The Principles of MRI Contrast agents
MRI contrast agents are molecules intended to improve the quality of medical magnetic resonance imaging diagnostics. The magnetic resonance imaging (MRI) technique is based on the phenomenon of nuclear magnetic resonance of the nuclei of hydrogen atoms - the protons - present in water molecules. These protons are provided with a magnetic moment (the spin), which can occupy two positions, and which, in the presence of the magnetic field of a magnet, correspond to energies distant from ΔE. The application of an energy radiofrequency wave ΔE makes it possible to modify the energetic states of the spins. When the radiofrequency wave is cut, the spins return to their ground state by restoring energy in the form of an MRI signal. This signal, called nuclear magnetic resonance signal, depends on the local proton concentration and on the longitudinal and transverse relaxations T1, T2 of the protons contained in the imaged tissues. MRI thus allows the reading of images weighted in T1, T2, or proton density. The signal is localized in space by slightly modifying the magnetic field using field gradients.
The purpose of injecting contrast agents is to accelerate the magnetic relaxation rates 1 / T1 and 1 / T2 of the protons of the water molecules, i.e., to shorten the time during which the spins of these protons return to their initial state after excitation by the radiofrequency wave. This is what increases the contrast of the signal observed by MRI.
Contrast agents: what requirements?
In addition to the criteria related to the technique of magnetic resonance, the design of contrast agents must take into account the constraints linked to their use in humans.
Most contrast agents are injectable intravenously, so they do not encounter the problem of crossing the intestinal barrier, unlike a large number of drugs.
However, their injection dose is generally large; a patient is conventionally injected with 4 grams of contrast agent in a 20 ml syringe and in a period of the order of 3 to 6 seconds. For example, angiography requires taking into account the physicochemical characteristics of the solution administered called solubility, osmolality, and viscosity.
In view of the large doses used, even for a single injection, it is necessary to closely monitor the tolerance of the body to these products. By definition, contrast agents are drugs within the meaning of the Public Health Code and are not exempt from the heavy protocols of preclinical toxicity tests, as well as clinical studies aimed at demonstrating the benefit/risk of the drug. It is thus at the very stage of their conception in the laboratory that the toxicity of contrast agents must be studied.
The effectiveness of contrast agents in MRI is based on the ability of the paramagnetic elements they contain to modify the relaxation times T1 and T2 of the water, and therefore to improve the contrasts of the images. Because of its well-adapted paramagnetic properties (seven single electrons), the gadolinium ion Gd 3+ is the element of choice for designing MRI contrast agents. It is now widely used in contrast to media.
The stability of contrast agents
its high toxicity. It actually has the same ionic radius as the calcium ion Ca 2+, an important element in the balance of the body, which would be greatly disturbed if Gd 3+ were injected. It is nevertheless possible to mask this toxicity by sequestering this ion in ligand molecules belonging to two large families, i.e., linear and macrocyclic polyamino carboxylates.
Indeed, according to studies carried out on mice, it is observed that the toxicity of the ion Gd 3+only is decreased a hundred times when chelated as a contrastophore. It is important to be able to guarantee the safety of such contrast agents throughout their stay in the body. This raises the crucial question of their stability in the organism, a question all the more relevant since a new pathology appeared in the 2000s, nephrogenic systemic fibrosis, which arose in patients suffering from severe renal insufficiency. It is previously known as a systemic skin disease characterized by diffuse lesions. It has proven to be a disease of much more serious course (affecting the muscle, lung, heart) and sometimes leading to death. To date, there is no validated treatment for this pathology.
This unfortunate discovery, therefore, raised the crucial question of the stability of contrast agents in MRI. The alerts were given by the public authorities. In the United States, the Food and Drug Administration has issued an alert on the injection of all gadolinium chelates, particularly in patients with severe renal impairment; while in Europe, three of the least stable products (Omniscan®, Optimark®, and Magnevist®) are contraindicated in these patients. The European Medicines Agency (EMEA) extends the precautionary statement to the use of all other gadolinium chelates in patients with severe renal impairment. In addition to the crucial issue of the stability of gadolinium chelates in terms of toxicity, it is necessary to be able to ensure good contrast of the MRI image, and without the need for excessive doses.
Relaxation in the quality of a contrast agent
The ability of contrast agents to thus accelerate the 1 / T1 and 1 / T2 relaxation rates of water protons is measured by one quantity, relaxivity. This depends on a set of parameters. The relaxivity (r) of a contrast agent is defined as the rate of relaxation, normalized by the concentration of the contrast agent. Relaxation is a physical quantity governed by mathematical equations with multiple parameters.
The principle: a classic approach to medicinal chemistry
In order to design stable and effective gadolinium contrast agents, a rational approach was adopted, starting from a single contrast agent structure, called a "platform," from which several contrast agents are created. The derivatives we will try to modulate the pharmacokinetic properties and the biodistribution - that is to say the accessibility to specific pathological regions.
The initial structure: the P730 platform
The starting structure chosen is the DOTA Gd complex, which is a particularly stable gadolinium-based contrast agent. The macrocyclic ligand DOTA indeed forms a cavity particularly well suited to the size of the Gd 3+ ion. From the DOTA Gd structure, chemists had the idea of grafting four "glutaric" peripheral arms, which then offer four possible chemical functionalization sites.
The P730 platform has proven to be as stable as the DOTA Gd. It decomplexes very little at physiological pH and has much better stability than certain commercial contrast agents, incriminated today in the occurrence of nephrogenic systemic fibrosis.
Indeed, we know that DOTA Gd has a long electronic relaxation time and, therefore, very favorable to relaxivity. This is attributed to the symmetry and rigidity of the DOTA macrocycle vis-à-vis the impacts of water molecules on the complex
The residence time (τ m ) of the water molecules in the internal sphere of the gadolinium complex is accelerated thanks to the addition of glutaric arms, which induce compression around the gadolinium. Finally, the rotation time of the complex (τ r ) is effectively slowed down by placing the gadolinium ion at the barycenter of the structure P730 and its derivatives.