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Radiopharmaceuticals and Methods of Radiolabeling. Definition of a Radiopharmaceutical. Definition of a Radiopharmaceutical. A radiopharmaceutical is a radioactive compound used for the diagnosis and therapeutic treatment of human diseases.
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Definition of a Radiopharmaceutical • A radiopharmaceutical is a radioactive compound used for the diagnosis and therapeutic treatment of human diseases. • In nuclear medicine nearly 95% of the radiopharmaceuticals are used for diagnostic purposes, while the rest are used for therapeutic treatment. • Radiopharmaceuticals usually have minimal pharmacologic e¤ect, because in most cases they are used in tracer quantities. • Therapeutic radiopharmaceuticals can cause tissue damage by radiation.
Definition of a Radiopharmaceutical • Because they are administered to humans, they should be sterile and pyrogen free, and should undergo all quality control measures required of a conventional drug. • A radiopharmaceutical may be a radioactive element such as 133Xe, or a labeled compound such as 131I-iodinated proteinsand 99mTc-labeled compounds.
Definition of a Radiopharmaceutical • Although the term radiopharmaceutical is most commonly used, other terms such as radiotracer, radiodiagnostic agent, and tracer have been used by various groups. • We shall use the term radiopharmaceutical throughout, although the term tracer will be used occasionally.
Definition of a Radiopharmaceutical • Another point of interest is the di¤erence between radiochemicals and radiopharmaceuticals. • The former are not usable for administration to humans due to the possible lack of sterility and nonpyrogenicity. • On the other hand, radiopharmaceuticals are sterile and nonpyrogenic and can be administered safely to humans.
Definition of a Radiopharmaceutical • A radiopharmaceutical has two components: a radionuclide and a pharmaceutical. • The usefulness of a radiopharmaceutical is dictated by the characteristics of these two components. • In designing a radiopharmaceutical, a pharmaceutical is first chosen on the basis of its preferential localization in a given organ or its participation in the physiologic function of the organ.
Definition of a Radiopharmaceutical • Then a suitable radionuclide is tagged onto the chosen pharmaceutical such that after administration of the radiopharmaceutical, radiations emitted from it are detected by a radiation detector. • Thus, the morphologic structure or the physiologic function of the organ can be assessed. The pharmaceutical of choice should be safe and nontoxic for human administration.
Definition of a Radiopharmaceutical • Radiations from the radionuclide of choice should be easily detected by nuclear instruments,and the radiation dose to the patient should be minimal.
Ideal Radiopharmaceutical • Since radiopharmaceuticals are administered to humans, and because there are several limitations on the detection of radiations by currently available instruments, radiopharmaceuticals should possess some important characteristics. • The ideal characteristics for radiopharmaceuticals are:
Ideal Radiopharmaceutical 1. Easy Availability • The radiopharmaceutical should be easily produced, inexpensive, and readily available in any nuclear medicine facility • Complicated methods of production of radionuclides or labeled compounds increase the cost of the radiopharmaceutical. • The geographic distance between the user and the supplier also limits the availability of short-lived radiopharmaceuticals.
Ideal Radiopharmaceutical 2. Short Effective Half-Life • A radionuclide decays with a definite half-life, which is called the physical half-life, denoted Tp (or t1=2). • The physical half-life is independent of any physicochemical condition and is characteristic for a given radionuclide
Ideal Radiopharmaceutical 2. Short Effective Half-Life (cont,..) • Radiopharmaceuticals administered to humans disappear from the biological system through fecal or urinary excretion, perspiration, or other mechanisms. • This biologic disappearance of a radiopharmaceutical follows an exponential law similar to that of radionuclide decay. • Thus, every radiopharmaceutical has a biologic half-life (Tb). • It is the time needed for half of the radiopharmaceutical to disappear from the biologic system and therefore is related to a decay constant= 0.693/λ= TP
Ideal Radiopharmaceutical 2. Short Effective Half-Life (cont,..) • Obviously, in any biologic system, the loss of a radiopharmaceutical is due to both the physical decay of the radionuclide and the biologic elimination of the radiopharmaceutical.
Ideal Radiopharmaceutical 2. Short Effective Half-Life (cont,..) • The net or e¤ective rate (le) of the loss of radioactivity is then related to the physical decay constant lp and the biologic decay constant lb. Mathematically, this is expressed as: • λe = λp + λb Since λ = 0.693/t1/2, it follows that • 1/Te = 1/Tp+ 1/Tb OR • Te = ( Tp X Tb) / ( Tp + Tb )
Problem 6.1 The physical half-life of 111In is 67 hr and the biologic half-life of 111In-DTPA used for measurement of the glomerular filtration rate is 1.5 hr. What is the e¤ective half-life of 111In-DTPA? Answer Using Eq. (6.3), Te ¼ 1:5 67 67 1:5 ¼ 100:5 68:5 ¼ 1:47 hr Radiopharmaceuticals
Ideal Radiopharmaceutical 3. Particle Emission • Radionuclides decaying by a- or b-particle emission should not be used as the label in diagnostic radiopharmaceuticals. • These particles cause more radiation damage to the tissue than do g rays. • Although g-ray emission is preferable, many b-emitting radionuclides, such as 131I-iodinated compounds, are often used for clinical studies.
Ideal Radiopharmaceutical 3. Particle Emission (cont,..) • However, a emitters should never be used for in vivo diagnostic studies because they give a high radiation dose to the patient. • But a and b emitters are useful for therapy, because of the effective radiation damage to abnormal cells.
Ideal Radiopharmaceutical 4. Decay by Electron Capture or Isomeric Transition • Because radionuclides emitting particles are less desirable, the diagnostic radionuclides used should decay by electron capture or isomeric transition without any internal conversion. • Whatever the mode of decay, for diagnostic studies the radionuclide must emit a Ɣ radiation with an energy preferably between 30 and 300 keV. Below 30 keV, Ɣ rays are absorbed by tissue
Ideal Radiopharmaceutical • Photon interaction in the NaI(T1) detector using collimators. A 30-keV photon is absorbed by the tissue. A> 300-keV photon may penetrate through the collimator septa and strike the detector, or may escape the detector without any interaction. • Photons of 30 to 300 keV may escape the organ of the body, pass through the collimator holes, and interact with the detector.
Ideal Radiopharmaceutical 4. Decay by Electron Capture or Isomeric Transition (cont,..) • and are not detected by the NaI(Tl) detector. • Above 300 keV, e¤ective collimation of g rays cannot be achieved with commonly available collimators. • However, recently manufacturers have made collimators for 511-keV photons, which have been used for planar or SPECT imaging using 18FFDG. • The phenomenon of collimation with 30- to 300-keV photons is illustrated • approximately 150 keV, which is most suitable for present-day collimators. • Moreover, the photon abundance should be high so that imaging time can be minimized due to the high photon flux.
Ideal Radiopharmaceutical 5. High Target-to-Nontarget Activity Ratio • For any diagnostic study, it is desirable that the radiopharmaceutical be localized preferentially in the organ under study since the activity from nontarget areas can obscure the structural details of the picture of the target organ. • Therefore, the target-to-nontarget activity ratio should be large.
Ideal Radiopharmaceutical 5. High Target-to-Nontarget Activity Ratio (cont,..) • An ideal radiopharmaceutical should have all the above characteristics to provide maximum effcacy in the diagnosis of diseases and a minimum radiation dose to the patient. • However, it is diffcult for a given radiopharmaceutical to meet all these criteria and the one of choice is the best of many compromises.
General Considerations • Many radiopharmaceuticals are used for various nuclear medicine tests. • Some of them meet most of the requirements for the intended test andtherefore 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 pharmaceuticalthat o¤er 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 di¤usion: 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 effcacy 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 e¤ect in humans due to the administration of a radiopharmaceutical, then the radiopharmaceutical is discarded.
Factors Influencing the Design of NewRadiopharmaceuticals The following factors need to be considered before, during, and after the preparation of a new radiopharmaceutical.
