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Radiopharmaceuticals and Methods of Radiolabeling. Design of New Radiopharmaceuticals. General Considerations. Many radiopharmaceuticals are used for various nuclear medicine tests. Some of them meet most of the requirements for the intended test and therefore need no replacement.
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General Considerations • Many radiopharmaceuticals are used for various nuclear medicine tests. • Some of them meet most of the requirements for the intended test and therefore need no replacement. • For example, 99mTc–methylene diphosphonate (MDP) is an excellent bone imaging agent and the nuclear medicine community is fairly satisfied with this agent such that no further research and development is being pursued for replacing 99mTc-MDP with a new radiopharmaceutical.
General Considerations (cont,..) • However, there are a number of other radio pharmaceuticals that offer only minimal diagnostic value in nuclear medicine tests and thus need replacement. • Continual effort is being made to improve or replace such radiopharmaceuticals.
General Considerations (cont,..) • Upon scrutiny, it is noted that the commonly used radiopharmaceuticals involve one or more of the following mechanisms of localization in a given organ: • Passive diffusion: 99mTc-DTPA in brain imaging, 99mTc-DTPA aerosol and 133Xe in ventilation imaging, 111In-DTPA in cisternography. • Ion exchange: uptake of 99mTc-phosphonate complexes in bone.
General Considerations (cont,..) 3. Capillary blockage: 99mTc macroaggregated albumin (MAA) particles trapped in the lung capillaries. 4. Phagocytosis: removal of 99mTc-sulfur colloid particles by the reticuloendothelial cells in the liver, spleen, and bone marrow. 5. Active transport: 131I uptake in the thyroid, 201Tl uptake in the myocardium. 6. Cell sequestration: sequestration of heat-damaged 99mTc-labeled red blood cells by the spleen.
General Considerations (cont,..) 7. Metabolism: 18F-FDG uptake in myocardial and brain tissues. 8. Receptor binding: 11C-dopamine binding to the dopamine receptors in the brain. 9. Compartmental localization: 99mTc-labeled red blood cells used in the gated blood pool study. 10. Antigen-antibody complex formation: 131I-, 111In-, and 99mTc-labeled antibody to localize tumors. 11. Chemotaxis: 111In-labeled leukocytes to localize infections.
General Considerations (cont,..) • Based on these criteria, it is conceivable to design a radiopharmaceutical to evaluate the function and/or structure of an organ of interest. • Once a radiopharmaceutical is conceptually designed, a definite protocol should be developed based on the physicochemical properties of the basic ingredients to prepare the radiopharmaceutical.
General Considerations (cont,..) • The method of preparation should be simple, easy, and reproducible, and should not alter the desired property of the labeled compound. • Optimum conditions of temperature, pH, ionic strength, and molar ratios should be established and maintained for maximum effcacy of the radiopharmaceutical.
General Considerations (cont,..) • Once a radiopharmaceutical is developed and successfully formulated, its clinical efficacy must be evaluated by testing it first in animals and then in humans. • For use in humans, one has to have a Notice of Claimed Investigational Exemption for a New Drug (IND) from the U.S. Food and Drug Administration (FDA), which regulates the human trials of drugs very strictly. • If there is any severe adverse effect in humans due to the administration of a radiopharmaceutical, then the radiopharmaceutical is discarded.
The following factors need to be considered before, during, and after the preparation of a new radiopharmaceutical. Factors Influencing the Design of NewRadiopharmaceuticals
Methods of Radiolabeling • The use of compounds labeled with radionuclides has grown considerably in medical, biochemical, and other related fields. • In the medical field, compounds labeled with β-emitting radionuclides are mainly restricted to in vitro experiments and therapeutic treatment, whereas those labeled with ɤemittingradionuclides have much wider applications. • The latter are particularly useful for in vivo imaging of different organs.
Methods of Radiolabeling (cont,..) • These methods and various factors affecting the labeled compounds are discussed below.
Isotope Exchange Reactions • In isotope exchange reactions, one or more atoms in a molecule are replaced by isotopes of the same element having different mass numbers. • Since the radiolabeled and parent molecules are identical except for the isotope e¤ect, they are expected to have the same biologic and chemical properties. • Examples are 125I-triiodothyronine (T3), 125I-thyroxine (T4), and 14C-, 35S-, and 3H-labeled compounds. • These labeling reactions are reversible and are useful for labeling iodine-containing material with iodine radioisotopes and for labeling many compounds with tritium.
Introduction of a Foreign Label • In this type of labeling, a radionuclide is incorporated into a molecule that has a known biologic role, primarily by the formation of covalent or coordinate covalent bonds. The tagging radionuclide is foreign to the molecule and does not label it by the exchange of one of its isotopes. • Some examples are 99mTc-labeled albumin, 99mTc-DTPA, 51Cr-labeled red blood cells, and many iodinated proteins and enzymes. • In several instances, the in vivo stability of the material is uncertain and one should be cautious about any alteration in the chemical and biologic properties of the labeled compound.
Introduction of a Foreign Label (cont,…) • In many compounds of this category, the chemical bond is formed by chelation, that is, more than one atom donates a pair of electrons to the foreign acceptor atom, which is usually a transition metal. Most of the 99mTc-labeled compounds used in nuclear medicine are formed by chelation. • For example, 99mTc binds to DTPA, gluceptate, and other ligads by chelation.
Labeling with Bifunctional Chelating Agents • In this approach, a bifunctional chelating agent is conjugated to a macromolecule (e.g., protein, antibody) on one side and to a metal ion (e.g., Tc) by chelation on the other side. • Examples of bifunctional chelating agents are DTPA, metallothionein, diamidedimercaptide (N2S2), hydrazinonicotinamide (HYNIC) and dithiosemicarbazone.
Labeling with Bifunctional Chelating Agents (cont,…) • There are two methods—the preformed 99mTc chelate method and the indirect chelator-antibody method. • In the preformed 99mTc chelate method, 99mTc chelates are initially preformed using chelating agents such as diamidodithiol, cyclam, and so on, which are then used to label macromolecules by forming bonds between the chelating agent and the protein.
Labeling with Bifunctional Chelating Agents (cont,…) • In contrast, in the indirect method, the bifunctional chelating agent is initially conjugated with a macromolecule, which is then allowed to react with a metal ion to form a metal-chelate-macromolecule complex. Various antibodies are labeled by the latter method. • Because of the presence of the chelating agent, the biological properties of the labeled protein may be altered and must be assessed before clinical use.
Labeling with Bifunctional Chelating Agents (cont,…) • Although the prelabeled chelator approach provides a purer metalchelate complex with a more definite structural information, the method involves several steps and the labeling yield often is not optimal, thus favoring the chelatorantibody approach.
Biosynthesis • In biosynthesis, a living organism is grown in a culture medium containing the radioactive tracer, the tracer is incorporated into metabolites produced by the metabolic processes of the organism, and the metabolites are then chemically separated. • For example, vitamin B12 is labeled with 60Co or 57Co by adding the tracer to a culture medium in which the organism Streptomycesgriseus is grown. • Other examples of biosynthesis include 14C-labeled carbohydrates, proteins, and fats.
Recoil Labeling • Recoil labeling is of limited interest because it is not used on a large scale for labeling. • In a nuclear reaction, when particles are emitted from a nucleus, recoil atoms or ions are produced that can form a bond with other molecules present in the target material. • The high energy of the recoil atoms results in poor yield and hence a low specific activity of the labeled product.
Recoil Labeling (cont,..) • Several tritiated compounds can be prepared in the reactor by the 6Li(n,α)3 • reaction. • The compound to be labeled is mixed with a lithium salt and irradiated in the reactor. • Tritium produced in the above reaction labels the compound, primarily by the isotope exchange mechanism, and then the labeled compound is separated.
Excitation Labeling • Excitation labeling entails the utilization of radioactive and highly reactive daughter ions produced in a nuclear decay process. • During b decay or electron capture, energetic charged ions are produced that are capable of labeling various compounds of interest. • Krypton-77 decays to 77Br and, if the compound to be labeled is exposed to 77Kr, then energetic 77Br ions label the compound to form the brominated compound. • Similarly, various proteins have been iodinated with 123I by exposing them to 123Xe, which decaysto 123I. • The yield is considerably low with this method
The majority of radiopharmaceuticals used in clinical practice are relatively easy to prepare in ionic, colloidal, macroaggregated, or chelated forms, and many can be made using commercially available kits. Several factors that influence the integrity of labeled compounds should be kept in mind. These factors are described briefly below. Important Factors in Labeling
Important Factors in Labeling Efficiency of the Labeling Process • A high labeling yield is always desirable, although it may not be attainable in many cases. • However, a lower yield is sometimes acceptable if the product is pure and not damaged by the labeling method, the expense involved is minimal, and no better method of labeling is available.
