Current Radiopharmaceuticals - Volume 5, Issue 3, 2012

The most important radioisotope for use in Nuclear Medicine is 99mTc, supplied in the form of a 99Mo/99mTc generator. After the supply crisis of 99Mo starting in 2008 the availability of 99Mo became a worldwide concern. The purpose of this work is to do a brief story of the availability of 99Mo in the world followed by an overview of the production routes of 99Mo and the generators technology.

44Ti/44Sc radionuclide generators are of interest for molecular imaging. The 3.97 hours half-life of 44Sc and its high positron branching of 94.27% may stimulate the application of 44Sc-labeled PET radiopharmaceuticals. This review describes the current status of 44Ti production, 44Ti/44Sc radionuclide generator development, post-processing of generator eluates towards medical application, identification of ligands adequate to ScIII co-ordination chemistry, proof-of-principle labeling of 44Sc-DOTA-octreotides, investigation of in vitro and in vivo parameters, and initial applications for molecular imaging – both in small animals and humans.

68Ge/68Ga radionuclide generators have been investigated for almost fifty years, since the cyclotronindependent availability of positron emitting 68Ga via the 68Ge/68Ga system had always attracted researches working in basic nuclear chemistry as well as radiopharmaceutical chemistry. However, it took decades and generations of research (and researchers) to finally reach a level of 68Ge/68Ga radionuclide generator designs adequate to the modern requirements of radiometal labelling chemistry. Nevertheless, most of the existing commercial generator systems address aspects of 68Ge breakthrough and safe synthesis of 68Ga radiopharmaceuticals by adopting eluate post-processing technologies. Among the strategies to purify 68Ga eluates, the cation exchange based version is relevant in terms of purification efficiency. In addition, it offers more options towards further developments of 68Ga radiopharmaceuticals. Today, one may expect that the 68Ge/68Ga radionuclide generator systems could contribute to the clinical impact of nuclear medicine diagnoses for PET similar to the established 99Mo/99mTc generator system for SPECT. The exciting perspective for the 68Ge/68Ga radionuclide generator system, in turn, asks for systematic chemical, radiochemical, technological and radiopharmaceutical efforts, to guarantee reliable, highly-efficient and medically approved 68Ge/68Ga generator systems.

68Ge/68Ga generators have received tremendous attention in the last years based on the success of 68Ga-labelled Somatostatin analogues for Positron-Emission Tomography (PET), which are today used routinely worldwide. Various commercially available generator types are based on different column matrices including TiO2, SnO2 or organic 68Gechelate coated silica, providing 68Ga as Ga3+ in HCl for radiolabeling procedures. These systems can serve as a stable source of 68Ga for PET applications over periods of more than one year with high yields. A number of methods for post processing of the eluate including fractionation, anion or cation exchange purification have been developed. These methods are particularly important for high specific activity labeling of biomolecules such as peptides ensuring small volumes, low metallic contamination and low 68Ge breakthrough. These systems have been implemented into fully automated modules allowing generator elution, post processing radiolabeling and formulation, complying with high regulatory demands. Quality aspects regarding the clinical use of 68Ga for patient applications including limit of 68Ge content, metal contamination, microbiological safety and radiochemical purity have been addressed. Overall, the establishment of 68Ge/68Ga generator technology together with the development of novel 68Ga-radiopharmaceuticals make 68Ga a most promising radionuclide for PET in the years to come.

The alpha emitters 225Ac and 213Bi are promising therapeutic radionuclides for application in targeted alpha therapy of cancer and infectious diseases. Both alpha emitters are available with high specific activity from established radionuclide generators. Their favourable chemical and physical properties have led to the conduction of a large number of preclinical studies and several clinical trials, demonstrating the feasibility, safety and therapeutic efficacy of targeted alpha therapy with 225Ac and 213Bi. This review describes methods for the production of 225Ac and 213Bi and gives an overview of 225Ac/213Bi radionuclide generator systems. Selected preclinical studies are highlighted and the current clinical experience with 225Ac and 213Bi is summarized.

Rhenium-188 is one of the most readily available generator derived and useful radionuclides for therapy emitting β- particles (2.12 MeV, 71.1% and 1.965 MeV, 25.6%) and imageable gammas (155 keV, 15.1%). The 188W/188Re generator is an ideal source for the long term (4-6 months) continuous availability of no carrier added (nca) 188Re suitable for the preparation of radiopharmaceuticals for radionuclide therapy. The challenges associated with the double neutron capture route of production of the parent 188W radionuclide have been a major impediment in the progress of application of 188Re. Tungsten-188 of adequate specific activity can be prepared only in 2-3 of the high flux reactors operating in the World. Several useful technologies have been developed for the preparation of clinical grade 188W/188Re generators. Since the specific activity of 188W used in the generator is relatively low 185 GBq(<5 Ci)/g], the eluted 188ReO4 - can have low radioactive concentration often insufficient for radiopharmaceutical preparation. However, several efficient post elution concentration techniques have been developed that yield clinically useful 188ReO4 - solutions. Rhenium-188 has been used for the preparation of therapeutic radiopharmaceuticals for the management of diseases such as bone metastasis, rheumatoid arthritis and primary cancers. Several early phase clinical studies using radiopharmaceuticals based on 188Re-labeled phosphonates, antibodies, peptides, lipiodol and particulates have been reported. This article reviews the availability and use of188Re including a discussion of why broader use of 188Re has not progressed as expected as a popular radionuclide for therapy.

Radium-223 is a short-lived alpha-particle-emitting radionuclide with potential applications in cancer treatment. Research to develop new radiopharmaceuticals employing 223Ra has been hindered by poor availability due to the small quantities of parent actinium-227 available world-wide. The purpose of this study was to develop innovative and cost-effective methods to obtain high-purity 223Ra from 227Ac. We obtained 227Ac from two surplus actinium-beryllium neutron generators. We retrieved the actinium/beryllium buttons from the sources and dissolved them in a sulfuric-nitric acid solution. A crude actinium solid was recovered from the solution by coprecipitation with thorium fluoride, leaving beryllium in solution. The crude actinium was purified to provide about 40 milligrams of actinium nitrate using anion exchange in methanol-water-nitric acid solution. The purified actinium was then used to generate high-purity 223Ra. We extracted 223Ra using anion exchange in a methanol-water-nitric acid solution. After the radium was separated, actinium and thorium were then eluted from the column and dried for interim storage. This single-pass separation produces high purity, carrier-free 223Ra product, and does not disturb the 227Ac/227Th equilibrium. A high purity, carrier-free 227Th was also obtained from the actinium using a similar anion exchange in nitric acid. These methods enable efficient production of 223Ra for research and new alpha-emitter radiopharmaceutical development.

Yttrium-90 (90Y, T1/2 64.14 h) is a key example of a high beta energy-emitting radionuclide which is available from the strontium-90 (90Sr)/90Y radionuclide generator system. Clinical uses of 90Y-labeled radiopharmaceutical agents have been pursued for many years and many applications have proven to be clinical effective. These most notably include the application of 90Y-labeled antibodies for a variety of applications such as for effective treatment of non-Hodgkin’s lymphoma. One of the major advantages for use of 90Y is ready availability from the very long-lived 90Sr parent (T1/2 28.78 y). Because of the importance of maintaining generator performance and minimizing parent breakthrough, this paper describes development, use and quality control of both high capacity cation adsorption-type and electrochemical generator systems. In addition, the preparation and targeting to tumors in mice of DOTA-conjugated Nimotuzamab (h-R3) antibody which recognizes the external domain of the EPFR antibody radiolabeled with 90Y obtained from the electrochemical generator is also described. As a key example for clinical applications of 90Y, the use of 90Y-labeled biotin for intra-operative pre-targeting for radionuclide therapy (IART®) of breast cancer is also described.

Positron emission tomography (PET) of slower biological processes calls for the use of longer lived positron emitting radioisotopes. Beyond radionuclide production considerations, practicality and rapidity of subsequent labeling chemistry further limits the selection of radioisotopes with potentially favorable nuclear properties. One additional limitation is the availability of PET radiotracers at the point-of-care with appropriate on-site production methodologies or robust radionuclide generator systems. The positron emitter 72As (half-life 26 h) is generated via decay of 72Se (half-life 8.5 d); this pair comprises and excellent generator system for clinical availability of a longer lived PET isotope. Many 72Se/As generator systems have been introduced utilizing the rich interplay of Se(IV)/Se(VI) and As(III) /As(V) chemical behavior. This paper describes available generator concepts, and briefly outlines some current arsenic labeling methodologies for the introduction of radioarsenic into biomolecules.

Electrochemical separation techniques are not widely used in radionuclide generator technology and only a few studies have been reported [1-4]. Nevertheless, this strategy is useful when other parent-daughter separation techniques are not effective or not possible. Such situations are frequent when low specific activity (LSA) parent radionuclides are used for instance with adsorption chromatographic separations, which can result in lower concentration of the daughter radionuclide in the eluent. In addition, radiation instability of the column matrix in many cases can affect the performance of the generator when long lived parent radionuclides are used. Intricate knowledge of the chemistry involved in the electrochemical separation is crucial to develop a reproducible technology that ensures that the pure daughter radionuclide can be obtained in a reasonable time of operation. Crucial parameters to be critically optimized include the applied potential, choice of electrolyte, selection of electrodes, temperature of electrolyte bath and the time of electrolysis in order to ensure that the daughter radionuclide can be reproducibly recovered in high yields and high purity. The successful electrochemical generator technologies which have been developed and are discussed in this paper include the 90Sr/90Y, 188W/188Re and 99Mo/99mTc generators. Electrochemical separation not only acts as a separation technique but also is an effective concentration methodology which yields high radioactive concentrations of the daughter products. The lower consumption of reagents and minimal generation of radioactive wastes using such electrochemical techniques are compatible with ‘green chemistry’ principles.