What are radiopharmaceuticals? |

The Fundamentals of Radioactivity

All matter consists of atoms, which contain a central nucleus and tiny particles called electrons that revolve around the nucleus. Electrons carry a small negative charge, while the nucleus is made up of particles called neutrons, which have no charge, and protons, which carry a positive charge. Atoms are generally neutral, with the number of protons in the nucleus equaling the number of electrons. Most objects are made up of atoms in which the neutron and proton numbers in their nuclei are arranged in such a way that they are stable. If the proton number or the neutron number in the nucleus is altered, the atom may become unstable. Such unstable atoms are termed radioactive and tend to reach a stable state by emitting radiation. This process is referred to as radioactive decay, and the elemental atoms that emit radiation are called radioisotopes or radionuclides. All stable elements can be made into radioactive elements by either adding or removing neutrons or protons, a process known as the artificial production of radioactivity. The few naturally occurring radioisotopes, such as radon 222 and uranium 235, are not used in nuclear medicine.

Radioactivity was first discovered by the French scientist Antoine-Henri Becquerel in 1896, when he observed that a photographic plate sitting next to a uranium sample had darkened. Appropriately, the international unit of radioactivity was chosen to be the becquerel. Radioactivity is a property of unstable atomic nuclei, and the rate of decay cannot be affected by normal physical and chemical processes such as heat, pressure, or the presence of magnetic or electric fields. The nuclei in a radioactive sample do not decay spontaneously or all at once. Rather, they decay randomly at a rate that is characteristic of the given radioisotope. While it is impossible to tell when a particular nucleus will decay or disintegrate, the fraction of nuclei in a sample that will decay in a given time can be determined. The decay rate of a radioactive sample is usually expressed in terms of its half-life, the time required for one-half of the original sample nuclei to decay. Half-life is a characteristic property of a particular radionuclide. The half-lives of radioactive isotopes vary from a small fraction of a second to millions of years. For example, carbon 14 has a half-life of 5,730 years, while the half-life of iodine 123 is thirteen hours. Naturally occurring uranium 238 decays with a half-life of 4.5 billion years, which is the approximate age of Earth itself. Hence, at present there remains only half of the original uranium 238 that was formed when the earth was born.

Radionuclides emit three types of radiation: alpha particles, beta particles, and gamma rays. Alpha particles are positively charged ions containing two protons and two neutrons. Beta particles are either positively (positron) or negatively (electron) charged and have the same mass as an electron. In contrast, gamma rays are electromagnetic waves that have no mass or charge and are sometimes called photons. Because alpha particles are relatively massive, they can be totally absorbed by a sheet of paper. Beta particles can penetrate up to about a centimeter or so into an object, depending on their energy. On the other hand, gamma rays of moderate energy can easily penetrate through the body, as with x-rays. When radionuclides that emit gamma rays are administered to patients, the gamma rays exit the body and are captured by a scintillation camera, which produces an image. The desirable energy of the gamma rays for external detection and imaging with gamma cameras is generally in the range of 100 kilo-electron volts to 300 kilo-electron volts. The half-life of the radionuclide emitting the gamma rays should be long enough to allow its uptake by the organ of interest, then subsequent imaging with a gamma camera, and short enough so as not to irradiate the patient long after the image is obtained. Half-lives between three hours and three days are considered optimal for diagnostic purposes. When radionuclides are used for therapy, the half-life is generally required to be in the range of several days, and the preferred form of radiation consists of beta particles because they tend to deposit their energy near the disintegration site.

Uses and Complications

If the physician is interested in imaging a particular organ, drugs that take the radionuclide preferentially to that organ are necessary. This is achieved by chemically attaching the radionuclide to a pharmaceutical carrier. Once the radiopharmaceutical is localized in the organ, the gamma rays that it emits are detected by a gamma camera, which electronically displays an image that is representative of the radionuclide distribution. Such images are of substantial diagnostic value. Similarly, radionuclides attached to drugs that selectively target cancer
cells can potentially deliver lethal doses of radiation to the cancer cells, a process called radioimmunotherapy. Hence, radiopharmaceuticals play an important role in medicine, providing new and promising avenues for diagnosis and therapy.

Radiopharmaceuticals are generally administered intravenously to patients. Blood flow to the organ of interest determines the fraction of the administered radioactivity that will be delivered. The ability of the organ to accumulate the circulating radiopharmaceutical is also an important determinant of the pathological condition of the organ. Such considerations are usually taken into account in developing appropriate pharmaceuticals.

Although many radionuclides are available, the most preferred one is called technetium 99m, an excited (metastable) state of technetium 99. This radionuclide is readily available, has a convenient half-life of six hours, and has very desirable radiation properties. Accordingly, many pharmaceuticals are labeled with this radionuclide for diagnostic nuclear medicine purposes. A few other radionuclides, such as thallium 201, iodine 123, gallium 67, and indium 111, can be used when technetium 99m compounds are not available.

The most widely used radiopharmaceutical for brain
imaging is technetium 99m pertechnetate. The primary advantage of this chemical is that it is inexpensive and can be easily prepared. Other radiopharmaceuticals used for
brain studies are technetium 99m diethylenetriamine-pentacetic acid (DTPA) and technetium 99m glucoheptonate. Brain imaging usually consists of a dynamic study immediately after bolus intravenous injection of the compound in which rapid sequential images are obtained as the radiopharmaceutical enters the brain. This is followed by a static image one hour later. When a brain lesion is suspected, a delayed static image is sometimes necessary three to four hours after an injection. These imaging techniques are valuable in detecting neoplastic tissue, inflammatory processes, infarction, Alzheimer’s disease, and stroke. Another class of radiopharmaceuticals has also been developed to study brain function. These compounds, such
as carbon 11 N-methylpiperone, use very short-lived radionuclides that need on-site radionuclide production facilities and require a sophisticated imaging system called a
positron emission tomography (PET) scanning unit. Imaging of cerebrospinal fluid is performed using DTPA labeled with indium 111 after an intrathecal administration. Radiopharmaceuticals for such administrations are tested carefully for their safety.

Lung imaging using radiopharmaceuticals is usually performed to study either pulmonary
perfusion or ventilation. For perfusion studies, the radiopharmaceutical of choice is microaggregated albumin (MAA) labeled with technetium 99m. Ventilation studies are performed using the radioactive inert gas xenon 133. The patient breathes while the images are obtained with a gamma camera. These lung studies are used extensively to detect several conditions, including pulmonary embolism, asthma, bronchitis, tumors, inflammatory disease, congestive heart failure, and deep-vein thrombus.

Bone imaging with radiopharmaceuticals often provides earlier diagnosis and better detection of lesions than other radiographic procedures. Furthermore, the extent of metastatic disease may be determined using radionuclide imaging techniques. Other applications of bone imaging include determination of the viability of bone; detection of infections in prosthetic joints, necrosis, and infarction; and evaluation of fractures and bone pain. Bone-seeking compounds are usually similar to calcium or phosphates in their chemical behavior. Hence, diphosphonate labeled with technetium 99m and its analogs are the compounds of choice for this purpose.

Radionuclide imaging techniques play an important role in evaluating the function of the heart. Coronary artery perfusion is studied using thallium 201 chloride. The patient is asked to exercise on a treadmill, and the radionuclide is injected at peak stress. The patient continues to exercise for an additional minute, and redistribution of the thallium 201 within the myocardium occurs immediately after cessation of the exercise. Gamma camera images are obtained soon thereafter. Abnormal thallium distribution is the basis for the detection and diagnosis of stress-induced ischemia and permanent myocardial damage. Acute myocardial infarction can be detected using pyrophosphate labeled with technetium 99m within twenty-four to seventy-two hours after the onset of symptoms. Other radiopharmaceuticals using technetium 99m as a label are also under development. To evaluate ventricular function, the radiochemical is administered intravenously and images are obtained during the first pass of the radionuclide through the heart, lungs, and great vessels. An alternate technique for this
purpose is to obtain images of the cardiac blood pool after the radiopharmaceutical has achieved equilibrium in the intravascular space. Such noninvasive studies are invaluable in the diagnosis of heart problems and in the management of patients with heart disease.

Evaluation of thyroid function using radioisotope techniques marked the beginning of the field of nuclear medicine. The element iodine is actively transported into the thyroid gland, where it is retained. Therefore, the readily available radioiodines iodine 131 and iodine 123 have been used for this purpose. Technetium 99m pertechnetate is sometimes used because of its low cost and favorable radiation characteristics. Thyroid uptake tests usually involve administration of a small dose of sodium iodide 131 in either liquid or capsule form and measurement of the radioiodine in the thyroid eighteen to twenty-four hours later. Significantly higher uptake compared to the normal value is a reflection of an overactive gland (hyperthyroidism). Conversely, a lower uptake indicates an underactive gland (hypothyroidism). Thyroid imaging is performed using either sodium iodide 123 or technetium 99m pertechnetate to detect cancer. Effective treatment of benign and malignant cancers, as well as hyperthyroidism, is accomplished by administering larger doses of iodine 131. Although the strong uptake of radioactive iodine by the thyroid gland is useful in nuclear medicine, uptake of iodine 131 in the thyroids of people living in nuclear-fallout zones, such as the one around the Chernobyl nuclear reactor, is a major concern. The risk from such exposure can be reduced by saturating the thyroid with nonradioactive iodine using orally administered doses of Lugol’s iodine solution.

Radiopharmaceutical studies of
kidneys are sometimes necessary to evaluate structural and functional abnormalities. Renal imaging is indicated to assess renal blood flow and the differential and quantitative functioning of natural or transplanted kidneys. Among the radiopharmaceuticals used for these studies are technetium-labeled glucoheptonate, 2,3-dimercaptosuccinic acid (DMSA), and DTPA. Iodine 123 hippurate is also employed for glomerular filtration studies.

Nuclear medicine techniques to image the
liver and
spleen are also available. Alcohol-related liver diseases can be readily diagnosed using liver images obtained after injection of technetium-labeled sulfur colloid. Primary liver cancers and metastases can also be detected, and the physiological functioning of transplanted livers can be assessed. Spleen imaging with technetium 99m sulfur colloid has been useful in detecting hepatomas, cysts, infarctions, and neoplasms. Gastrointestinal hemorrhaging and associated bleeding are identified by removing a small portion of the patient’s red blood cells, labeling them with technetium 99m, and injecting the labeled cells back into the patient. Similarly, white blood cells labeled with indium 111 are used to image abscesses and inflammation. Radionuclide procedures also provide a method to assess digestive disorders and esophageal transit noninvasively. A variety of tumors can be diagnosed when gallium 67 citrate is used for imaging. This radionuclide is also used in studying
patients with Acquired immunodeficiency syndrome (AIDS).

Radiopharmaceuticals are also playing an important role in treating many functional disorders and cancers. As pointed out earlier, hyperthyroidism and thyroid carcinoma are best treated with iodine 131. Malignant pheochromocytomas and other neuroendocrine lesions can be treated with metaiodine 131 benzylguanidine. Gold 198 colloid has been used to assist in the therapy of peritoneal metastases and recurrent malignant ascites. Phosphorus 32 colloids are employed in treating malignant pericardial effusion associated with breast and lung carcinomas. Intra-arterial injection of phosphorus 32 colloid to treat inflammatory arthritis of bone joints is also common. The uncontrolled proliferation of bone marrow cells is checked by administering phosphorus 32 orthophosphate. Patients with advanced bone metastases and intractable bone pain are also often treated with single or multiple doses of phosphorus 32 orthophosphate. Other radionuclides that are useful for this purpose are strontium 89, rhenium 186, and yttrium 90.

The implementation of
monoclonal antibodies labeled with suitable radionuclides to treat cancer has received considerable attention. This approach involves selecting an antibody that is directed against a tumor-specific antigen and labeling the antibody with an energetic beta particle-emitting radionuclide. If the tumor selectively concentrates these labeled antibodies, then it can be lethally irradiated without seriously affecting the normal tissues and organs. Thus far, however, clinical trials using this approach have met with limited success because of insufficient tumor uptake and bone marrow toxicity. Nevertheless, labeled antibodies are becoming useful in diagnosing a variety of primary and metastatic tumors.

Perspective and Prospects

Although radioactivity was discovered in the late nineteenth century, application of radionuclides as biological tracers did not begin until 1924, when Georg von Hevesy used a bismuth radionuclide to study circulation in rabbits. In that same year, bismuth 214 was used in humans to measure the blood circulation time after injecting the radionuclide in one arm and then following the arrival of radioactivity in the other arm. The researchers found that it takes eighteen seconds in normal patients, and longer in patients with heart disease. The discovery of artificial radioactivity by Frédéric Joliot and Irène Joliot-Curie in 1934 led to the wider use of radionuclides as tracers. When Enrico Fermi artificially produced several radionuclides, Hevesy used phosphorus 32 to study phosphorus metabolism in rats. Such artificial production of radionuclides became possible after the pioneering work of Ernest Lawrence, who invented the cyclotron in 1929. Cyclotrons are still widely employed to produce a variety of radionuclides for medical use. The most commonly used one in nuclear medicine imaging is technetium 99m; this radionuclide is generated in the decay of another radionuclide called molybdenum 99, which was first produced by a cyclotron in 1938.

Radiopharmaceuticals and nuclear medicine took a major leap forward when technetium 99m, the radionuclide of choice for imaging, became readily available. Concurrent development of the scintillation camera by Hal Anger in 1958 advanced the field of nuclear medicine imaging. Radiolabeled compounds are also used extensively in biomedical research to trace biologically important molecules. The
radioimmunoassay is another area in which labeled compounds are used to diagnose diseases; here, an antigen-antibody interaction is utilized. These procedures require only a trace amount of radioactivity, along with a blood sample of the patient.

Radiopharmaceutical imaging techniques have become important for the diagnosis and treatment of many diseases, and they will continue to play a major role in improving the quality of health care. Improvements in imaging instrumentation technology and the availability of computer technology to process the images are likely to further the accuracy of nuclear medicine images. Future developments in biotechnology should also assist in designing new pharmaceuticals that are more target-specific, thus further reducing the risks and enhancing both the diagnostic quality of the images and the therapeutic efficacy of radiolabeled compounds.

Another challenge for future research may include searching for new ways to create and manufacture radiopharmaceuticals. In the early part of the twenty-first century, planned and unplanned closures of nuclear reactors created shortages of radiopharmaceutical materials in Europe; given this, one area of future research may be to find the means to develop these materials in other ways. In December, 2009, the Food and Drug Administration issued a ruling (effective December, 2011) on regulations about the manufacturing process of radiopharmaceuticals for PET scanning, designed to accommodate producers in commercial and nonprofit, academically oriented institutions.

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