The synthesis of radiolabeled compounds via organometallic intermediates (original) (raw)

Current use and future potential of organometallic radiopharmaceuticals

European Journal of Nuclear Medicine and Molecular Imaging, 2002

Contrary to common belief, organometallic compounds exhibit remarkable stability in aerobic and even diluted aqueous solutions. Technetium-sestamibi (Cardiolite) is one of the most prominent examples of this class of compounds routinely used in nuclear medicine. This review summarises the recent progress in labelling of biomolecules with organometallic complexes for diagnostic and therapeutic application in radiopharmacy and exemplifies in detail developments focussing on organometallic technetium-and rhenium-tricarbonyl technologies. The value of such technologies has been recognised and they have become a valuable alternative to common labelling methodologies. An increasing number of groups have started to employ an organometallic precursor for the purpose of radioactive labelling of various classes of biomolecules, and the advantages and limitations of this new technique are compared with those of other labelling methods. The synthetic access to appropriate precursors via double-ligand exchange or aqueous carbonyl kit preparation for routine application is described. Strategies and examples for the design of appropriate bifunctional chelating agents for the Tc/Re-tricarbonyl core are given. The functionalisation of biomolecules such as tracers for the central nervous system (dopaminergic and serotonergic), tumour affine peptides (somatostatin receptors, neuroreceptors) and tumour binding single-chain antibody fragments is summarised. Where possible and appropriate, the in vitro and in vivo results in respect of these examples are compared with those obtained with classical 99m Tc/ 188 Re(V)-and 111 Inlabelled analogues. The preclinical results show the in many ways superior characteristics of organometallic labelling techniques.

Fifty Years of Radiopharmaceuticals

Journal of nuclear medicine technology, 2020

To celebrate the 50th anniversary of the founding of the SNMMI Technologist Section in 1970, the Radiopharmaceutical Sciences Council board of directors is pleased to contribute to this celebratory supplement of the Journal of Nuclear Medicine Technology with a perspective highlighting major developments in the radiopharmaceutical sciences that have occurred in the last 50 years.

Radionuclides in drug development

Drug Discovery Today, 2014

Recently, molecular imaging has gained broad interest for the stratification procedures in personalized therapies. In this regard, the importance of radionuclides for the drug development process shall not be underestimated. The methods range from target identification, pharmacokinetics studies, Phase 0 microdosing studies, endoradiotherapy with low molecular weight drugs to radioimmunotherapeutics such as Zevalin 1 . This review provides a comprehensive overview of the use of radionuclides in medical sciences from autoradiography over radioimmunoassay, post-labeling and target identification to the determination of the pharmacokinetics and metabolization and molecular imaging techniques. We demonstrate the enormous potential of different radionuclides with respect to specific classes of drugs, the radiolabeling procedures and their limitations, the instrumentation technologies and their implementation in the drug development process.

Radiopharmaceutical chemistry: Iodination techniques

The labeling of compounds with radioiodine has a long and varied history in biomedical research and the practice of nuclear medicine. In its simplest radiochemical form, sodium [ 131 I]iodide (t½ = 8.05 d) has had tremendous impact on the diagnostic evaluation of thyroid function in vivo as well as in the treatment of hyperthyroidism and thyroid cancer. Dramatic improvement in diagnostic image quality and marked reduction in patient absorbed radiation dose were achieved when 123 I (t½ = 13.3 h) was introduced into clinical practice. However, the application of any radioisotope of iodine is generally limited to the thyroid gland as long as the chemical form is restricted to the iodide (I -) anion.

Automated Synthesis of Radiopharmaceuticals

Clinical PET and PET/CT, 2012

Drug discovery is accelerating as a result of mapping of molecular targets and the rapid synthesis of high-throughput in vitro testing of compounds in their early stage of the drug development process. The development of radiolabeled biochemical compounds, understanding molecular pathways and imaging devices to detect the radioactivity by external imaging has expanded the use of nuclear molecular imaging studies in drug development. Nuclear molecular imaging modalities, positron emission tomography (PET), and single photon emission computed tomography (SPECT), are in vivo imaging methods that use gamma radiotracers to track biochemical processes in humans and animals. The cyclotron-produced positron emitters commonly used to label compounds are 11 C(t ½ = 20.4 min); 18 F (t ½ = 110 min); 13 N(t ½ = 10 min),

Radiopharmaceuticals: Production and Availability

A. Introduction 1. The use of specific radiotracers called radiopharmaceuticals for imaging organ function and disease states is a unique capability of nuclear medicine. Unlike other imaging modalities such as Computed Tomography (CT), Magnetic Resonance Imaging (MRI) and Ultrasonography (US), nuclear medicine procedures are capable of mapping physiological function and metabolic activity and thereby giving more specific information about the organ function and dysfunction (1). The mapping of the radiopharmaceutical distribution in vivo provides images of functional morphology of organs in a non-invasive manner and plays an important role in the diagnosis of many common diseases associated with the malfunctioning of organs in the body as well as in the detection of certain type of cancers. The widespread utilization and growing demands for these techniques are directly attributable to the development and availability of a vast range of specific radiopharmaceuticals. B. Radioisotopes for Radiopharmaceuticals: History and Growth 2. Radiopharmaceuticals are medicinal formulations containing radioisotopes which are safe for administration in humans for diagnosis or for therapy. Although radiotracers were tried as a therapeutic medicine immediately after the discovery of radioactivity, the first significant applications came much later with the availability of cyclotrons for acceleration of particles to produce radioisotopes. Subsequently, nuclear reactors realised the ability to prepare larger quantities of radioisotopes. Radioiodine (iodine-131), for example, was first introduced in 1946 for the treatment of thyroid cancer, and remains the most efficacious method for the treatment of hyperthyroidism and thyroid cancer. 3. One of the major goals for setting up nuclear research reactors was for the preparation of radioisotopes. Among the several applications of radioisotopes, medical applications were considered to be of the highest priority. Most of the medium flux and high flux research reactors now are routinely used to produce radioisotopes for medical, and also industrial, applications. The most commonly used reactor produced isotopes in medical applications are molybdenum-99 (for production of technetium-99m), iodine-131, phosphorus-32, chromium-51, strontium-89, samarium-153, rhenium-186 and lutetium-177 (2). 4. The early use of cyclotron in radiopharmaceuticals field was for the production of long lived radioisotopes that can be used to prepare tracers for diagnostic imaging. For this, medium to high energy (20-70 MeV) cyclotrons with high beam currents were needed. Isotopes such as thallium-201, iodine-123 and indium-111 were prepared for use with single photon emission computed tomography (SPECT). With the advent of positron emission tomography (PET), there has been a surge in the production of low energy cyclotrons (9-19 MeV) exclusively for the production of short lived PET radionuclides such as fluorine-18, carbon-11, nitrogen-13 and oxygen-15. Figure 1 shows such a machine. The majority of the cyclotrons (~350) worldwide are now used for the preparation of fluorine-18 for making radiolabelled glucose for medical imaging (3).

Studies of the mechanism of the in-loop synthesis of radiopharmaceuticals

Applied Radiation and Isotopes, 2004

A series of experiments were performed to better understand the mechanism of the In-loop [ 11 C]CH 3 I-methylation. The timing of [ 11 C]CH 3 I delivery is critical for the high yield of radiolabeling since in-loop radioactivity trapping is reversible. Trapped radioactivity escapes faster from a Tefzel loop compared to a PEEK-or stainless steel loop. Up to 50% of delivered radioactivity may be concentrated at the loop origin (representing 8.1% of the total loop volume). A five-fold reduction of the reaction solvent volume and/or precursor amount may lead to a decrease of the product radiochemical yield either by lowering the in-loop radioactivity trapping or by diminishing conversion of [ 11 C]CH 3 I into the product. r

Radiolabeling Strategies for Tumor-Targeting Proteinaceous Drugs

Molecules, 2014

Owing to their large size proteinaceous drugs offer higher operative information content compared to the small molecules that correspond to the traditional understanding of druglikeness. As a consequence these drugs allow developing patient-specific therapies that provide the means to go beyond the possibilities of current drug therapy. However, the efficacy of these strategies, in particular "personalized medicine", depends on precise information about individual target expression rates. Molecular imaging combines non-invasive imaging methods with tools of molecular and cellular biology and thus bridges current knowledge to the clinical use. Moreover, nuclear medicine techniques provide therapeutic applications with tracers that behave like the diagnostic tracer. The advantages of radioiodination, still the most versatile radiolabeling strategy, and other labeled compounds comprising covalently attached radioisotopes are compared to the use of chelator-protein conjugates that are complexed with metallic radioisotopes. With the techniques using radioactive isotopes as a reporting unit or even the therapeutic principle, care has to be taken to avoid cleavage of the radionuclide from the protein it is linked to. The tracers used in molecular imaging require labeling techniques that provide site specific conjugation and metabolic stability. Appropriate choice of the radionuclide allows tailoring the properties of the labeled protein to the application required. Until the event of positron emission tomography the spectrum of nuclides used to visualize cellular and biochemical processes was largely restricted to iodine isotopes and 99m-technetium. Today, several nuclides such as 18-fluorine, 68-gallium and 86-yttrium have fundamentally extended the possibilities of tracer design and in turn caused the need for the development of chemical methods for their conjugation.