceuticals

Metallic radionuclides are the mainstay of both diagnostic and therapeutic radiopharmaceuticals. Therapeutic nuclear medicine is less advanced but has tremendous potential if the radionuclide is accurately targeted. Great interest exists in the field of inorganic chemistry for developing target specific radiopharmaceuticals based on radiometals for non-invasive disease detection and cancer radiotherapy. This perspective will focus on the nuclear properties of a few important radiometals and their recent applications to developing radiopharmaceuticals for imaging and therapy. Other topics for discussion will include imaging techniques, radiotherapy, analytical techniques, and radiation safety. The ultimate goal of this perspective is to introduce inorganic chemists to the field of nuclear medicine and radiopharmaceutical development, where many applications of fundamental inorganic chemistry can be found.     

Towards molecular imaging and treatment of disease with radionuclides: the role of inorganic chemistry

Molecular imaging and radiotherapy using radionuclides is a rapidly expanding field of medicine and medical research. This article highlights the development of the role of inorganic chemistry in designing and producing the radiopharmaceuticals on which this interdisciplinary science depends.     

A review on <Superscript>90</Superscript>Y-labeled compounds and biomolecules

The field of therapeutic nuclear medicine is emerging rapidly as choice of treatment in oncology and other cellular malignancies. The growth of this branch of nuclear medicine is greatly facilitated by the introduction of a number of new radiopharmaceuticals and radionuclides. ⁹⁰Y-radiopharmaceuticals have confirmed their worth in medical and clinical areas in a very short span of time. The ⁹⁰Y is a radioisotope widely used for therapeutic purposes and considerable perfection has been made to understand the chemistry of ⁹⁰Y-labeled radiopharmaceuticals. The development of these radiopharmaceuticals can be made favorable by using appropriate buffer, incubation period, optimal pH, specific activity and reaction temperature. In this review, we have discussed the preparation of range of ⁹⁰Y transporting biological molecules such as antibodies radiolabeled peptides, antigens and microsphere with their clinical applications.     

The Chemical Scaffold of Theranostic Radiopharmaceuticals: Radionuclide,Bifunctional Chelator,and Pharmacokinetics Modifying Linker

Therapeutic radiopharmaceuticals have been researched extensively in the last decade as a result of the growing research interest in personalized medicine to improve diagnostic accuracy and intensify intensive therapy while limiting side effects. Radiometal-based drugs are of substantial interest because of their greater versatility for clinical translation compared to non-metal radionuclides. This paper comprehensively discusses various components commonly used as chemical scaffolds to build radiopharmaceutical agents, i.e., radionuclides, pharmacokinetic-modifying linkers, and chelators, whose characteristics are explained and can be used as a guide for the researcher.     

64Cu放射性药物化学

64Cu半衰期为12.7 h,其衰变过程既发射β+粒子(β+,0.655 MeV,17.8%),又发射β-粒子(β-,0.573 MeV,38.4%)。近20年来,随着铜配位化学的发展,新型配体不断出现(如DOTA、TETA、NOTA、CB-TE2A、C3B-DO2A等)。Cu(Ⅱ)的络合物在生物体内/外的稳定性不断提高,64Cu已经成功标记在氨基酸、多肽、蛋白、核酸等分子以及纳米颗粒上。64Cu可制成正电子显像药物用作诊断,同时也有发展为放射性治疗药物的潜力。新型铜配体和标记方法以及新的药物靶标的研究已经成为64Cu放射性药物研究的热点,至今已研制出了多种64Cu标记的放射性药物,如64Cu-ATSM是有效的肿瘤乏氧显像剂,64Cu-PTSM是优良的血流示踪剂等。本文旨在介绍64Cu(Ⅱ)几种主要类型的含氮配体以及64Cu标记的放射性药物在显像和治疗方面的最新研究进展,并展望其发展趋势。     

The role of coordination chemistry in the development of copper and rhenium radiopharmaceuticals

There are several isotopes of copper and rhenium that are of interest in the development of new molecular imaging or radiotherapeutic agents. This perspective article highlights the role of coordination chemistry in the design of copper and rhenium radiopharmaceuticals engineered to selectively target tissue of interest such as cancer cells or pathological features associated with Alzheimer's disease. The coordination chemistry of copper bis(thiosemicarbazone) derivatives and copper macrocyclic complexes is discussed in terms of their potential application as targeted positron emission tomography tracers for non-invasive diagnostic imaging. A range of rhenium complexes with different ligands with rhenium in different oxidation states are introduced and their potential to be translated to new radiotherapeutic agents discussed.     

Quality management systems in radiochemistry and radiopharmacy — applications in academy and industry

Except the nuclear fuel reprocessing and nuclear materials safeguards, at present there are two areas of an increased responsibility of nuclear scientists for their results: radioecology and human medicaments. At both of them, quality and trustfulness of results is of great importance for their end-users and may have serious economical and legal consequences. The trends of implementation of good laboratory and manufacturing practices under umbrella of international quality management standards like ISO 17025:2005 and ISO 9001:2000 in radiochemical and radiopharmaceutical laboratories are discussed as expanding to “good scientific practice”. The case studies of the Comenius University laboratory LARCHA authorized for radiochemical analysis, and the company BIONT producing medical radionuclides and PET radiopharmaceuticals are used as the examples.     

Metal complexes of cyclen and cyclam derivatives useful for medical applications: a discussion based on thermodynamic stability constants and structural data

A series of the most common chelators used in magnetic resonance imaging (MRI) and in radiopharmaceuticals for medical diagnosis and tumour therapy, H(4)dota, H(4)teta, H(8)dotp and H(8)tetp, is examined from a chemical point of view. Differences between 12- and 14-membered tetraazamacrocyclic derivatives with methylcarboxylate and methylphosphonate pendant arms and their chelates with divalent first-series transition metal and trivalent lanthanide ions are discussed on the basis of their thermodynamic stability constants, X-ray structures and theoretical studies.     

生产99Mo、131I和89Sr医用同位素的水溶液堆

99Mo1、31I和89Sr等医用同位素对人类健康和医学的发展具有非常重要的作用。与靶辐照反应堆相比,用水溶液堆生产99Mo1、31I和89Sr具有安全性好,结构简单,经济价值高,无靶件制备、溶解工艺,产生废物少等优点,用水溶液堆生产医用同位素具有很好的发展前景。由于多堆芯水溶液堆、高功率水溶液堆均能显著提高产率,低富集度235U水溶液堆符合核不扩散条约中对235U浓缩度的要求,因此这三种堆是水溶液堆未来的发展方向。     

Application of radioisotopes in the field of nuclear medicine

A comprehensive review has been made to discuss the role of various radionuclides of lanthanide series elements in the field of nuclear medicine. The role of several pharmaceuticals labeled with radiolanthanides and used for investigative purposes like measurement of cerebral blood flow, bone density measurement, bone marrow imaging, etc., have been described. The role of lanthanide radionuclides in radiation synovectomy, radioimmunotherapy, etc., have also been discussed. Methods of preparation of some representative radiopharmaceuticals like¹⁵³Sm-EDTMP,¹⁵³Sm-HYP, have been presented. An outline on the production of carrier free radioisotopes of lanthanide series elements has been given.     

Ruthenium metallopharmaceuticals

The well-developed synthetic chemistry of ruthenium, particularly with ammine, amine and imine ligands, provides for many approaches to innovative new metallopharmaceuticals. Advantages of utilizing ruthenium am(m)ine complexes in drug development include, (1) reliable preparations of stable complexes with predictable structures; (2) the ability to tune ligand affinities, electron transfer and substitution rates, and reduction potentials; and (3) an increasing knowledge of the biological effects of ruthenium complexes. Many Ru(II) and Ru(III) am(m)ine complexes selectively bind to imine sites in biomolecules. Collectively, these lend ruthenium complexes to redox-activation and photodynamic approaches to therapy as well as the development of radiopharmaceuticals containing one of several radionuclides of ruthenium. Ruthenium red and the related Ru360 strongly inhibit calcium ion uptake in the mitochondria. A number of ruthenium compounds with anticancer activity appear to penetrate tumors through a transferrin-mediated process and bind to cellular DNA following intracellular activation by reduction. Ruthenium complexes exhibit both nitric oxide release and scavenging functions that can affect vasodilation and synapse firing. Simple ruthenium complexes are unusually effective in suppressing the immune response by inhibiting T cell proliferation.     

Radioanalysis in the Benelux

A general survey on the development of the radiochemistry in the Benelux is given. Production of radionuclides and radiopharmaceuticals, application of gamma-irradiation, the activation analysis and measurement of capture gamma-rays, tracer studies, actinide research and detection of radionuclides in environmental samples are mentioned and briefly discussed as the main subjects, going on in the radioanalytical laboratories of the Benelux.     

Dual-targeting conjugates designed to improve the efficacy of radiolabeled peptides

Radiolabeled regulatory peptides are useful tools in nuclear medicine for the diagnosis (imaging) and therapy of cancer. The specificity of the peptides towards GPC receptors, which are overexpressed by cancer cells, and their favorable pharmacokinetic profile make them ideal vectors to transport conjugated radionuclides to tumors and metastases. However, after internalization of the radiopeptide into cancer cells and tumors, a rapid washout of a substantial fraction of the delivered radioactivity is often observed. This phenomenon may represent a limitation of radiopeptides for clinical applications. Here, we report the synthesis, radiolabeling, stability, and in vitro evaluation of a novel, dual-targeting peptide radioconjugate designed to enhance the cellular retention of radioactivity. The described trifunctional conjugate is comprised of a Tc-99m SPECT reporter probe, a cell membrane receptor-specific peptide, and a second targeting entity directed towards mitochondria. While the specificity of the first generation of dual-targeting conjugates towards its extracellular target was demonstrated, intracellular targeting could not be confirmed probably due to non-specific binding or hindered passage through the membrane of the organelle. The work presented describes a novel approach with potential to improve the efficacy of radiopharmaceuticals by enhancing the intracellular retention of radioactivity.     

Synthesis of 11C, 18F, 15O, and 13N radiolabels for positron emission tomography

Positron emission tomography (PET) is a powerful and rapidly developing area of molecular imaging that is used to study and visualize human physiology by the detection of positron-emitting radiopharmaceuticals. Information about metabolism, receptor/enzyme function, and biochemical mechanisms in living tissue can be obtained directly from PET experiments. Unlike magnetic resonance imaging (MRI) or computerized tomography (CT), which mainly provide detailed anatomical images, PET can measure chemical changes that occur before macroscopic anatomical signs of a disease are observed. PET is emerging as a revolutionary method for measuring body function and tailoring disease treatment in living subjects. The development of synthetic strategies for the synthesis of new positron-emitting molecules is, however, not trivial. This Review highlights key aspects of the synthesis of PET radiotracers with the short-lived positron-emitting radionuclides (11)C, (18)F, (15)O, and (13)N, with emphasis on the most recent strategies.     

A practical guide to the construction of radiometallated bioconjugates for positron emission tomography

Positron emission tomography (PET) has become a vital imaging modality in the diagnosis and treatment of disease, most notably cancer. A wide array of small molecule PET radiotracers have been developed that employ the short half-life radionuclides (11)C, (13)N, (15)O, and (18)F. However, PET radiopharmaceuticals based on biomolecular targeting vectors have been the subject of dramatically increased research in both the laboratory and the clinic. Typically based on antibodies, oligopeptides, or oligonucleotides, these tracers have longer biological half-lives than their small molecule counterparts and thus require labeling with radionuclides with longer, complementary radioactive half-lives, such as the metallic isotopes (64)Cu, (68)Ga, (86)Y, and (89)Zr. Each bioconjugate radiopharmaceutical has four component parts: biomolecular vector, radiometal, chelator, and covalent link between chelator and biomolecule. With the exception of the radiometal, a tremendous variety of choices exists for each of these pieces, and a plethora of different chelation, conjugation, and radiometallation strategies have been utilized to create agents ranging from (68)Ga-labeled pentapeptides to (89)Zr-labeled monoclonal antibodies. Herein, the authors present a practical guide to the construction of radiometal-based PET bioconjugates, in which the design choices and synthetic details of a wide range of biomolecular tracers from the literature are collected in a single reference. In assembling this information, the authors hope both to illuminate the diverse methods employed in the synthesis of these agents and also to create a useful reference for molecular imaging researchers both experienced and new to the field.     

Relating β+ radionuclides’ properties by order theory

We studied 27 β⁺ radionuclides taking into account some of their variants encoding information of their production, such as integral yield, threshold energy and energy of projectiles used to generate them; these radionuclides are of current use in clinical diagnostic imaging by positron emission tomography (PET). The study was conducted based on physical, physico-chemical, nuclear, dosimetric and quantum properties, which characterise the β⁺ radionuclides selected, with the aim of finding meaningful relationships among them. In order to accomplish this objective the mathematical methodology known as formal concept analysis was employed. We obtained a set of logical assertions (rules) classified as implications and associations, for the set of β⁺ radionuclides considered. Some of them show that low mass defect is related to high and medium values of maximum β⁺ energy, and with even parity and low mean lives; all these parameters are associated to the dose received by a patient subjected to a PET analysis.     

[161Tb]Tb-Thz-Phe-D-Trp-Lys-Thr-DOTA: A potential radiopharmaceutical for the treatment of neuroendocrine tumors

Thz-Phe-D-Trp-Lys-Thr-DOTA, a conjugate of the DOTA chelator and the Thz-Phe-D-Trp-Lys-Thr pentapeptide, was labeled with ¹⁵²Eu and ¹⁶¹Tb radionuclides, where ¹⁶¹Tb has decay characteristics suitable for its use in cancer therapy. For the [¹⁵²Eu]Eu-Thz-Phe-D-Trp-Lys-Thr-DOTA complex, the biodistribution in nude mice bearing IMR-32 tumors was evaluated for the first time. It was shown that the complexes of the conjugate demonstrate accumulation in the tumor at the level of DOTA-TATE, another peptide conjugate widely used in nuclear medicine for the diagnosis and therapy of neuroendocrine tumors, which allows Thz-Phe-D-Trp-Lys-Thr-DOTA to be considered as a potential biological vector for radiopharmaceuticals.     

Paper chromatographic and paper elettrophoretic study of the solution chemistry of Tc-99m-methylendiphosphonate and of Tc-99m-dimercaptosuccinate for improving the tumour-affinity of Tc-99m during scintigraphic imaging of cancer

In order to find the conditions under which Tc-99m-methylenediphosphonate (Tc-99m-MDP) and Tc-99m(V)-dimercaptosuccinate (Tc-99m(V)-DMSA) may become tumour-seeking agents, leaving healthy organs free from the radionuclide uptake, the solution chemistry of these radiopharmaceuticals was studied by paper chromatography and paper electrophoresis in distilled water, in physiological saline, in NAHCO3, and ascorbic acid solutions. Both radiopharmaceuticals are anionic in the radiopharmaceutical solution but get easily hydrolysed to form cationic Tc-99m species which concentrates in healthy bone and in some bone metastases. Tc-99m (V)-DMSA being more stable remains long in the blood pool giving undesirable presence of the radionuclide in lung, heart and kidneys, in addition to its reduced uptake in bone metastases and in some primaries. We are trying to eliminate these drawbacks of healthy organ uptake of Tc-99-m(V)-DMSA not only to get a clean scintigraphic image of the tumour with this radiopharmaceutical but to extend its formulation, thus obtained, to prepare radiopharmaceutical with Re-188, which is the higher homologue of Tc-99m, for systemic therapy of cancer. Essentially similar solution chemistry of both radiopharmaceuticals suggests that like Tc-99m-MDP, technetium-99m-dimercaptosuccinate is also a complex of tetravalent Tc-99m and not of pentavalent Tc-99m as so far supposed to be.     

Generator-based PET radiopharmaceuticals for molecular imaging of tumours: on the way to THERANOSTICS

Generator-derived radionuclides for PET/CT imaging are promising for optimizing targeted radiotherapy by an individual patient-based approach, applying pre-therapeutic evaluation, as well as dosimetric calculations, and for measuring treatment response after radionuclide therapy.     

The role of coordination chemistry in the development of target-specific radiopharmaceuticals

There is a great current interest in developing target-specific radiopharmaceuticals for early detection of diseases and radiotherapy of cancers. This critical review will focus on the role of coordination chemistry in the development of target-specific radiopharmaceuticals. It will also discuss the recent development in technetium, copper, gallium, indium, yttrium and lanthanide chemistry, as well as analytical tools for quality control and characterization of radiolabeled small biomolecules (159 references).