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  • The atom is made up of protons and neutrons in the nucleus, with electrons located in discrete energy states around the nucleus. The number of electrons varies from one to over 100 and determines the chemical nature of the atom. The atom has a radius of approximately 10-8cm., with the nucleus having a radius of 10-12cm.

  • The stability of the atom depends on the neutron to proton ratio (n/z)ratio in the nucleus.

  • Protons are positively charged with a mass 1800times that of electron.

  • Neutrons have the same mass like protons but carry no charge.


  • The number of protons of an atom is referred to the atomic number (z).

  • The number of protons plus the number of neutrons combined the mass number (A).

  • Isotopes are atoms of various mass number, but have the same atomic number.

  • Radiation refers to particles or waves coming from the nucleus of the atom through which the atom attempts to attain a more stable configuration.

  • Radioactivity is the several processes by which atomic nuclei spontaneously decay or disintegrate by one or more discrete energy levels or transitions until a stable state is reached.


Types of radioactivity
Types of radioactivity number (z).

A-Natural radioactivity

When the process of decay takes place in a material without the addition of energy

B-Artificial radioactivity (man-made radioactivity)

In which the radioactivity produced by particle bombardment or electromagnetic radiation:

1-Charged particle reactions : Reactions of these types may be produced with

  • Protons (11H or P) as 1123Na

  • Deutrons (12H or d)

  • Alpha particles (24He or α)

  • Electrons or beta particles (0-1e or 0-1b)


2-Photon induced reactions number (z).

Electromagnetic radiations or photons may induce nuclear reactions. The source of electromagnetic energy utilized may be a gamma emitting radionuclide or a high voltage X ray generators

3-Neutron induced reactions

One of the most important and also most widely used method for producing artificially radioactive nuclides is the bombardment of a non radioactive target nucleus with a source of thermal neutrons.


Radioactive decay
Radioactive decay number (z).

  • Radioactive species exist in a high exited unstable state, characterized by an excess energy.

  • These nuclides achieve stability through the process of radioactive decay and the release of large amounts of energy.

  • In the process of decay there are three parameters which are characteristic for a given radioisotope:

    -The rate of decay

    -The type of radiation exhibited in the decay scheme

    -The energy of theses radiations


  • The equation describe the radioactive decay is a typical first order

  • N=N0e-λt

    When λ is the decay constant and the half life is T1/2=0.693/ λ (half life decay)

    When the activity (A) remaining in a sample after a given time and the intensity of radiation after time, t can be determined.

    A=A0e-0.693/T1/2 or I=Ioe-0.693/T1/2


Mode of radioactive decay first order

1-Orbital electron capture;

  • Occurs mainly in the K-shell, in which a nuclear proton is transformed into a neutron by capturing within the nucleus an electron from the K shell and emitting a neutron. This results in the formation of a decay product in which the z number has been reduced by one and there is a vacancy in the K-shell.

  • After rearrangement of electrons and the emission of specific rays resulting from this rearrangement, the products of such a reaction are the same as if a positron had been emitted.

  • 2451Cr +-10e 2351V +hν


Measurment of radiation
: first orderMeasurment of radiation:

  • Radiation exposure is measured by roentgens. A roentgen (r) is a specific quantity of x or gamma radiation such that the number of ion pairs produced in one cubic centimeter (cc) of air will produced one electrostatic unit of electrical charge (2.58x10-4 coulomb/kg).

  • The rad is a unit of absorbed radiation dose. The rad represents the amount of energy that has been absorbed per gram of tissue.


  • Different types of radiation may have different relative toxicities. By multiplying the rad dose by a qualifying factor (QF), such as a distribution factor or a specific toxicity factor, the rem dose is obtained (dose equivalent).

  • Curie(Ci) refers only to the rate of disintegration of radioactive materials.

  • Curie is 3.7x1010 disintegration per second (dps).

  • Millicurie (mCi)=3.7x107 dps

  • Microcurie (mCi)=3.7x104 dps


  • Specific activity toxicities. By multiplying the rad dose by a qualifying factor (QF), such as a distribution factor or a specific toxicity factor, the rem dose is obtained (dose equivalent).is the ratio of any quantity of radioactive material per some unit quantity of total material and has a theoretical unit of 0 to1. It can be measured as μCi/mg, dpm/g.

  • Specific concentration i.e radioactivity per unit volume, can be utilized in some radiation measurements, e.g. blood volume determination. In blood volume determinations, the administered iv dose in CPM/ml is related to the radioactivity after dilution by the patients.

  • Carrier free material is a material in which all of the atoms present are radioactive and so it has specific activity of one.


Radiation effects on biological systems
Radiation effects on biological systems toxicities. By multiplying the rad dose by a qualifying factor (QF), such as a distribution factor or a specific toxicity factor, the rem dose is obtained (dose equivalent).

  • The irradiation of biological molecules either in dry state or in aqueous solution leads to a number of chemical and physicochemical changes. These changes results in alteration in enzymatic, hormonal, toxic and immunological function.

  • The energy absorbed from ionizing radiation can inactivate biological materials in two ways.

    1- Direct action which describes the chemical events occuring in the target molecules as a result of radiation energy deposition.


  • These processes include ejection of electrons from atoms in the DNA structure as a result of passage of ionizing photon

  • This form of damage in the DNA structure was attributed to the radiation induced biological changes in the target molecule in the dry state.

    2- Indirect action occurs in aqueous solution in which damages occurs within the biological molecules due to the highly reactive diffusible free radicals produced from the radiolytic products of water.


  • The radiolysis of water as follows: the DNA structure as a result of passage of ionizing photon

    A- The initial physical change lasting only a fraction (10-16) of second in which the energy is deposited in the cell and causing ionization of water

    H2O ionizing radiation H2O++e-

    B- The physicochemical stage lasting about 10-16 seconds in which the ions interacts with other water molecules resulting in a number of new products

    H2O+ dissociation H++OH.

    H2O+e- H2O-

    H2O- H. +OH--


  • The existence of oxygen in most biological systems may account for radiosenstivity of cells by forming peroxides

  • H+ and OH- take a part in the subsequent reactions, the free readicals H. and OH. have an unpaired electron; the hydroxyl radical is a powerful oxidant anh the hydrogen atom is a powerful reductant. Both undergo rapid chemical reaction with organic molecules.

    C- The chemical stage lasting few seconds, the free radical and oxidizing agent attach the complex molecules and attach themselves to a molecule or cause links in long chain molecules to be broken.


  • The liver appears to be a relatively radioresistant organ due to its large regenerative capacity of its cells and its low oxygen tension of its tissues.

  • An increase in permeability of capillaries occurred after moderate doses of radiation, this is due to depolymerization of mucopolysaccharides which permits blood to leave the vascular system so haemorrhage was commonly observed following irradiation.

  • Also irradiation disturbed the enzymatic activity of cabohydrate metabolism.


Radiopharmaceuticals are preparations of adequately constant composition, radiochemical, radionucledic purity and uniformity of physiological action for use in nuclear medicine as diagnostic aid or therapeutic agents.

A radiopharmaceutical has two components: a radionuclide and a pharmaceutical. A pharmaceutical is chosen on the basis of its preferential localization in a given organ or its participation in the physiologic function of the organ. 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



  • The practice of radiopharmacy composition, radiochemical, radionucledic purity and uniformity of physiological action for use in nuclear medicine as diagnostic aid or therapeutic agents.

  • A-Formulation and dispensing:

    The following factors need to be considered before, during and after the preparation of a new radiopharmaceutical:

    1-Compatibility:

    When a labeled compound is to be prepared, the first criterion to be considered is whether the label can be incorporated into the molecule to be labeled. This may be assessed from the knowledge of the chemical properties of the two partners.


  • For example, composition, radiochemical, radionucledic purity and uniformity of physiological action for use in nuclear medicine as diagnostic aid or therapeutic agents.99mTc ion can form coordinate covalent bonds with ligands containing O, N or S atoms with lone pair of electrons that can be donated to form coordinate covalent bonds. When 99mTc ion and ligand like DTPA are mixed under appropriate physicochemical conditions, 99mTc-DTPA is formed and remains stable for a long time. If, however, 99mTc ion is added to benzene or similar compounds, it would not label them. Iodine primarily binds to the tyrosyl or hestidyl group of the protein. Mercury radionuclides bind to the sulfhydryl group of the protein.


2-Charge of the molecule: composition, radiochemical, radionucledic purity and uniformity of physiological action for use in nuclear medicine as diagnostic aid or therapeutic agents.

The charge on a radiopharmaceutical determines its solubility in various solvents. The greater the charge, the higher the solubility in aqueous solution. Non polar molecules tend to be more soluble in organic solvents and lipids.

3-Size of molecule:

The molecular size of a radiopharmaceutical is an important determinant in its absorption in the biologic system. Larger molecules (M.W  60000) are not filtered by the glomeruli in the kidney. This information should give some clue about the range of molecular weight of the desired radiopharmaceutical that should be chosen for a given study.


4-Stoichiometry: composition, radiochemical, radionucledic purity and uniformity of physiological action for use in nuclear medicine as diagnostic aid or therapeutic agents.

In preparing a new radiopharmaceutical, one needs to know the amount of each component to be added. This is particularly important in tracer level chemistry and in 99mTc chemistry. The concentration of 99mTc in the 99mTc-eluate is approximately 10-9 M. Although for reduction of this trace amount of 99mTc requires only an equivalent amount of Sn2+ is needed, 1000 to one million times more of the latter is added to the preparation in order to ensure complete reduction. Similarly, enough chelating agent is also added in order to consume all the reduced 99mTc.


5-Protein binding: composition, radiochemical, radionucledic purity and uniformity of physiological action for use in nuclear medicine as diagnostic aid or therapeutic agents.

Almost all drugs, radioactive or not, bind to plasma proteins to variable degrees. The primary candidate for this type of binding is albumin, although many compounds specifically bind to globulin and other proteins as well. Protein binding is greatly influenced by a number of factors, such as the charge on the radiopharmaceutical molecule, the pH, the nature of protein and the concentration of anions in plasma. At a lower pH, plasma proteins become more positively charged, and therefore anionic drugs bind firmly to them.


  • The nature of a protein, particularly its content of hydroxyl, carboxyl and amino groups and their configuration in the protein structure determines the extent and strength of its binding to the radiopharmaceutical. Metal chelates can exchange the metal ions with proteins because of the stronger affinity for the metal. Such process is called “transchelation” and leads to in-vivo breakdown of the chelate. Protein binding affects the tissue distribution and plasma clearance of a radiopharmaceutical and its uptake by the organ of interest. Therefore, one should determine the extent of protein binding of any new radiopharmaceutical before its clinical use.


6-Solubility: hydroxyl, carboxyl and amino groups and their configuration in the protein structure determines the extent and strength of its binding to the radiopharmaceutical. Metal chelates can exchange the metal ions with proteins because of the stronger affinity for the metal. Such process is called “transchelation” and leads to

For injection, the radiopharmaceutical should be in aqueous solution at a pH compatible with blood pH 7.4. The ionic strength and osmolarity of the agent should also be appropriate for blood.

In many cases, lipid solubility of a radiopharmaceutical is a determining factor in its localization in an organ. The cell membrane is primarily composed of phospholipids, and unless the radiopharmaceutical is lipid soluble, it will hardly diffuse through the cell membrane. The higher the lipid solubility of a radiopharmaceutical, the greater the diffusion through the cell membrane and hence the greater its localization in the organ.


  • Protein binding reduce the lipid solubility of a radiopharmaceutical. Ionized drugs are less lipid soluble, whereas non-polar drugs are highly soluble in lipids and hence easily diffuse through cell membrane. Lipid solubility and protein binding of any drugs play a key role in its in-vivo distribution and localization

    7-Stability:

    The stability of a labeled compound is one of the major problems in labeling chemistry. It must be stable both in-vitro and in-vivo. Temperature, pH and light affect the stability of many compounds and the optimal range of these physicochemical conditions must be established for the preparation and storage of labeled compounds.

  • 1.7.2.2 Short effective half-life:

  • A radionuclide decays with a definite physical half-life. The physical half-life is independent of any physicochemical condition and is characteristic for a given radionuclide. Radiopharmaceuticals administered to humans disappear from the biologic 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 biological half-life.


In-vivo radiopharmaceutical. Ionized drugs are less lipid soluble, whereas non-polar drugs are highly soluble in lipids and hence easily diffuse through cell membrane. Lipid solubility and protein binding of any drugs play a key role in its breakdown of a radiopharmaceutical results in an undesirable biodistribution of radioactivity.

8-Biodistribution:

Studying of the biodistribution of a radiopharmaceutical is essential in establishing its efficacy and usefulness. The rate of localization of a radiopharmaceutical in an organ is related to its rate of plasma clearance after administration.


B-Product development: radiopharmaceutical. Ionized drugs are less lipid soluble, whereas non-polar drugs are highly soluble in lipids and hence easily diffuse through cell membrane. Lipid solubility and protein binding of any drugs play a key role in its

  • The extent to which a radiopharmacist is required to function in this area depends on the complexity of the nuclear medicine department that utilizes his services.

  • If a significant amount of clinical research is carried out, product development can become an exceedingly important aspect of the practice of radiopharmacy.

    C-Quality control:

    The radiopharmaceutical quality control include

    I-Pharmaceutical consideration:

    a-Inspection of label amount


  • Product identity radiopharmaceutical. Ionized drugs are less lipid soluble, whereas non-polar drugs are highly soluble in lipids and hence easily diffuse through cell membrane. Lipid solubility and protein binding of any drugs play a key role in its

  • Manufaturer-name&address

  • Product list&lot number

  • Total radioactivity (time, date)

  • Concentration (time, date)

  • Specific activity

  • Diluent

  • Additive

  • Expiration date

  • Storage conditions


B-Appearance radiopharmaceutical. Ionized drugs are less lipid soluble, whereas non-polar drugs are highly soluble in lipids and hence easily diffuse through cell membrane. Lipid solubility and protein binding of any drugs play a key role in its

  • Color

  • Clarity

  • Particle size

    C-pH determination of liquid formulation

    D- Biological testing or certification

  • A pyrogenicity and sterility (parenterales)

  • Acute toxicity and safety

  • Chronic toxicity

  • Efficacy


II-Radiation consideration: radiopharmaceutical. Ionized drugs are less lipid soluble, whereas non-polar drugs are highly soluble in lipids and hence easily diffuse through cell membrane. Lipid solubility and protein binding of any drugs play a key role in its

Assuming product contains mixed beta-gamma or pure gamma emitters

A- Radionuclidic assay

  • Total activity in containers

  • Activity per unit volume

  • Dose calibration

    B- Radiation purity

  • Radio chromatography

  • Electrophoresis

    C- Removable contamination

  • Smear of surface of container


Groups of 99m tc radiopharmaceuticals
Groups of radiopharmaceutical. Ionized drugs are less lipid soluble, whereas non-polar drugs are highly soluble in lipids and hence easily diffuse through cell membrane. Lipid solubility and protein binding of any drugs play a key role in its 99mTc-radiopharmaceuticals:

1-Pertechnetate ion (99mTcO4-):

Technetium-99m eluted directly from 99Mo/99mTc generator as the 99mTcO4- ion, which was first evaluated as possible biological tracer. When 99mTcO4- administrated intravenously in human patient, it haswide spread use for brain tumor localization and for thyroid imaging.

2-99mTc-Labeled colloids and particulates:

99mTc-sulfur colloid is prepared by heating mixture of 99mTcO4- and sodium thiosulphate in acidic medium for 5 to 10 min in boiling water bath. Gelatin is added before the reaction with the acid in order to stabilize sulfur in colloid state. It is used for scintigraphy of the recticuloendothelial system.


3 - radiopharmaceutical. Ionized drugs are less lipid soluble, whereas non-polar drugs are highly soluble in lipids and hence easily diffuse through cell membrane. Lipid solubility and protein binding of any drugs play a key role in its 99mTc-Chelates for skeletal imaging:

These 99mTc-chelates are used for skeleton scintigraphy such as MDP, HEDP, HMDP, pyrophosphates and polyphosphates. Diphosphonates chelating agents are analogue to pyrophosphate whose P–O–P structure is replaced by P–C–P which is more stable against enzymatic decomposition by phosphatase enzyme. The organic phosphonates are more stable than the inorganic phosphates against in-vivo metabolism.


4- radiopharmaceutical. Ionized drugs are less lipid soluble, whereas non-polar drugs are highly soluble in lipids and hence easily diffuse through cell membrane. Lipid solubility and protein binding of any drugs play a key role in its 99mTc-Chelates for renal imaging:

Several 99mTc-chelates, like a variety of organic acids and bases are filtered by the glomerulus. A few of them may be partially secreted by the proximal tubular cells and may undergo partial tubular reabsorption passively depending on their Pka,s, lipid solubility, and pH of the tubular fluid. The tubular cells retain a variety of metal ions by chelation with thiol groups present in these proteins. Numerous 99mTc-complexes are frequently used for kidney function study such as 99mTc iron-ascorbate, diethylene triamine pentaacetic acid


5- radiopharmaceutical. Ionized drugs are less lipid soluble, whereas non-polar drugs are highly soluble in lipids and hence easily diffuse through cell membrane. Lipid solubility and protein binding of any drugs play a key role in its 99mTc-Chelates for myocardial imaging:

The cationic complexes of 99mTc (III) with the neutral ligands of arsine and phosphine like the monovalent alkali metal ions localize in the muscle cells. The cationic technetium-99m complexes, alkyl isonitriles complexes, where the alkyl groups are methyl, ethyl, tertairy butyl or methoxy isobutyl were synthesized.


6- radiopharmaceutical. Ionized drugs are less lipid soluble, whereas non-polar drugs are highly soluble in lipids and hence easily diffuse through cell membrane. Lipid solubility and protein binding of any drugs play a key role in its 99mTc-Complexes for brain imaging:

The principle of brain imaging is governed by a mechanism called blood brain barrier (BBB), which excludes many substances from entering the brain from the blood. The BBB is probably a function mixture of anatomic, physiologic, and metabolic phenomena, and which of these are effective in a particular instance depends on the physicochemical properties of the substance in question. Recently, two groups of ligands have been studied extensively for their ability to form neutral lipid soluble complexes with reduced technetium capable of penetrating the blood brain barrier


  • The first group comprises diaminodioxime derivatives, while the second comprises diaminodithiol derivatives. Several derivatives of propylene amineoxime (PnAO) were synthesized by different methyl substitutions on the amineoxime backbone. The most important one of these derivatives is d,l–hexamethyl propylene amine oxime (d,l-HMPAO). 99mTc-d,l-HMPAO is neutral lipid soluble complex used for measurement of cerebral perfusion of brain by SPECT technique (36). The 99mTc complex of L,L-ethylcysteinate dimer (ECD) demonstrated cerebral uptake and longer retention time in brain.


  • 7- the second comprises diaminodithiol derivatives. Several derivatives of propylene amineoxime (PnAO) were synthesized by different methyl substitutions on the amineoxime backbone. The most important one of these derivatives is d,l–hexamethyl propylene amine oxime (d,l-HMPAO). 99mTc-Chelates for hepatobillary imaging:

    The derivatives of iminodiacetates (IDA) are excellent chelating agents for 99mTc. The first complex involved is 2,6–dimethylacetanilido-imino-diacetate .99mTc-IDA derivatives are prepared by the direct reduction of pertechnetate with Sn(II) in presence of the ligand (IDA) where a 99mTc-IDA complex is formed. A variety of 99mTc-chelate of IDA derivatives were evaluated clinically, the 3-bromo-2,4,6-trimethyl, iodo and tertiary butyl derivatives of IDA were found to be excellent ligands.


8- the second comprises diaminodithiol derivatives. Several derivatives of propylene amineoxime (PnAO) were synthesized by different methyl substitutions on the amineoxime backbone. The most important one of these derivatives is d,l–hexamethyl propylene amine oxime (d,l-HMPAO). 99mTc-Complexes for lung imaging:

Lung perfusion imaging is based on the trapping of large particles in the capillary bed of the lungs. Particles larger than 10 mm are lodged in the capillary in the first pass of circulation through the pulmonary artery following intravenous administration. The most widely used 99mTc-labeled particles for lung study are:

  • 1- Microspheres of denatured human serum albumin.

  • 2- Macroaggregated albumin (MAA).

  • 3- 99mTc-labeled Aerosol.


  • 9- the second comprises diaminodithiol derivatives. Several derivatives of propylene amineoxime (PnAO) were synthesized by different methyl substitutions on the amineoxime backbone. The most important one of these derivatives is d,l–hexamethyl propylene amine oxime (d,l-HMPAO). 99mTc-Complexes of proteins:

    Several proteins (human serum albumin, neoga–lactoalbumin, monoclonal and polyclonal antibodies) have been labeled with 99mTc radionuclide. The labeling was accomplished by direct chelation of macromolecules (which contain large number of binding sites) with reduced 99mTc or by indirect conjugation of 99mTc-complex (precomplexing agent method) to protein via bifunctional chelating agent .


Good radiopharmaceutical requirements: the second comprises diaminodithiol derivatives. Several derivatives of propylene amineoxime (PnAO) were synthesized by different methyl substitutions on the amineoxime backbone. The most important one of these derivatives is d,l–hexamethyl propylene amine oxime (d,l-HMPAO).

Since radiopharmaceuticals are administered to humans, they should possess some important characteristics. The ideal characteristics for diagnostic radiopharmaceuticals are: 

1-Ease of availability:

The radiopharmaceutical should be easily produced, inexpensive andreadily available in any nuclear medicine facility. Complicated methods of production of radionuclide or labeled compounds increase the cost of the radiopharmaceuticals.


2-Short effective half-life: the second comprises diaminodithiol derivatives. Several derivatives of propylene amineoxime (PnAO) were synthesized by different methyl substitutions on the amineoxime backbone. The most important one of these derivatives is d,l–hexamethyl propylene amine oxime (d,l-HMPAO).

  • A radionuclide decays with a definite physical half-life. The physical half-life is independent of any physicochemical condition and is characteristic for a given radionuclide. Radiopharmaceuticals administered to humans disappear from the biologic 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 biological half-life.


3-No particle emission: the second comprises diaminodithiol derivatives. Several derivatives of propylene amineoxime (PnAO) were synthesized by different methyl substitutions on the amineoxime backbone. The most important one of these derivatives is d,l–hexamethyl propylene amine oxime (d,l-HMPAO).

  • Radionuclides decaying by  or - particle emission should not be used in labeling of radiopharmaceuticals. These particles cause more radiation damage to the tissue than -rays do. Although -ray emission is preferable, many - emitting radionuclides, such as 131I-iodinated compounds, are often used for clinical therapeutic studies. However, -emitters should never be used for in-vivo clinical studies because they give a high radiation dose to the patient.


4-Decay by electron capture or isomeric transition: the second comprises diaminodithiol derivatives. Several derivatives of propylene amineoxime (PnAO) were synthesized by different methyl substitutions on the amineoxime backbone. The most important one of these derivatives is d,l–hexamethyl propylene amine oxime (d,l-HMPAO).

  • Because radionuclides emitting particles are less desirable, the radionuclides used should decay by electron capture or isomeric transition without any internal conversion. Whatever the mode of decay, the radionuclide must emit -radiation with energy between 30 and 300 KeV. Below 30 KeV, -rays are absorbed by tissue and are not detected by the NaI (TI) detector. Above 300 KeV, effective collimator of -rays can not be achieved with lead or denser metal.


5-High target to non- target activity ratio: the second comprises diaminodithiol derivatives. Several derivatives of propylene amineoxime (PnAO) were synthesized by different methyl substitutions on the amineoxime backbone. The most important one of these derivatives is d,l–hexamethyl propylene amine oxime (d,l-HMPAO).

  • For any diagnostic study, it is desirable that the radiopharmaceutical must be localized preferentially in the organ under study since the activity from non-target areas can obscure the structural details of the picture of the target organ. Therefore, the target to non-target ratio should be high.


  • Preparation of injectable radiopharmaceuticals: the second comprises diaminodithiol derivatives. Several derivatives of propylene amineoxime (PnAO) were synthesized by different methyl substitutions on the amineoxime backbone. The most important one of these derivatives is d,l–hexamethyl propylene amine oxime (d,l-HMPAO).

    Only the purest grade of chemicals or those of stated purity should be used in the preparation of radiopharmaceuticals and dilutions. Solutions of dilute acids and alkalis used for pH adjustment or in the preparation should be prepared from concentrated acid or from 1:1 by weight sodium hydroxide solution, in sterile pyrogen-free water. Dilute solutions may be sterilized by filtration through a 0.22 m pore size membrane filter, since heat sterilization may cause the formation of silica flakes from the glass or breakdown of the active ingredients.


Preparation of injectable radiopharmaceuticals the second comprises diaminodithiol derivatives. Several derivatives of propylene amineoxime (PnAO) were synthesized by different methyl substitutions on the amineoxime backbone. The most important one of these derivatives is d,l–hexamethyl propylene amine oxime (d,l-HMPAO).

Ligands:

  • In general, complex formation occurs for compounds having functional groups such as hydroxyl, carboxyl, amino, mercapto and phosphonate groups. Bidentate and multidentate ligands are most commonly used. High oxidation states of technetium prefers ligands that are able to compensate the very high positive charge of the central atom. In the oxidation state of +5, technetium is stabilized as oxotechnetium or nitrotechnetium, where the lower oxidation states prefer ligands containing soft donor atoms such as sulphur, phosphorus and arsenic ones.


Buffers: the second comprises diaminodithiol derivatives. Several derivatives of propylene amineoxime (PnAO) were synthesized by different methyl substitutions on the amineoxime backbone. The most important one of these derivatives is d,l–hexamethyl propylene amine oxime (d,l-HMPAO).

  • Buffers are considered as an important components in cold kit formulation to provide an optimal pH for complex formation. Buffers commonly employed are mixtures of acetates and acetic acid, carbonate, citric acid and citrates, glycine and its salts, phosphates and others. They are freshly prepared and preferably sterilized by filtration, checked for sterility and retained under refrigeration. They should be inspected periodically for the presence of “floaters” and foreign particles. It is generally used in the pH range of 7 to 9 and should be non-toxic and chemically compatible with all of the other ingredients.


Antioxidants: the second comprises diaminodithiol derivatives. Several derivatives of propylene amineoxime (PnAO) were synthesized by different methyl substitutions on the amineoxime backbone. The most important one of these derivatives is d,l–hexamethyl propylene amine oxime (d,l-HMPAO).

  • A common problem, which limits the post reconstitution shelf life, is the oxidation of the complexed reduced technetium to free pertechntate. In such case, antioxidants have been used to provide radiopharmaceuticals with greater stabilty. These stabilizers act as radical scavenger for free radicals resulting from ionization of the medium under the effect of radiation. Stabilizers are added to maintain the integrity of a radiopharmaceutical or a labeled compound in its original state. Ascorbic acid, ascorbate, gentisic acid, citrates and acetates are commonly used stabilizers for 99mTc-labeled preparations.


Fillers: the second comprises diaminodithiol derivatives. Several derivatives of propylene amineoxime (PnAO) were synthesized by different methyl substitutions on the amineoxime backbone. The most important one of these derivatives is d,l–hexamethyl propylene amine oxime (d,l-HMPAO).

  • For the majority of cold kits, kit solids are seen as fine "plug" characterization. They are controlled by freeze-drying cycle in kit production and if necessary by presence of innert fillers. Sodium chloride and mannitol are typical examples of fillers used in cold kits. Sodium chloride to be used in these preparations may be rendered pyrogen free by heating in the dry form to 180 oC for 30 min. The stability of chemicals used in the preparation of injectable radiopharmaceuticals will determine the manner of sterilization. Heat sterilization in the final container is optimal when permissible.


  • For heat sensitive materials or where changes may occur in the physical form, sterilization by filtration through a definite pore size membrane filter such as the millipore or others may be used.

  • Bactericidal agents are used to prevent bacterial growth in a solution. Benzyl alcohol in a concentration of 0.9 % is widely used for this purpose. Such a low concentration of this compound is used because it has a vasodilating effect. Benzyl alcohol also reduces radiolysis in the radiopharmaceutical preparation. Sometimes ethanol, 2%, is used as a bactericidal agent. These agents are not usually added to 99mTc- chelates.


  • Surface active agents such as tween-80 is used in preparation of 99mTc labeled albumin microspheres to prevent aggregation. Gelatin is a widely used stabilizer for colloidal preparations, but its property, as a growth medium tends to encourage bacterial growth.

  • Preservatives are added to many radiopharmaceuticals or labeled compounds in order to preserve their integrity and efficacy. Labeled compounds are prone to degradation due to radiolysis and there is a possibility of bacterial growth in many radiopharmaceuticals. In many cases additives prevent these complications. A preservative can act as a stabilizer, an antioxidant, or a bactericidal agent, and some additives can perform all these functions simultaneously.


  • Quality control of radiopharmaceuticals: preparation of

    Since radiopharmaceuticals are intended to use for human administration, it is imperative that they undergo strict quality control measures. The quality control tests are carried out as the following: physicochemical tests and biological tests. The physicochemical tests indicate the level of radionuclidic and radiochemical impurities. However, the biological tests are carried out essentially to establish the biodistribution, sterility, a pyrogenicity, and undue toxicity of the radiopharmaceuticals before human administration.


1-Physicochemical tests: preparation of

  • Various in-vitro physicochemical tests are essential for the deter-mination of the purity and integrity of any pharmaceutical preparation. Some of these tests are unique for radiopharmaceuticals because they contain radionuclides and are not applicable to conventional drugs. 

    Physical characteristics:

  • The physical appearance, color and state of radiopharmaceutical is important both on receipt and subsequently. A true solution should not contain any particulate matter. Colloidal or aggregate preparations must have a proper size range of particles for a given purpose. In aggregate preparations, the particle size should vary between 10 and 100 m.


pH and ionic strength: preparation of

  • All radiopharmaceuticals should have an appropriate pH value for their stability and integrity. The ideal pH of a radiopharmaceutical should be 7.4 (pH of the blood), although it can vary between 2 and 9 because of the high buffer capacity of the blood. Radiopharmaceuticals must also have proper ionic strength, isotonicity and osmolarity in order to be suitable for human administration. Ionic strength and pH are important factors for stability of a radiopharmaceutical.


Determination of the radionuclidic purity: preparation of

  • The radionucledic purity is defined as the fraction of the total radioactivity in the form of the desired radionuclide present in a radiopharmaceutical form. Impuriries arise from extraneous nuclear reactions are due to the isotopic impurities in the target material. The presence of these extraneous radionuclides increases undue radiation exposure to the patient and may also obscure the scintigraphic imaging. These impurities can be removed by appropriate chemical methods. Radionuclidic purity is determined by measuring the half-lives and the characteristics of the emitted radiations by the individual radionuclides using multichannel analyzer.


Determination of the radiochemical purity: preparation of

  • It is the proportion of total activity in the desired chemical form

  • Different chromatographic methods are used to determine the radiochemical purity of 99mTc-radiopharmaceuticals (70). Determination of reduced hydrolyzed 99mTc can be performed either by thin layer on silica gel or by gel filtration chromatography.

  • In gel chromatography, biogels are used such as sephadex, network polydextran gel. The separation of components depends on the molecular size of the species, the largest molecules are eluted faster.


  • Electrophoresis is a separation technique which relies on the different migration velocities of charge solute species dissolved in an electrolyte solution under the influence of an electric field gradient. Solute migration will depend on a number of factors including the sign and mutiplicity of the charge, and the effective hydrodynamic volume. The direction of migration will depend on the sign of the charge: cationic species C+ will migrate towards the cathode (-ve electrode) while anionic species A- migrate towards the anode (+ve electrode). Neutral molecules and insoluble species will not migrate but may be carried a small distance by the flow of electrolyte generated by electroendosmosis.


  • The partition method is used to determine radiochemical purity, as a number of workers have used a modified form of the classical shake flask solvent. In a typical experiment a small sample of the radiopharmaceutical is diluted with aqueous buffer and the same volume of immiscible organic solvent (octanol, chloroform, diethylether are all popular) is added. The tube is capped and the phases are mixed, allowed to separate, then samples counted. The results are expressed as percentage of the lipophilic radioactivity in the organic phase calculated from the expression:

  • C(organic at equilibrium)

  • % lipophilicity = x 100

  • C(aqueous at start)


2-Biological tests: purity, as a number of workers have used a modified form of the classical shake flask solvent. In a typical experiment a small sample of the radiopharmaceutical is diluted with aqueous buffer and the same volume of immiscible organic solvent (octanol, chloroform, diethylether are all popular) is added. The tube is capped and the phases are mixed, allowed to separate, then samples counted. The results are expressed as percentage of the lipophilic radioactivity in the organic phase calculated from the expression:

Biological tests are carried out essentially to examine the sterility, a pyrogenicity and undue toxicity of the radiopharmaceuticals before human administration.

Sterility indicates the complete absence of any viable bacteria or microorganisms in a radiopharmaceutical preparation. The methods of sterilization varies depending on the nature of products, the solvent and various additives. Millipore (0.22m) filtration method is the most common method used in nuclear pharmacy.


  • Radiopharmaceuticals are required to be pyrogen free. Pyrogens are certain protiens and polysaccharides produced by the metabolism or breakdown of microorganisms. They are soluble, not removable by ultra filtration and heat stable. The best recourse to prevent pyrogenic contamination is to use sterile glasswares, solutions and equipments.

  • Before any radiopharmaceutical is approved for human use, its toxic effect and safe dose must be established. The test for acute or chronic toxicity can be carried out in various animals such as mice, rats, rabbits and dogs. The dose of a radiopharmaceuticals required to produce 50 % mortality in 30 days (LD 50 / 30) is determined.


QALITY CONTROL OF RADIOPHARMACEUTICALS Pyrogens are certain protiens and polysaccharides produced by the metabolism or breakdown of microorganisms. They are soluble, not removable by ultra filtration and heat stable. The best recourse to prevent pyrogenic contamination is to use sterile glasswares, solutions and equipments.


Chemical Purity Pyrogens are certain protiens and polysaccharides produced by the metabolism or breakdown of microorganisms. They are soluble, not removable by ultra filtration and heat stable. The best recourse to prevent pyrogenic contamination is to use sterile glasswares, solutions and equipments.

To check the chemical purity of radio compounds by analytical methods e.g. elemental analysis, molecular and atomic spectroscopy, quantitative potentiometric assay and HPLC were currently used in testing raw materials.


Radionuclidic Purity Pyrogens are certain protiens and polysaccharides produced by the metabolism or breakdown of microorganisms. They are soluble, not removable by ultra filtration and heat stable. The best recourse to prevent pyrogenic contamination is to use sterile glasswares, solutions and equipments.

Radionuclidic purity was defined as the fraction of the total activity in the form of the desired radionuclide. Radionuclidic impurities generally arise from extraneous nuclear reactions. The small levels of impurities in the target materials due to unavoidable nuclear reactions and chain decays and the unfavourable conditions of separation, may associate with fission and parent-daughter products and account for radionuclidic impurities. Radioiodine may exists as molecular iodine, iodide, iodate, periodate and as iodo-organic compound (hippurane). Radionuclidic purity had been checked by checked by g-spectrometer and multichannel analyzer.


Radiochemical Purity Pyrogens are certain protiens and polysaccharides produced by the metabolism or breakdown of microorganisms. They are soluble, not removable by ultra filtration and heat stable. The best recourse to prevent pyrogenic contamination is to use sterile glasswares, solutions and equipments.

The radiochemical purity was defined as the proportion of the activity that is present in the specified chemical form. In the labelling of iodo-organic compounds with radioiodine, not all of the radioiodine exchanged with the inactive iodine in the organic molecule. The radiochemical purity was determined as mentioned before by TLC, EP, HPLC and Gel permeation.

These techniques are tailed to each product and designed to separate the precursors, impurities, decomposition products and to identify the desired product.


Sterility, Apyrogenecity, Toxicity and Biological Distribution

Radiopharmaceutical compounds are used for human diagnosis by intravenous injection. The radioiodinated or technetium labelled compounds are tested for sterility with thioglycolate medium and for pyrogens in rabbits according to the pharmacopeia procedures. The toxicity test and biological distribution are performed in mice.


Stability Distribution of RadiolabelledCompounds :

The stability of radio compounds includes chemical stability, radiation stability, aging stability (storage time and temperature) and biological stability.

The chemical stability of the radio compounds are controlled by a number of factors :

i-The radioactive tag and its position in the molecule;

ii-The labelledmolecule itself;

iii-The average of b- or g-emission;

iv-The total amount of radioactivity in the preparation;

v-The radioactive concentration of the solution;

vi-The concentration of oxygen in the solution,

Vii-The presence of foreign chemical species as catalyzers of the instability.