DISCUSSION ON RADIOISOTOPE & RADIOPHARMACEUTICAL: IT’S USES

About Authors:
C.P.Meher*, S.P.Sethy, B.Pochaiah
Asst. Professor
Maheshwara Institute of  Pharmacy,
Department Of Pharmaceutical Chemistry
Chitkul, Patancheru, Medak, A.P
*chaitanyameher84@gmail.com

ABSTRACT
Radioactive isotope, also called radioisotope,  any of several species of the same chemical element with different masses whose nuclei are unstable and dissipate excess energy by spontaneously emitting radiation in the form of alpha, beta, and gamma rays. Radioisotopes are elements that are atomically unstable and radioactive. Radioisotopes stabilize by releasing energy and matter. Natural radioisotopes, which have relatively low radioactive energy, have been largely replaced by artificially produced radioisotopes. Artificially produced radioisotopes are widely utilized as sources of radiation for radiography, gauging, and as tracers for a multitude of measurements that are not easily made by other methods. Radiopharmaceuticals are drugs containing a radionuclide and are used routinely in nuclear medicine for the diagnosis and therapy of various diseases. Presented article is concerned with brief discussion about the radioisotope & Radiopharmaceuticals.

Reference Id: PHARMATUTOR-ART-1588

INTRODUCTION
Radioactive nuclides, or radionuclides, are species of unstable atomic nuclei without the restriction of being forms of the same element. Radioactive nuclides consist of all the sets of radioactive isotopes. Radiochemistry a subdivision of chemistry which deals with the study of radioactive substances. it includes the nuclear transformation involved, transmutation of one element into another,and the nature and properties of the radiation emitted. it also deals with the use of this radiation in chemical tracer analysis, for geological & archeological (chemical dating), and for initiation of cross-lining(polymerazation)  [1] Spontaneous nuclear transformation of nuclide into another nuclide, accompanied by emission of nuclear radiation ,either corpuscular or electromagnetic. it may be natural, as with radium, artificial (caused bybombardment of a stable nucleus with neutrons or deuterons), or induced, as in radioactive carbon.the emanations are in the form of alpha, beta, gamma rays. the natural radioactive elements are uranium, radium, radon and thorium(the principal members of the uranium decay series), the ultimate end products being stable isotope of elements,e.g.,sodium,iodine etc., can be made radioactive by bombardment with neutrons, deuterons.or other heavy particles. Radionuclides, mainly ³H & ¹⁴C, are widely used as tracers in analysis, and in distribution and metabolism studies of drugs in animals.such isotope with long half-lives are not suitable for use in human medicine,but a number of radioisotopes with comparatively short half-lives, measured in hours or days,are now widely used in radiopharmaceutical preparations as diagnostic agents and in the treatment of neoplastic disease. these include ³²P,⁵¹Cr,⁵⁷Co,⁵⁹Fe,⁷⁵Se,¹²⁵I.¹³¹I & ^99mTc.  [2] Isotopes are generally distinguished by three analytical means. The first of them makes use of radioactive isotopes, such as tritium (3H), 14C, 32P etc. This is a highly sensitive technique, but special facilities are required to handle radioactive material. Mass spectroscopy can also be used to detect isotopes. This is also a highly sensitive technique. When the fragmentation pattern of a compound is known, mass spectral data provide a wealth of information. The third, and at present the most frequently used technique is nuclear magnetic resonance. This technique requires an NMR active nucleus such as 2H, 13C, 17O etc. and is relatively less sensitive. But the ease of operation more than compensates for its limitations.[3]

According to the different condition for storage ,handling,disposal and the manner in which the radionuclide are used they are categorized into two groups (1)sealed (2)unsealed. In radio therapy sealed radio isotope are used that are encapsulated to prevent the loss of the radioisotopes. On the other hand most radiopharmaceuticals are used in unsealed state. i.e. the radio isotope is present in the liquid , particular or gaseous state. These offers some hazards which include contamination by skin contact and accidental inhalation or ingestion.[4]

Types of radioactive isotopes by origin

1) Long-lived radioactive nuclides
Some radioactive nuclides that have very long half lives were created during the formation of the solar system (~4.6 billion years ago) and are still present in the earth. These include ⁴⁰K (t½ = 1.28 billion years), ⁸⁷Rb (t½ = 48.8 billion years), ²³⁸U (t½ = 447 billion years), and ¹⁸⁶Os (t½ = 2 x 106 billion years, or 2 million billion years).

2) Cosmogenic
Cosmogenic isotopes are a result of cosmic ray activity in the atmosphere. Cosmic rays are atomic particles that are ejected from stars at a rate of speed sufficient to shatter other atoms when they collide. This process of transformation is called spallation. Some of the resulting fragments produced are unstable atoms having a different atomic structure (and atomic number), and so are isotopes of another element. The resulting atoms are considered to have cosmogenic radioactivity. Cosmogenic isotopes are also produced at the surface of the earth by direct cosmic ray irradiation of atoms in solid geologic materials.

Examples of cosmogenic nuclides include ¹⁴C, ³⁶Cl, ³H, ³²Si, and ¹⁰Be. Cosmogenic nuclides, since they are produced in the atmosphere or on the surface of the earth and have relatively short half-lives (10 to 30,000 years), are often used for age dating of waters.

3) Anthropogenic
Anthropogenic isotopes result from human activities, such as the processing of nuclear fuels, reactor accidents, and nuclear weapons testing. Such testing in the 1950s and 1960s greatly increased the amounts of tritium (³H) and ¹⁴C in the atmosphere; tracking these isotopes in the deep ocean, for instance, allows oceanographers to study ocean flow, currents, and rates of sedimentation. Likewise, in hydrology it allows for the tracking of recent groundwater recharge and flow rates in the vadose zone. Examples of hydrologically useful anthropogenic isotopes include many of the cosmogenic isotopes mentioned above: ³H, ¹⁴C, ³⁶Cl, and ⁸⁵Kr.

4) Radiogenic
Radiogenic isotopes are typically stable daughter isotopes produced from radioactive decay. In the geosciences, radiogenic isotopes help to determine the nature and timing of geological events and processes. Isotopic systems useful in this research are primarily K-Ar, Rb-Sr, Re-Os, Sm-Nd, U-Th-Pb, and the noble gases (⁴H, ³H-³He, ⁴⁰Ar).

Because of their stable evolution in groundwater, such naturally occurring isotopes are useful hydrologic tracers, allowing evaluation of large geographic areas to determine flowpaths and flow rates. Consequently, they are helpful in building models that predict fracturing, aquifer thickness, and other subterranean features.

Production of radioisotope
Production of radioisotopes includes three principle categories, which are (1) neutron activation (bombardment), (2) fission product separation, and (3) charged particle bombardment. Nuclear bombardment constitutes the major method for obtaining industrially important radioisotope materials. Radioisotopes may exist in any form of matter, with solid materials comprising the largest group.

Emission of radioisotope
Three main type of radiation from radioactive substance are alpha(α),beta(β) and gamma(γ) rays.most source emit more than one type of emission, The penetrating power of each radiation varies considerably according to it’s nature and it’s energy. Alpha particle are completely absorbed in a thickness of a few micrometers to some tens of micrometer of solid or liquid. Beta particle are completely absorbed in a thickness of several millimeter to several centimeter. Gamma rays are not completely absorbed but only attenuated. The denser the absorbent , the shorter the range of alpha, beta particle and greater the attenuation of gamma rays.[5]

Cause of desirable effect of shorter half-lives radionuclide
In general, radionuclides (RN) with shorter half-lives are desirable for use in diagnostic nuclear medicine (NM) because they usually produce less total dose to the patient, thus yielding reduced biological impact compared to longer-lived radionuclides. Radionuclides that are selected for diagnostic NM procedures preferably emit photonic radiation (usually gamma rays) that have an energy in the approximate range from 100 to 150 keV. This energy is desirable since it is high enough to ensure reasonable penetration of the human body so that photons are able to reach the imaging device, usually a gamma camera; additionally this energy is detected with high efficiency by the detectors in the cameras and is low enough so that camera collimators work effectively to record primarily photons moving in a direction more-or-less perpendicular to the face of the detector. This is necessary in order to obtain acceptably sharp images without appreciable blurring. A final desirable property is that the radionuclide emits minimal amounts of particulate radiation such as beta particles and alpha particles so as not to produce excess patient dose while doing nothing to improve image quality. There are both long- and short-lived radionuclides that could fulfill these recommendations.

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RADIOPHARMACEUTICALS
Radiopharmaceuticals are drugs containing a radionuclide and are used routinely in nuclear medicine for the diagnosis and therapy of various diseases. Depending upon their medical applications radiopharmaceuticals are divided into two classes’ viz. diagnostic radiopharmaceuticals and therapeutic radiopharmaceuticals. They are briefly discussed below.

Diagnostics Radiopharmaceuticals
Diagnostic radiopharmaceuticals are molecules which are tagged with a gamma ray emitting radioisotope. Such agents when administered into the body localize in certain organs or tissue, for which they are designed for, and the radiation emitted by the associated radionuclide could be detected from outside with the help of suitable instrument like gamma camera. The analysis of the resultant images obtained from the gamma camera could reveal useful information regarding the disease condition of the patient.

Therapeutic Radiopharmaceuticals
Therapeutic Radiopharmaceuticals are very similar much to the diagnostic radiopharmaceuticals but the only difference being the use of a therapeutic radionuclide instead of a diagnostic radionuclide. In this case the primary aim is not to get diagnostic information but to deliver therapeutic doses of ionizing radiations to specific diseased sites. Further discussion on therapeutic radiopharmaceuticals is beyond the scope of present work. The various isotope used as therapeutic, diagnostic or research work are listed below in table-1 [6]

Isotopes used in radiopharmaceuticals with application

Table-1

The use of radioisotope in medicine is different upon the type of radiation emitted by it. Usually beta and gamma radiation are utilized for medical purpose because of the case with which they can be detected and measure.

Uses of radioactivity/radiation
There are many practical applications to the use of radioactivity/radiation. Radioactive sources are used to study living organisms, to diagnose and treat diseases, to sterilize medical instruments and food, to produce energy for heat and electric power, and to monitor various steps in all types of industrial processes.

Tracers
Tracersare a common application of radioisotopes. A tracer is a radioactive element whose pathway through which a chemical reaction can be followed. Tracers are commonly used in the medical field and in the study of plants and animals. Radioactive Iodine-131 can be used to study the function of the thyroid gland assisting in detecting disease.

Nuclear reactors
Nuclear reactorsare devices that control fission reactions producing new substances from the fission product and energy. Recall our discussion earlier about the fission process in the making of a radioisotope. Nuclear power stations use uranium in fission reactions as a fuel to produce energy. Steam is generated by the heat released during the fission process. It is this steam that turns a turbine to produce electric energy.

Other uses of radioactivity
Sterilization of medical instruments and food is another common application of radiation. By subjecting the instruments and food to concentrated beams of radiation, we can kill microorganisms that cause contamination and disease. Because this is done with high energy radiation sources using electromagnetic energy, there is no fear of residual radiation. Also, the instruments and food may be handled without fear of radiation poisoning.
Radiation sources are extremely important to the manufacturing industries throughout the world. They are commonly employed by nondestructive testing personnel to monitor materials and processes in the making of the products we see and use every day. Trained technicians use radiography to image materials and products much like a dentist uses radiation to x-ray your teeth for cavities. There are many industrial applications that rely on radioactivity to assist in determining if the material or product is internally sound and fit for its application. Radioactive isotopes have many useful applications. In medicine, for example, cobalt-60 is extensively employed as a radiation source to arrest the development of cancer. Other radioactive isotopes are utilized as tracers for diagnostic purposes, as well as in research on metabolic processes. When a radioactive isotope is added in small amounts to comparatively large quantities of the stable element, it behaves exactly the same as the ordinary isotope chemically; it can, however, be traced with a Geiger counter or other detection device. Iodine-131 has proved effective in locating brain tumours, measuring cardiac output, and determining liver and thyroid activity. Another medically important radioactive isotope is carbon-14, which is useful in studying abnormalities of metabolism that underlie diabetes, gout, anemia, and acromegaly. In industry, radioactive isotopes of various kinds are used for measuring the thickness of metal or plastic sheets; their precise thickness is indicated by the strength of the radiations that penetrate the material being inspected. They also may be employed in place of large X-ray machines to examine manufactured metal parts for structural defects. Other significant applications include the use of radioactive isotopes as compact sources of electrical power—e.g., plutonium-238 in cardiac pacemakers and spacecraft. In such cases, the heat produced in the decay of the radioactive isotope is converted into electricity by means of thermoelectric junction circuits or related devices.

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Extraction of radioisotope
Some isotopes occur in nature. If radioactive, these usually are radioisotopes with very long half-lives. Uranium 235, for example, makes up about 0.7 percent of the naturally occurring uranium on the earth.The challenge is to separate this very small amount from the much larger bulk of other forms of uranium. The difficulty is that all these forms of uranium, because they all have the same number of electrons, will have identical chemical behavior: they will bind in identical fashion to other atoms. Chemical separation, developing a chemical reaction that will bind only uranium atoms, will separate out uranium atoms, but not distinguish among different isotopes of uranium. The only difference among the uranium isotopes is their atomic weight. A method had to be developed that would sort atoms according to weight. One initial proposal was to use a centrifuge. The basic idea is simple: spin the uranium atoms as if they were on a very fast merry-go-round. The heavier ones will drift toward the outside faster and can be drawn off. In practice the technique was an enormous challenge: the goal was to draw off that very small portion of uranium atoms that were lighter than their brethren. The difficulties were so enormous the plan was abandoned in 1942. Instead, the technique of gaseous diffusion was developed. Again, the basic idea was very simple: the rate at which gas passed (diffused) througha filter depended on the weight of the gas molecules: lighter molecules diffused more quickly. Gas molecules that contained U-235 would diffuse slightly faster than gas molecules containing the more common but also heavier U-238. This method also presented formidable technical challenges, but was eventually implemented in the gigantic gas diffusion plant at Oak Ridge, Tennessee. In this process, the uranium was chemically combined with fluorine to form a hexafluoride gas prior to separation by diffusion. This is not a practical method for extracting radioisotopes for scientific and medical use. It was extremely expensive and could only supply naturally occurring isotopes. A more efficient approach is to artificially manufacture radioisotopes. This can be done by firing high-speed particles into the nucleus of an atom. When struck, the nucleus may absorb the particle or become unstable and emit a particle. In either case, the number of particles in the nucleus would be altered, creating an isotope. One source of high-speed particles could be a cyclotron. A cyclotron accelerates particles around a circular race track with periodic pushes of an electric field. The particles gather speed with each push, just as a child swings higher with each push on a swing. When traveling fast enough, the particles are directed off the race track and into the target. A cyclotron works only with charged particles, however. Another source of bullets are the neutrons already shooting about inside a nuclear reactor. The neutrons normally strike the nuclei of the fuel, making them unstable and causing the nuclei to split (fission) into two large fragments and two to three "free" neutrons. These free neutrons in turn make additional nuclei unstable, causing further fission. The result is a chain reaction. Too many neutrons can lead to an uncontrolled chain reaction, releasing too much heat and perhaps causing a "meltdown." Therefore, "surplus" neutrons are usually absorbed by "control rods." However, these surplus neutrons can also be absorbed by targets of carefully selected material placed in the reactor. In this way the surplus neutrons are used to create radioactive isotopes of the materials placed in the targets. With practice, scientists using both cyclotrons and reactors have learned the proper mix of target atoms and shooting particles to "cook up" a wide variety of useful radioisotopes.

Official preparation
Calcium -47 is supplied as calcium chloride in the form of an injection. it’s half life is shorter i.e.4.54 days. Calcium -47 has been used as a urinary & faecal marker. Chromium -51 is supplied as sodium chromate solution or injection. It is used to label RBC so that red cell survival and red cell volume can be measured. chromium-51 activity in the faeces can be used to estimate gastro intestinal blood lossess. Cobalt -57,cobalt-58 and cobalt-59 are usually supplied as cynocobalamin in the form of aqueous solution. Cobalt -57,cobalt-58 are used for the measurement of absorption of vitamin B₁₂ in the diagnosis of pernicious anaemia. Erabium-169 is supplied as erabium citrate (169EV) in the form of an injectable suspension.it is used in the treatment of arthritic condition of small joints. Fluorine-18 is a position emitting radionuclide. Fluorine-18 labelled analogous of glucose, principally 2-fluoro-2-deoxy-D-glucose, have been clinically used in assessment of regional cerebral and myocardial metabolism and for the detection of tumours in the lungs and liver. Fluorine-18-labelled amino acid have also been used for pancreatic scintigraphy. Gallium-67 is supplied as gallium citrate in the form of a carrier free injection. It is used for the diagnosis of various infections, sarcoidosis and other inflammatory lesions. Gold-198 used in the treatment of rheumatoid arthritis, is supplied as sterile colloidal suspension of metallic gold stabilized with gelatin & glucose. Indium-11, supplied as a complex of indium with bleomycin in the form of a carrier free,injection is used for the detection of tumours in cerebrospinal fluid studies, cistergraphy, ventriculography. Iodine-125 is not very suitable for external counting of radioactivity in the thyroid gland because it’s gamma energy is weak and tissue absorption is high. Many labelled compound of I-125 are available for in-vitro assay to detect and estimate drugs and hormone in the body fluid. I-131 mainly used in the study of thyroid function for test on the function of the heart, kidney, liver and on fat absorption or protein loss in the gastro intestinal tract. Iron-59 is supplied as ferric choloride(⁹⁹Fe) in the form of a solution or as ferric citrate in the form of an injection. It is used in the measurement of iron absorption and utilization. Krypton-81m is a daughter of rubidium-81 and is prepared immediately before use. It is used as a gas in lung ventilation studies or as an intravenous infusion in perfusion studies of the lung,heart and brain. Phosphorous-32 is supplied as sodium phosphate in the form of an injection and used in the treatment of polycythaemia vera and in the diagnosis of malignant neoplasms. K-42 is supplied as KCLin the form of an injection . it is used to measure exchangeable potassium and for myocardial scanning. Selenium-75 is supplied as L-selenomethionine (⁷⁵Se ) in the form of an injection. Malignant lymphomas is located with it’s help. Sodium-22, supplied as NaCl in the form of an injection,is used in the determination of bodies exchangeable sodium. Strontium-85 ,mainly used for bone scanning, is available as strontium chloride in the form of an injection. Sulpher-35  is marketed as sodium sulphate in the form of a carrier free injection and is used for the estimation of the extracellular fluid volume. Technetium-99m is a daughter of molybdenum-99. Due to it’s short half life(66.2 h), it is normally prepared just before use. Because it has a short half life , its administration in relatively large doses and detection of its gamma emission readily, technetium-99m is very widely used for scanning bone organ such as brain, gallbladder, kidney, liver, lung, spleen and thyroid. It also may be used to measure cerebral blood flow and for scintography of the salivary glands, stomach,heart, joints. Allergic reaction have been reported with technetium-99m preparation. Thallium-201 is supplied as thallus chloride(²⁰¹TI) in the form of aninjection abd employed for scanning the myocardium in the investigation of coronary artery disease ,acute myocardial infarction and for post surgical assessment of coronary artery. Xenon-133 is available as an injection and used for measurement of lung perfusion and regional blood flow. Yttrium-90 marketed as a colloidal aq. Suspension with silicate ,is used in the treatment of arthritic condition of joints.[5]

Various radiopharmaceuticals that are used in therapeutic or diagnosis are listed below in table-2 with their respective target organs.[7]

Table-2

HAS-human serum albumin, MIBG- m-iodo benzylquanidine, MAA-macroaggregated albumin

DTPA-diethylenetriamine pentaacetic acid or pentate, HIPD-NNN,-Trimethyl-N&