New Trends in Preparation, Bio Distribution, and Pharmacokinetics of Radiopharmaceuticals in Diagnosis and Research

Abstract

Radiopharmaceuticals are radioactive compounds which have a bound radionuclide in their structure. It is used to direct the radionuclide to a location to be treated or to obtain images. Nuclear medicine is the science that in the charge of employing radiopharmaceuticals, which is very useful support for medicine assisting in several diagnoses and treatments for cancer. The main aim of this work is to shed lights on the main radionuclides and metal complexes which are used as radiopharmaceuticals. Radiopharmaceuticals are compounds of technetium (99mTc) is considered as the main metal complexes like sodium pertechnetate and methylenediphosphonate MDP99mTc and other compounds which used in nuclear medicine for diagnosis such as: (1) indium (111In); (2) thallium (201Tl); (3) gallium (67Ga, 68Ga); (4) iodine (123I and 131I); (5) chromium (51Cr); (6) sulfur (35S); (7) phosphorus (32P); (8) a18F. They are very important in the early diagnosis for several diseases such as cancer, kidney, cardiovascular, liver. Generally, technetium compounds are main radiopharmaceuticals, widely all over the word.

1. Introduction

It is very effective to provide an introduction to this chapter of the field of nuclear medicine and how radioisotopes are used in nuclear medicine for both diagnostic and therapeutic applications. Radiopharmaceuticals are compounds that administered intravenously whether diagnostic or therapeutic applications [1]. Diagnostic applications in nuclear medicine use low activity tracer levels of generally gamma- or positron-emitting radioisotopes which are generally produced in nuclear reactors and accelerators. In other hands, therapeutic applications use particle-emitting radionuclides for induction of radio toxicity to kill cells in the intended tissue. It is also noted that in the form of radioactive sources, therapeutic radioisotopes are also used in other clinical specialties will be discussed in this chapter. As well as this chapter focuses on the description of radioactive materials which are used for nuclear medicine therapy and how they are produced.

Improving the utilization of radiopharmaceuticals in the development of pharmaceutical drug delivery systems, the behavior of the tracers administered by various ways must be investigated. The main aim of radio pharmacology is to study the chemical properties of radiotracers and their interactions with living organisms. Radiopharmaceuticals are unique medicinal formulations containing radioisotopes which are used in major clinical areas for diagnosis and/or therapy. Radiopharmaceuticals is currently considered the cornerstone of nuclear medicine. That is why there is a requirement for new radiopharmaceuticals that could be utilized to explore more subtle mechanisms of body functions.

This part of chapter which presented in the symposium reflect current and future developments in diagnostic and therapeutic agents as it deals with (Tc-99 m), highlighting its continuing importance to nuclear medicine and the role of imaging as an important tool. The emerging interest in therapeutic radiopharmaceuticals based on beta emitting short lived isotopes such as Iodine (I-131).

It worth mentioning that The properties of bio distribution and pharmacokinetics play a major role in affecting and defining the efficacy and safety for the treatment with a medicine. Currently, several image guided modalities have been applied in nuclear medicine such as Single-Photon Emission Computed Tomography (SPECT), (SPECT/CT), Tomography Computed Tomography (PET/CT), and Positron Emission.

The use of radionuclides for medical applications has continued to grow at a very rapid pace. That is why, it is required to learn more about The use of radiotracers for nuclear medicine imaging as well as discussing in this part of chapter the different methods of preparation, bio distribution and pharmacokinetics of radio pharmaceuticals for diagnosis and research.

2. What is radiopharmaceutical?

Radiopharmaceuticals can be defined as a chemicals substances that contain radioactive atoms within its structure and suitable for administration to human used for either diagnose or treat diseases [2].

Radiopharmaceuticals can be categorized into:

1. Diagnostic radiopharmaceuticals are administered to a patient and enable physicians and researchers to see the biochemical activity of cells, to diagnose or stage disease

2. Therapeutic radiopharmaceuticals are administered to a patient to seek out and deliver cell-killing radiation to the site of disease.

3. Nuclear medicine and radiopharmaceuticals

Radiopharmaceuticals can be categorized into two groups:

1. First group includes radionuclides with radioactive decay period (half-life) less than 2 h

2. The group includes radionuclides with half life higher than 2.

Cameras in nuclear medicine are suitable for identifying radioactive particles. The type of camera can be defined by The type of radiation emitted:

1. SPECT cameras are used to detect nuclides that decay through direct emission of single gamma rays

2. PET cameras are able to detect the pair of gamma rays emitted after a decay of positron.

4. Nuclear stability

when the number of neutrons (N) and protons (P) are approximately equal it’s called stable nuclei. The ratio of N/P is equal one when the elements become heavier, the ratio of neutrons (N) to protons (P) for nuclear stability increases from 1to 1.5. meanwhile the nucleuses has too high (Neutron rich) stability decreases at the line of stability See Figure 1.If the N/P ratio is too low for stability, the radioactive decay take places in a manner that will be reduce the number of protons and increase the number of neutrons by the net conversion of proton to neutron.

Figure 1.

Nuclear stability diagram.

5. Fundamentals of radioisotopes for radiopharmaceuticals

1. Radiopharmaceuticals are medicinal formulations involving radioisotopes which are safe for administration in humans with the purpose of diagnosis or for therapy.

2. Nuclear reactors have the ability to produce larger quantities of radioisotopes. Radioiodine (iodine-131), which was used as treatment of thyroid cancer, and still has the same importance but becomes the most efficacious method for the treatment of hyperthyroidism and thyroid cancer.

3. Preparing of radioisotopes is considered one of the most important and has the most priority among the several applications The medium flux and high flux research reactors are considered the most important source that used to produce radioisotopes for medical, and also industrial, applications and for producing isotopes in medical applications like molybdenum-99 (for production of technetium-99 m), iodine-131, phosphorus-32, chromium-51, strontium-89, samarium-153, rhenium-186 and lutetium-177.

4. Producing long lived radioisotopes use cyclotron in radiopharmaceuticals to prepare tracers for diagnostic imaging. Cyclotrons with high beam currents required For medium to high energy (20–70 MeV).

Most cyclotrons (~350) all over the world are used for the preparation of fluorine-18 for making radiolabelled glucose for medical imaging in the nuclear medicine.

6. Nuclear medicine techniques

Radioactive tracers is used by Diagnostic techniques in nuclear medicine that emit gamma radiation. The camera produces an image from the points at the radiation emission. The nuclear medicine techniques include

1. Single Photon Emission Computerized Tomography (SPECT)

2. Positron Emission Tomography (PET),

3. computed tomography-PET (PET-CT) (for better anatomical visualization)

4. micro-PET (with ultra-high resolution)

5. micro computerized axial tomography micro-CAT.

All above techniques are utilized to analyze biochemical dysfunctions with the purpose of showing early signs of the disease, their mechanisms and association with disease states.

7. Radiopharmaceuticals for diagnosis in human body

A large number of chemicals that are absorbed by specific organs have been identified by specialists. For examples Thyroid absorbs iodine while the brain absorbs glucose. To monitor blood flow to the brain, liver, lung, heart, and kidney diagnostic radiopharmaceuticals can be used for that purposes see Figure 2. Destroying or weakening cancer cells can be done by particulate radiation as well as beta radiation causes ([3], p. 7).

Figure 2.

Lists the radionuclides most commonly used for diagnosis and treatment of different organs of the human body.

This can be concluded that each organs of the human body requires different Radiopharmaceuticals to be administrated to it for the purpose of diagnose or treatment. This depends on the absorption of this organ to this chemical.

We can summarize the difference between normal medicines and radiopharmaceuticals is that the normal medicine has therapeutic effect while the latter does not. Besides that, radiopharmaceuticals have a short half-life, because of their rapid decay. For this reason, radiopharmaceuticals must be prepared immediately before their administration. The preparation and use of radiopharmaceuticals with safety and expertise are therefore vital for operator and patient protection.

8. The Main characteristics for radiopharmaceuticals clinically useful for imaging

Firstly, we should discuss the characteristics for radiopharmaceuticals to help us understand how to deal with it during the chapter and these characteristics can be summarized in the below points:

1. The decay of the radionuclide should be in specific ranges of energy emissions (511 keV for positron emission tomography – PET and 100–200 keV for gamma cameras) and in sufficient quantity for tomography detection.

2. It should have particulate radiation beta emissions because it the radiation dose is increased in the patients.

3. The half-life should be for a minimal hours.

4. The radionuclides should not be mixed with other radionuclides of the same element or its stable radionuclides.

5. radiopharmaceuticals are supposed to have certain activity as well as the highest specific activity comes from carrier-f456ree radionuclides.

6. The radiopharmaceuticals are supposed not to have toxicity and do not manifest physiological impact.

7. The radiopharmaceutical should be available for instant usage and easy to compound and reach the target organ quickly and accurately.

9. Production of radionuclides

Generally

Most radionuclides are produced using two types of instruments:

9.1 In nuclear reactors

Through the fission, neutrons are generated of nuclear fuel or neutron-capture reactions on stable targets. These neutrons are then utilized to create neutron-rich radionuclides that typically decay through beta emission and are therefore appropriate for the aimed radiotherapy.

Meanwhile, Accelerators, in contrast, accelerate protons or other charged particles to induce nuclear reactions on target materials. During these reactions proton-rich radionuclides can be created that decay by positron emission and are therefore useful for imaging applications.

In the following lines, we are going to discuss the production of Radionuclides with more details.

The production of radiopharmaceuticals involves the handling of large quantities of radioactive substances and chemical processing. The radionuclides used to make radiopharmaceuticals are produced artificially, mainly in a cyclotron or in a nuclear reactor. The type of radionuclides produced in a cyclotron or in a reactor depends on the type of energy of the bombarding particles and the target material ([4], p. 5).

9.1.1 A-production of radionuclides in the cyclotron

The Cyclotrons are considered the most common type of accelerator which normally produce medical radionuclides through bombardment with charged particles. Its main usage is to accelerate charged particles in a circular fashion, cyclotrons used to take up less space than their linear counterparts.

The Cyclotrons typically accelerate charged particles to energies between 11 and 30 MeV, Despite the availability of the larger machines. Consequently, Cyclotrons can accelerate positive (e.g., protons, alpha particles) or negative (e.g., hydride ions) ions, but the majority of commercial machines manufactured today are negative ion.

The most important steps fundamentals of cyclotrons:

1. The radionuclides produced by the cyclotron are distinguished by a presence of fewer neutrons, and their nuclear stability is obtained through electron capture or positron emission.

2. A cyclotron is a charged particle (cation or an ion) accelerator that transfers high energy to these particles, accelerating them in circular orbits by means of alternating electromagnetic fields until they collide with a target, with the consequent nuclear reaction and the production of positron-emitting radionuclides. The cyclotron was developed by with the purpose of accelerating particles such as protons or deuterons to achieve high levels of kinetic energy.

3. All cyclotrons are comprised of two electrodes in the form of semi-circular chambers (D) in which a vacuum is produced, and they are configured with the adjacent perimeter diameters in a uniform magnetic field. The Ds are coupled to a high-frequency electrical system that alternates about 107 times a second while the cyclotron is operating See Figure 3.

4. In each D, the ions are forced into a circular trajectory by means of an alternating magnetic field. When the ions complete a semi-circumference in the semi-period, the electrical field inverts polarity, causing acceleration of the ions in the electrical fields between the Ds, while also increasing the radius of their circular trajectory. This increase in acceleration involves an increase in kinetic energy See Figure 4.

5. continuously, this process is repeated, in semi-circular orbits that move in resonance with the oscillating field. In this way they gain energy continuously, describing a spiral trajectory until the periphery of the Ds is reached with the energy needed to escape from them and collide with the target, where the nuclear reactions will take place.

6. During nuclear reactions, The impacting particle can exit the nucleus after the interaction, and part of its energy is left in the nucleus, or it may be completely absorbed by the latter. In either case, a nucleus in an excited state is generated, and the excitation energy is released through the emission of nucleons (i.e., protons and neutrons). The emission of gamma radiation then occurs. Depending on the energy transmitted by the impacting particle, a random number of nucleons are emitted from the irradiated target, resulting in the formation of different nuclides. When the energy of the irradiating particle increases, more nucleons are generated and a greater variety of radionuclides are therefore produced. The radionuclides produced in a cyclotron are generally neutron-deficient and therefore decay with the emission of β + particles or through electron capture.

7. Radionuclides produced by the cyclotron and which are of interest in nuclear medicine comprise ([4], p.8):

Figure 3.

Production processes in the cyclotron.

Figure 4.

The process of producing of radionuclides in cyclotron.

Fluor-18: 18F - Carbon-11: 11C - Nitrogen-13: 13 N- Oxygen-15: 15O - Gallium-68: 68Ga - Scandium-44: 44Sc - Zirconium-89: 89Zr - Iodine-124: 124I See Figure 5.

Figure 5.

Selected radionuclides produced by cyclotrons.

9.1.2 Production of radionuclides in the nuclear reactor

The process of producing radionuclides in nuclear medicine generated in nuclear reactors has two kinds of nuclear reactions including an interaction with neutrons:

• Neutron capture

• The fission of heavy elements.

  1. During the neutron capture, the target nucleus captures a thermal neutron, emitting gamma radiation to produce an isotope of the same element as the target nuclides. Some instances of radionuclides formed by this type of reaction are 131Te, 99Mo, 197Hg, 59Fe, 51Cr, etc.

  2. Fission of heavy elements is categorized by the splitting of a heavy nucleus into two fragments of roughly the same mass, supplemented by the emission of two or three neutrons.

Each fission reaction releases a considerable amount of energy that is take out through heat exchangers to provide electricity in nuclear energy plants. When a fissionable heavy element target is interleaved into the core of the reactor, the heavy nuclides absorb thermal neutrons and experience the so-called fission reaction. Some fissionable heavy elements with an atomic number over 90 are: 235U, 239Pu, 237Np, 233U 232To. On the other hand, many clinically suitable radionuclides for instance 131I, 99Mo 133Xe and 137Cs are attained from the fission of 235 U See Figures 6 and 7.

Figure 6.

Selected radionuclides produced by nuclear fission.

Figure 7.

Radionuclide reactors.

The diagram illustrates the typical components found in radionuclide generator. It helps in the separation and elution of the daughter radionuclide and the parent radionuclide. This elution results in a product that is sterile and free of impurities thus making it immediately suitable for human injection See Figure 8.

Figure 8.

Radionuclide generator.

9.1.3 What are the main purpose of the radionuclide reactors?

They are considered a source of radionuclides which used for the production of radiopharmaceuticals. The ⁹⁹Mo → ^99mTc reactor often referred to as a technetium reactor is the most important radionuclide reactor for radiopharmaceutical preparation that is why it gets its importance. The reactor is capable of supplying short-lived radionuclides (short half-lives) over a time period much longer than this short half-life. It is also a unique equilibrium that is establishment between a long-lived “parent” radionuclide and its short-lived radioactive daughter. The second a ability to physically is the separation of the parent and daughter radionuclides to allow the daughter to be utilized for the preparation of short-lived radiopharmaceuticals. In the 99Mo → 99mTc reactor the parent is 99Mo with a half-life of 66 hours, which decays for producing the radioactive daughter 99mTc with a half-life of 6 hours. The separation of the parent and daughter is completed by simply washing the daughter from the reactor with sterile saline See Figure 9 [5].

Figure 9.

Products of Radiocludes.

9.1.4 The Most common isotopes used in medicine

Several radioisotopes are produced by nuclear reactors and cyclotrons. As neutron-rich ones need to be made in reactors while neutron-depleted ones are made in cyclotrons, some examples of them as follows:

9.1.4.1 Cyclotron radioisotopes

• Carbon-11, Nitrogen-13, Oxygen-15, Fluorine-18: These positron emitters used in PET for studying brain physiology and pathology. They also have a significant role in cardiology. F-18 in FDG (fluorodeoxyglucose) is very important

• Iodine-123 (13 h): Increasingly used for diagnosis of thyroid function, it is a gamma emitter without the beta radiation of I-131.

• Thallium-201 (73 h): Used for diagnosis of coronary artery disease other heart conditions as well as it is used as substitute for technetium-99 in cardiac-stress tests.

9.1.4.2 Reactor radioisotopes

• Iodine-131 (8 d): Widely used in treating thyroid cancer and in imaging the thyroid also in urinary tract obstruction it is also strong gamma emitter, but used for beta therapy.

• Iridium-192 (74 d): it is used as an internal radiotherapy source for treating cancer.

• Lutetium-177 (6.7 d): Lu-177, it emits just enough gamma for imaging while the beta radiation does the therapy on small (e.g., endocrine) tumors. Because its half-life is long enough to allow sophisticated preparation for use.

• Molybdenum-99 (66 h)*: generally, used as the ‘parent’ in a reactor to produce technetium-99 m.

• Palladium-103 (17 d): Mainly used to make brachytherapy permanent implant seeds for early stage prostate cancer. Emits soft x-rays.

• Technetium-99 m (6 h): Used in to image the skeleton and heart muscle in particular, but also for brain, thyroid, lungs (perfusion and ventilation), liver, spleen, kidney (structure and filtration rate), over 80% of scans of the nearly 25 million diagnostic nuclear medicine studies carried out annually are done with this single isotope. This percentage share is estimated to remain for the foreseeable future.

10. Radiopharmaceutical safety

It is required to have all the protective procedures towards the radiations in general and Pharmaceutical productions specifically Health and safety are an integral for protecting the patients, doctors, personnel and workers. The pharmacists are constantly being exposed to chemical and biological hazards which pose a serious threat to their health. Furthermore, during the production, lack of enough safety standards and non-compliance may cause negative impact in the long run. Therefore, it is important to have optimal health and safety practices while ensuring that all employees adhere to such regulations. Here are the tips to maintain improved health and safety standards in the pharmaceutical industry.

11. Health and Safety Standards in handling chemicals

In case transporting or handling pharmaceuticals inappropriately, they can be dangerous. The trained staff are able to prevent chemical releases which can cause explosions and fire. That is why to reduce and minimize the risk and ensure more safety, Classification of Chemicals should be done by an effective way of handling hazardous chemicals. This can be done by trained and professional staff.

In addition, the Classification of Chemicals is an effective method to identify the way of how the chemicals can have harmful effects. It also helps in labeling correctly and handled in a legally manner to avoid health risks. Exploding or releasing chemicals normally can be caused by high temperature, high pressure or oxidation. This problem can be processed by lowering the oxidation work scale and understanding the right flammable limits. Certainly pharmaceutical companies have the main role to reduce these risks [6].

12. Practice primary laboratory safety

In the pharmaceutical industry, basic safety has to be maintained in the laboratory as well as employees must be conscious to the basic health and safety practices and take preventive processes during work in a hazard environment. These procedures can be carried out to maintain health and safety at the laboratory such as [6]:

• Practice frequent cleaning

• particularly Never eat, drink or smoke inside the laboratory

• Making wearing suitable Personal Protective Equipment mandatory inside the laboratory

• Coveralls, eye gear, protective helmet, shoe covers, etc.

13. Conclusion

We can conclude that the Radionuclides which are used in nuclear medicine are considered mostly to be artificial ones. We learned that these are primarily produced in a cyclotron or a reactor. The type of radionuclide produced in a cyclotron or a reactor depends mainly on the irradiating particle, its energy, and the target nuclei. Generally, it is noted the facilities which having such equipment are limited and supply radionuclides to remote facilities that do not possess them. Nuclear medicine is the medical specialty that employs radiopharmaceuticals, has presented itself as a very useful assistant for medicine supporting in several diagnoses and treatments. The main aim of this work is to define the vital radionuclides and metal. At the end, this chapter aims to be useful for all whom working in nuclear medicine and to be a guide for them. It is a guide to be used to shed some lights on radiopharmaceuticals and their uses, production and safety during handling [7].