Radiopharmaceuticals

The radiotracer and magic bullet concepts have been combined to develop the concept of radiopharmaceuticals. These compounds transport a radioactive isotope to the action site, such as cancerous tissue or for neurologic diseases, either to image the tissue or to deposit a dose of ionizing radiation to kill the diseased cells. In the case of cancer, surgery, chemotherapy, and radiotherapy, alone or in various combinations, have fallen short of effectively controlling tumors and are associated with significant morbidity. Therefore, new therapy options of cancer raise some of the most challenging questions in medicine.

For some radiopharmaceuticals, the radioactive isotope also acts as vector (¹³¹I as sodium iodide for scintigraphy of thyroid glands, ^99mT as sodium pertechnetate for scintigraphy of the thyroid and salivary glands). But it is mostly constituted by a tracer that determines the spatial distribution of the molecule, which is fixed to a vector having tropism for a particular organ or function. This last determines the biodistribution of this molecule and used to assess the target organ. Radiopharmaceutical must be very stable in vivo, namely, hydrolysis, redox transchelation and transmetallation reaction, so it must be thermodynamically and kinetically stable. The pharmacokinetic of a radiopharmaceutical depends on several parameters: the particular solubility, charge, lipophilicity, molecular weight and composition. Depending on the physical properties of the radionuclide, the specific targeted radiopharmaceuticals or infusion can be adapted either for diagnosis or therapy.

I.1.1. Selection criteria for radionuclides

Several factors are involved in the choice of a radionuclide for therapeutic or diagnostic purposes. It is primarily the physical characteristics of the radionuclide itself, mainly the type

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and energy of radiation and its half-life; then the exact position of the target to be irradiated as well as its chemical properties and biological variables that govern its in vivo biodistribution.

I.1.1.1.The type and energy of radiation

The choice of the radionuclide is based on the use of the radiopharmaceutical: therapeutic or diagnostic:

-Radionuclides for diagnostic purposes, emitting mainly a positron β⁺ or γ radiation, penetrating and little ionizing to limit the dosimetric risks while being perfectly detectable externally.

-Radionuclides for therapeutic purposes, principally emitting α or β^- radiation, it is the nature of the ionizing radiation emitted by the radionuclide which will guide the selection. Indeed, from the nature and intensity of this radiation will depend the destruction of the targeted cell.

 The α radiation is a very ionizing radiation with a very important delivered energy, of about 5-7 MeV over a short distance, from 50 to 90 μm. Some examples are the use of

211At [57], ²¹²Bi/²¹³Bi [58] and ²²³Ra [59] in therapy.

 The β radiation: two types of radiation exist, as the emitted particle is an electron (β^-) or a positron (β⁺). The β^- with a distance traveled of approximately some µm to10 mm, is often used in therapy. The β^- emitters mostly used are ⁹⁰Y, ¹⁷⁷Lu and ^186/188Re [60].

The β⁺ emission is used for PET imaging diagnosis. These rays interact with the electrons of the environment and give two γ photons of 511 Kev.

 The γ radiation: The γ radiations are formed by electromagnetic waves of very variable energy. They are very penetrating and can pass through large thicknesses of material. Due to this character, the γ emissions can be detected by the camera and are therefore used in diagnostic nuclear medicine. The optimal emission for current cameras is around 150 Kev (70 to 500 keV).

 The Auger electrons: particle radiation, coming from the decay of the isotope by electron capture or internal conversion. Auger electrons have a high linear energy transfer (LET) (few nanometers) and their LET decreases compared to that of ^-. Their therapeutic effect is much localized and requires introducing isotope near the target and hence of the cell nucleus.

I.1.1.2. Half-life

The half-life of the radionuclide must be related to the biodistribution of the biological molecule (vector) to which it is associated and therefore the biological half-life of radioligand.

To be used in nuclear medicine, radionuclides must have a sufficiently long physical period to

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allow proper exploration of an organ or the study of metabolism but also short enough to not cause excessive, unnecessary and harmful irradiation of the patient.

Physical periods of radionuclides commonly used in nuclear medicine range from several hours to several days. In addition, the half-life determines the possibility of using a radionuclide remote location of its production. More the value of half-life is shorter; the production yield must be higher for compensating the loss of radioactivity due to the decay.

I.1.1.3. Production method

Another criterion to consider is the mode of production and the costs related thereto.

Radionuclides must have a high specific activity, be as pure as possible, and be readily available and inexpensive. All isotopes used in nuclear medicine are produced from cyclotron (¹²³I), nuclear reactor (¹³¹I) or generators (^99mTc). The use of generators allows producing a radionuclide on the same site of its use with a high specific activity, the parent isotope being isolated from the isotope son. Finally, the conditions for a radioisotope use in in vivo imaging are the following:

- Emission of γ radiation with an energy between 100 and 200 keV, or β⁺ emission, followed by the emission of two 511 keV γ radiation,

- As part of the PET scan, the isotope should have a half-life compatible with routine use (> 1 hour), and be pure in order to limit radiation protection constraints

- Absence of strongly ionizing particles (α or β^-), - Relatively short effective period.

For use in therapy:

- Radionuclides are β^-emitters whose radiation energy varies between 0.5 MeV and 2 Mev and whose γ contribution is low. Indeed a γ emission may accompany the decay of radioisotopes used in internal radiotherapy. This radiation contributes very little to the therapeutic efficacy and increases the irradiation of healthy tissue.

However, if the energy of photons emitted is in the diagnostic range (between 100 and 200 keV), it can be used for in vivo imaging and localization as function of time.

I.1.1.4. Related to the vector molecule

The properties of the biological carrier substance determine the pharmacokinetic properties of the radiopharmaceutical and its specificity. Indeed, depending on the vector molecule used, radiopharmaceutical will have a tropism for a function or a member to be displayed (diagnostic) or to be irradiated (therapeutic). The presence of a biological vector is intended to

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target tumor area, to limit the irradiation of healthy tissues. This biological vector may be an antibody, a peptide, a sugar, a vitamin, a protein, a nanoparticle; an enzyme ... This targeting is achieved by means of recognition between grafted biomolecule, and the surface of the malignant area.

Figure 3: radiolabeling using a bifunctional chelating agent.

A chelate must have the following characteristics:

* An anchoring site for grafting a biomolecule: this function does not participate in the coordination of the radionuclide but is kept for coupling to: a bifunctional chelating agent.

* High thermodynamic stability: a strong interaction between the metal and the ligand to ensure the complete complexation of the radionuclide.

* A high kinetic inertness of radioisotope-ligand complex to prevent the dissociation of the complex and thus the release of the radionuclide in the biological medium.

These parameters of stability and inertia are specific for each studied metal-ligand system.