Radionuclides and radiopharmaceuticals for single-photon emission tomography, positron emission tomography and radiotherapy in Russia

The current status of the manufacture of radiopharmaceuticals for diagnostic and therapeutic application in Russia is discussed, consideration being given to various aspects of the production and distribution of radionuclides, radioisotope generators and kits as well as individual radiopharmaceuticals in different regions of the country. The major focus is on the recent developments in production technologies for therapeutic and single-photon emission tomography radionuclides, technetium chemistry and synthetic approaches for the labelling of compounds with short-lived positron emitters. The status of positron emission tomography and its application are considered. The major factors restricting the expansion of nuclear imaging techniques and radiotherapy in Russia are also discussed.     

Radionuclides and radiopharmaceuticals for single-photon emission tomography, positron emission tomography and radiotherapy in Russia.

The current status of the manufacture of radiopharmaceuticals for diagnostic and therapeutic application in Russia is discussed, consideration being given to various aspects of the production and distribution of radionuclides, radioisotope generators and kits as well as individual radiopharmaceuticals in different regions of the country. The major focus is on the recent developments in production technologies for therapeutic and single-photon emission tomography radionuclides, technetium chemistry and synthetic approaches for the labelling of compounds with short-lived positron emitters. The status of positron emission tomography and its application are considered. The major factors restricting the expansion of nuclear imaging techniques and radiotherapy in Russia are also discussed.     

Cyclotrons and positron emission tomography radiopharmaceuticals for clinical imaging

Positron emission tomography (PET) requires positron-emitting radionuclides that emit 511-keV photons detectable by PET imagers. Positron-emitting radionuclides are commonly produced in charged particle accelerators, eg, linear accelerators or cyclotrons. The most widely available radiopharmaceuticals for PET imaging are carbon-11-, nitrogen-13-, and oxygen-15-labeled compounds, many of which, either in their normal state or incorporated in other compounds, serve as physiological tracers. Other useful PET radiopharmaceuticals include fluorine-18-, bromine-75-, gallium-68 (68Ga)-, rubidium-82 (82Rb)-, and copper-62 (62Cu)-labeled compounds. Many positron emitters have short half-lives and thus require on-site cyclotrons for application, and others (68Ga, 82Rb, and 62Cu) are available from radionuclides generators using relatively long-lived parent radionuclides. This review is divided into two sections: cyclotrons and PET radiopharmaceuticals for clinical imaging. In the cyclotron section, the principle of operation of the cyclotron, types of cyclotrons, medical cyclotrons, and production of radionuclides are discussed. In the section on PET radiopharmaceuticals, the synthesis and clinical use of PET radiopharmaceuticals are described.     

Recent advances in copper radiopharmaceuticals

Copper has five radioisotopes ((60)Cu, (61)Cu, (62)Cu, (64)Cu, and (67)Cu) that can be used in copper radiopharmaceuticals. These radioisotopes decay by mixed emissions of β+, β-, and γ with a wide range of half-lives from 9.74 min ((62)Cu) to 2.58 d ((67)Cu), which enable the design and synthesis of a variety of radiopharmaceuticals for different biomedical applications in diagnostic and therapeutic nuclear medicine. However, due to the availability and production cost, the research efforts in copper radiopharmaceuticals are mainly focused on the use of (64)Cu (t(1/2) = 12.7 h; 17.4% β+, 43% EC, 39% β-), a radioisotope with low positron energy (E β+max = 0.656 MeV) that is ideal for positron emission tomography (PET) imaging quantification and β- emissions along with Auger electron for radiotherapy. Driven by the ever-increasing availability of preclinical and clinical PET scanners, a considerable interest has been seen in the development of novel copper radiopharmaceuticals in the past decade for a variety of diseases as represented by PET imaging of cancer. To avoid unnecessary literature redundancy, this review focuses on the unrepresented research aspects of copper chemistry (e.g. electrochemistry) and their uses in the evaluation of novel nuclear imaging probe design and recent advances in the field towards the practical use of copper radiopharmaceuticals.     

Applications of 211At and 223Ra in targeted alpha-particle radiotherapy

Targeted radiotherapy using agents tagged with α-emitting radionuclides is gaining traction with several clinical trials already undertaken or ongoing, and others in the advanced planning stage. The most commonly used α-emitting radionuclides are 213Bi, 211At, 223Ra and 225Ac. While each one of these has pros and cons, it can be argued that 211At probably is the most versatile based on its half life, decay scheme and chemistry. On the other hand, for targeting bone metastases, 223Ra is the ideal radionuclide because simple cationic radium can be used for this purpose. In this review, we will discuss the recent developments taken place in the application of 211At-labeled radiopharmaceuticals and give an overview of the current status of 223Ra for targeted α-particle radiotherapy.     

Copper bis(diphosphine) complexes: radiopharmaceuticals for the detection of multi-drug resistance in tumours by PET

Experience with imaging of the multi-drug resistance (MDR) phenotype in tumours using technetium-99m sestamibi, a substrate of the P-glycoprotein (Pgp) transporter, suggests that better quantification of images and separation of MDR from other variables affecting tracer uptake in tumours are required. One approach to these problems is the development of short half-life positron-emitting tracers which are substrates of Pgp. Several lipophilic cationic copper(I) bis(diphosphine) complexes labelled with copper-64 have been synthesised and evaluated in vitro as substrates for Pgp. The synthesis is rapid and efficient with no need for purification steps. The chemistry is suitable for use with very short half-life radionuclides such as copper-62 (9.7 min) and copper-60 (23.7 min). Incubation of the complexes with human serum in vitro showed that they are sufficiently stable in serum to support clinical imaging, and the more lipophilic members of the series are taken up rapidly by cells (Chinese hamster ovary and human ovarian carcinoma) in vitro with great avidity. Uptake in human ovarian carcinoma cells is significantly reduced after several months of conditioning in the presence of doxorubicin, which induces increased Pgp expression. Uptake in hooded rat sarcoma (HSN) cells, which express Pgp, is significantly increased in the presence of the MDR modulator cyclosporin A. Biodistribution studies in hooded rats show rapid blood clearance, excretion through both kidneys and liver, and low uptake in other tissues. The one complex investigated in HSN tumour-bearing rats showed uptake in tumour increasing up to 30 min p.i. while it was decreasing in other tissues. We conclude that diphosphine ligands offer a good basis for development of radiopharmaceuticals containing copper radionuclides, and that this series of complexes should undergo further evaluation in vivo as positron emission tomography imaging agents for MDR.     

Radiolabelling of peptides for diagnosis and therapy of non-oncological diseases.

Radiolabelled peptides have significant potential as radiopharmaceuticals for the diagnosis and therapy of receptor-expressing diseases. Methods have been developed for labelling peptides with a variety of radionuclides having a broad range of chemical and physical properties. These methods include both direct (where the radionuclide is bound directly to one or more atoms of the peptide structure) and indirect techniques in which bifunctional coupling agents are employed. Although most commonly applied to date in the field of oncology, a significant number of applications in non-oncological diseases have also been proposed and these can be expected to expand as the technology progresses. An overview is presented of some peptide-receptor systems in radiopharmaceutical development and the techniques which have been employed to radiolabel these peptides with isotopes of iodine, yttrium, indium, gallium, copper and technetium. While many of the examples employed are derived from cancer related indications, identical radiopharmaceutical chemistry can also be applied to peptides with applications in the fields of immunology, infection and other inflammatory conditions.     

Copper bis(diphosphine) complexes: radiopharmaceuticals for the detection of multi-drug resistance in tumours by PET

Experience with imaging of the multi-drug resistance (MDR) phenotype in tumours using technetium-99m sestamibi, a substrate of the P-glycoprotein (Pgp) transporter, suggests that better quantification of images and separation of MDR from other variables affecting tracer uptake in tumours are required. One approach to these problems is the development of short half-life positron-emitting tracers which are substrates of Pgp. Several lipophilic cationic copper(I) bis(diphosphine) complexes labelled with copper-64 have been synthesised and evaluated in vitro as substrates for Pgp. The synthesis is rapid and efficient with no need for purification steps. The chemistry is suitable for use with very short half-life radionuclides such as copper-62 (9.7 min) and copper-60 (23.7 min). Incubation of the complexes with human serum in vitro showed that they are sufficiently stable in serum to support clinical imaging, and the more lipophilic members of the series are taken up rapidly by cells (Chinese hamster ovary and human ovarian carcinoma) in vitro with great avidity. Uptake in human ovarian carcinoma cells is significantly reduced after several months of conditioning in the presence of doxorubicin, which induces increased Pgp expression. Uptake in hooded rat sarcoma (HSN) cells, which express Pgp, is significantly increased in the presence of the MDR modulator cyclosporin A. Biodistribution studies in hooded rats show rapid blood clearance, excretion through both kidneys and liver, and low uptake in other tissues. The one complex investigated in HSN tumour-bearing rats showed uptake in tumour increasing up to 30 min p.i. while it was decreasing in other tissues. We conclude that diphosphine ligands offer a good basis for development of radiopharmaceuticals containing copper radionuclides, and that this series of complexes should undergo further evaluation in vivo as positron emission tomography imaging agents for MDR. Received 14 December 1999 and in revised form 12 February 2000     

Radiopharmaceuticals 1994

On the basis of the discussions at a symposium held in Düsseldorf and attended by respresentatives of various interested bodies, European legislation as it affects radiopharmaceuticals is reviewed. Due consideration is given to the new, centralised and decentralised, registration procedures, effective since 1 January 1995. The dossier required to support an application for marketing authorisation is discussed, separate consideration being given to single-photon emitters, therapeutic radionuclides and positron-emitting radiopharmaceuticals. The role of the European Pharmacopoiea is also considered. It is concluded that the new, modified procedures for the registration of medicinal products in the European Union may actually inhibit free availability of radiopharmaceuticals within the Community, and that there is a strong case for modification of the European Directives so that radiopharmaceuticals are placed in a separate category to therapeutic drugs, with less stringent registration requirements.     

An update on therapeutic uses of radiotracers in neoplastic disease

The key to delivering radiation to a lesion by means of internally administered radiopharmaceuticals is specificity of localization (a high lesion-background ratio). Factors that may limit this localization are pointed out. Potential alteration of the residence time within the lesion and use of radiation-sensitizing agents may bring new applications for radionuclides in therapy. The most common therapeutic applications of radiopharmaceuticals are outlined.     

Radiopharmaceuticals for bone lesions. Imaging and therapy in clinical practice.

Bone scintigraphy continues to be one of the most commonly performed procedures in nuclear medicine. The radionuclide bone scan remains an excellent modality to detect metastatic disease in patients suffering from primary malignancies. This article reviews a number of aspects of bone scintigraphy such as bone physiology, radiopharmaceuticals and uptake mechanisms. As 99mTc labelled bis(di)phosphonates are the most frequently used this article is centred around these imaging agents. In addition to diagnostic bone scintigraphy the use of various bone seeking agents has been extended to the palliative treatment of bone metastases. In this context the radiobiological characteristics of various radionuclides as 89Sr, 32p, 153Sm, 186Re and 117Sn is elucidated. In addition, the clinical efficacy for pain killing of these radionuclides is elucidated on the basis of the radiation properties of these agents. It is concluded that 89Sr and 186Re are presently the radionuclides of choice. The latter agent has a slight advantage as its imaging photons enable individual dosimetry, resulting in an optimosed application scheme.     

Radioiodinated tracers for myocardial imaging

Recent advances in the efficient production of high purity radioiodine (123I) and new efficient radiolabeling techniques have allowed the development of new classes of cardiovascular radiopharmaceuticals. These include 123I-labeled fatty acids to assess myocardial metabolism, 123I-metaiodobenzylguanidine (MIBG) for myocardial neuronal activity, labeled monoclonal antibodies for myocardial necrosis, and labeled lipoproteins for receptor concentration. 123I-labeled fatty acids and MIBG are under clinical investigation with encouraging results. 123I- and 111In-labeled fragments of monoclonal antibodies to myosin have been used for imaging myocardial necrosis in humans. The development of radiotracers for imaging of cholinergic and adrenergic receptors is still in the experimental stage. Recent advances in imaging instrumentation and radiopharmaceuticals have resulted in cardiac imaging applications beyond blood pool ventriculography, perfusion, and infarct-avid imaging. Developments of radioiodine (123I)-labeled agents promise to play an important role in the assessment of myocardial metabolism, neuronal activity, and receptor concentration. The chemistry of iodine is well defined compared with that of 99mTc; therefore, iodine isotopes are well suited for labeling biologically important molecules. Among the iodine isotopes, 123I has nearly ideal nuclear properties for nuclear medical applications with a 13.3-hour half-life (T1/2) and 159 keV gamma emission (83%). Despite the nearly ideal chemical and nuclear properties of 123I, the widespread application of 123I-based radiopharmaceuticals in clinical practice has been limited by high production costs (123I is produced in a cyclotron), relatively limited availability, and the presence of undesirable radionuclidic impurities (124I, T1/2 = 4.2 days; 125I, T1/2 = 60 days; 126I, T1/2 = 13.1 days). The relatively long T1/2 and beta particle emission can substantially increase the higher radiation burden to the patient. High energy gamma rays (greater than 600 KeV) from these impurities can degrade images obtained using low energy collimators. Recent developments in production techniques have greatly reduced the levels of the undesirable radionuclides in 123I. Ready availability of pure 123I at modest cost, in concentrations suitable for the radio-labeling of a variety of useful biomolecules, should enhance the clinical applications of 123I-labeled compounds. Molecules labeled with 123I that are useful in cardiac imaging studies are fatty acid analogs, monoclonal antibodies, receptor binding agents, and norepinephrine analogs. This article will discuss developments in radioiodine (123I)-labeled radiotracers for myocardial imaging.     

Needs for radioactivity standards and measurements in the life sciences.

For almost 100 years, radioactivity has been one of the major tools in medicine. Therapeutic applications that began with 226Ra and 222Rn implants have rapidly grown to include about 20 radionuclides with radiations specifically chosen to treat at different depths in tissue--ranging from a few millimeters for intravascular therapy to a few centimeters in the case of large solid tumors. Systemic treatments with radiopharmaceuticals have grown from the traditional 131I to more than ten candidate nuclides which are to be labeled to tumor-specific radiopharmaceuticals. Diagnostic radiopharmaceuticals are used in over 13 million procedures in the United States annually. About 40 nuclides are under investigation for these applications including single photon emitters for SPECT (single photon emission computed tomography) and positron emitters for PET (positron emission tomography). In addition to the mainstays of therapeutic and diagnostic radiology, radionuclides are widely used for in vitro tracers in the life sciences and represent one of the main tools in the field of molecular biology.     

The role of radionuclides in clinical oncology

The major role of radionuclides in clinical oncology is, in the broadest sense, "tumor scanning". This includes evaluating specific organs for the presence of tumor (usually with different radiopharmaceuticals for each organ) or the entire body (generalized tumor searches with radiopharmaceuticals with 67Ga-citrate or 111Inlabeled bleomycin). The clinician uses these agents in the initial evaluation of the extent of tumor (staging) and in the subsequent management of the patient with cancer to assess response to treatment, to detect early relapse, and to assist in making decisions concerning treatment. The uses and limitations of the agents currently available for tumor scanning are summarized in this review (by major tumor type) from the perspective of the practicing oncologist. Other potential roles for radionuclides, including use as components of combined modality treatment programs, use as labels for antibodies or as drugs for both diagnosis and treatment, and use in the prediction of response to treatment, which are of great interest now and which will become realities for the oncologist in the future, are also considered.     

In vivo evaluation of copper-64-labeled monooxo-tetraazamacrocyclic ligands

Copper-64 (T_1/2=12.7 h; β⁺: 0.653 MeV, 17.4%; β⁻: 0.578 MeV, 39%) has applications in positron emission tomography (PET) imaging and radiotherapy, and is conveniently produced on a biomedical cyclotron. Tetraazamacrocyclic ligands are the most widely used bifunctional chelators (BFCs) for attaching copper radionuclides to antibodies and peptides due to their relatively high kinetic stability. In this paper, we evaluated three monooxo-tetraazamacrocyclic ligands with different ring sizes and oxo group positions. H1 [1,4,7,10-tetraazacyclotridecan–11-one], H2 [1,4,8,11-tetraazacyclotetradecan-5-one] and H3 [1,4,7,10-tetraazacyclotridecan-2-one] were radiolabeled with ⁶⁴Cu in high radiochemical yields under mild conditions. The three ⁶⁴Cu-labeled complexes are all +1 charged, as determined by their electrophoretic mobility. While they demonstrated >95% stability in rat serum out to 24 h, both biodistribution and microPET imaging studies revealed high uptake and long retention of the compounds in major clearance organs (e.g., blood, liver and kidney), which suggests that ⁶⁴Cu dissociated from the complexes in vivo. Of the three complexes, ⁶⁴Cu-2⁺, which has a cyclam backbone (1,4,8,11-tetraazacyclotetradecane), exhibited the lowest nontarget organ accumulation. The data from these studies may invalidate the candidacy of the monooxo-tetraazamacrocyclics as BFCs for copper radiopharmaceuticals. However, the data presented here suggest that neutral or negatively charged Cu(II) complexes of tetraazamacrocyclic ligands with a cyclam backbone (tetradecane) are optimal for copper radiopharmaceutical applications.     

Newer methods of labeling diagnostic agents with Tc-99m

The past several years have seen marked advances in technetium/rhenium chemistry applicable to the preparation of new 99mTc-labeled radiopharmaceuticals. This article focuses on recent developments in technetium chemistry, including the preparation of "3 + 1" complexes, the preparation and use of (99mTc[CO]3)+ complexes for labeling biomolecules, the preparation of rhenium steroid inclusion complexes, improvements in both hydrazinonicotinamide labeling chemistry and in the preformed 99mTc complex method of labeling biomolecules, and new solid-phase separation techniques that may allow the isolation of high specific-activity radiopharmaceuticals in a clinical setting.     

Utility of γH2AX as a Molecular Marker of DNA Double-Strand Breaks in Nuclear Medicine: Applications to Radionuclide Therapy Employing Auger Electron-Emitting Isotopes

There is an intense interest in the development of radiopharmaceuticals for cancer therapy. In particular, radiopharmaceuticals which involve targeting radionuclides specifically to cancer cells with the use of monoclonal antibodies (radioimmunotherapy) or peptides (targeted radiotherapy) are being widely investigated. For example, the ultra-short range Auger electron-emitting isotopes, which are discussed in this review, are being considered in the context of DNAtargeted radiotherapy. The efficient quantitative evaluation of the levels of damage caused by such potential radiopharmaceuticals is required for assessment of therapeutic efficacy and determination of relevant doses for successful treatment. The DNA double-strand break surrogate marker, γH2AX, has emerged as a useful biomonitor of damage and thus effectiveness of treatment, offering a highly specific and sensitive means of assessment. This review will cover the potential applications of γH2AX in nuclear medicine, in particular radionuclide therapy.     

Cell Irradiation caused by diagnostic nuclear medicine procedures: dose heterogeneity and biological consequences

Most radionuclides used for diagnostic imaging emit Auger electrons (technetium-99m, iodine-123, indium-111, gallium-67 and thallium-201). Their very short range in biological tissues may lead to dose heterogeneity at the cellular level with radiobiological consequences. This report describes the dosimetric models used to calculate the mean dose absorbed by the cell nucleus from Auger radionuclides. The techniques used to determine the biodistribution of radiopharmaceuticals at the subcellular level are also described and compared. Published examples of cellular dosimetry computations performed with radiotracers are reviewed in various clinical settings.Finally, the biological implications of the subcellular localization of Auger emitters are examined. While a number of efforts have been made to obtain dosimetric models and to estimate subcellular distribution of radioactivity, little is known of the cellular dosimetry of most radiopharmaceuticals used in diagnostic imaging. However, biological examples of selective radiotracer uptake have been shown, leading to extremely strong cell-cell dose heterogeneity. Furthermore, radiobiological experiments show that the biological effects of Auger emitters incorporated into DNA can be severe, with relative biological effectiveness greater than 1 compared with external X-rays. These findings clearly show that the assessment of biological risks associated with internal administration of diagnostic radiopharmaceuticals must focus not only on target organs as a whole, but also on the cellular level. This review proposes the most appropriate model for dosimetric computations (cellular or conventional) according to the subcellular distribution of radiotracers. The radionuclide of choice and the general strategy used to design new diagnostic radiopharmaceuticals are also discussed.     

Cell irradiation caused by diagnostic nuclear medicine procedures: dose heterogeneity and biological consequences

Most radionuclides used for diagnostic imaging emit Auger electrons (technetium-99m, iodine-123, indium-111, gallium-67 and thallium-201). Their very short range in biological tissues may lead to dose heterogeneity at the cellular level with radiobiological consequences. This report describes the dosimetric models used to calculate the mean dose absorbed by the cell nucleus from Auger radionuclides. The techniques used to determine the biodistribution of radiopharmaceuticals at the subcellular level are also described and compared. Published examples of cellular dosimetry computations performed with radiotracers are reviewed in various clinical settings. Finally, the biological implications of the subcellular localization of Auger emitters are examined. While a number of efforts have been made to obtain dosimetric models and to estimate subcellular distribution of radioactivity, little is known of the cellular dosimetry of most radiopharmaceuticals used in diagnostic imaging. However, biological examples of selective radiotracer uptake have been shown, leading to extremely strong cell-cell dose heterogeneity. Furthermore, radiobiological experiments show that the biological effects of Auger emitters incorporated into DNA can be severe, with relative biological effectiveness greater than 1 compared with external X-rays. These findings clearly show that the assessment of biological risks associated with internal administration of diagnostic radiopharmaceuticals must focus not only on target organs as a whole, but also on the cellular level. This review proposes the most appropriate model for dosimetric computations (cellular or conventional) according to the subcellular distribution of radiotracers. The radionuclide of choice and the general strategy used to design new diagnostic radiopharmaceuticals are also discussed.     

Use of tissue-to-air ratio in computation of specific absorbed fraction.

This paper describes a new approach for computing specific absorbed fractions that can be used for estimating doses that result from the internal administration of radiopharmaceuticals. This approach uses the concept of the tissue-to-air ratio (TAR) which can either be calculated or experimentally determined for the radionuclides of interest. Good agreement exists between the specific absorbed fraction values obtained using measured and computed values of TAR. This implies that the measured values of TAR can be used to obtain specific absorbed fractions for all radionuclides.