Contrast agent for medical imaging

Abstract

Contrast agent for medical imaging. The invention relates to a contrast agent comprising a gadolinium compound in an effective amount, said gadolinium compound comprising a complexing group in the form of an N-hydroxylamine that can be protonated or deprotonated depending on the pH and another complexing group in the form of an imine (preferably a pyridine). Preferred gadolinium compounds are those with chemical structures (A) and (B): (A) (B) The invention also relates to a method for acquiring medical imaging images comprising the administration of said contrast agent, as well as its use in the diagnosis of tissue acidosis. Figure for the abstract: Fig. 1.

Description

Title of the invention: Contrast agent for medical imaging

[0001] The present invention relates to a contrast agent for medical imaging.

[0002] Magnetic resonance imaging (hereinafter abbreviated as "MRI") allows for non-invasive imaging of the human body. It is based on the difference in relaxation of protons in water molecules after they have been subjected to electromagnetic irradiation. Indeed, the human body is composed of 68% water, and the rate of relaxation depends on the tissues and organs.

[0003] A contrast agent is generally administered to a patient intravenously or intramuscularly before a clinical examination in order to increase the contrast of the imaging image and facilitate its interpretation.

[0004] The contrast agent may comprise a complex of a highly paramagnetic metal whose coordination sphere is unsaturated and complemented by a water molecule. The strong paramagnetism of the metal drastically alters the relaxation of this water molecule. This coordinated water molecule is in chemical exchange with the surrounding water, thus contributing to modifying its relaxation, hence the contrast. The effectiveness of a contrast agent is quantified by the relaxivity "r", expressed in mM⁻¹ s⁻¹, which represents the influence of the contrast agent on the rate of water relaxation. This value "r" is weighted by the amount of contrast agent. A distinction is made between r², related to longitudinal relaxation, and r², related to transverse relaxation. The higher the r, the more effective the contrast agent.

[0005] There are primarily three parameters that influence the relaxivity of the contrast agent: - The number of water molecules bound to the metal: the higher the number, the greater the relaxivity. However, a high number of water molecules is associated with a weaker chelating effect, with a risk of metal release into the tissues (and therefore toxicity); - The size of the contrast agent: the larger it is, the slower it moves, leading to high relaxivity at high fields of view; - the exchange rate of the water molecule.

[0006] Gadolinium is the metal of choice for designing contrast agents for MRI because the Gd(III) ion is both very stable and the element in the periodic table with the largest number of unpaired electrons (7 in total). Therefore, contrast agents are known to comprise a gadolinium complex, which is a molecular compound in which this metal and an organic structure (hereinafter referred to as "the ligand") are combined.

[0007] Gadolinium chelates are thus injected daily in France to improve the contrast of medical images. Examples include acid gadoteric acid, gadobutrol, gadoteridol, gadobenate dimeglumine, and gadoxetic acid. All these contrast agents are based on polyaminecarboxylate chelating frameworks, which are either linear or macrocyclic.

[0008] Commercial contrast agents for 1TRM containing gadolinium have a relaxivity ρ of approximately 4 to 4.5 mM 1 s⁻¹. This corresponds to a water molecule coordinated to the metal, and this relaxivity does not vary significantly with pH over a range of 4 to 9. Thus, these commercial contrast agents do not exhibit significant pH-dependent relaxivity variation within the physiological pH range of 6.4 to 7.4. Furthermore, there is a linear relationship between relaxation and contrast agent concentration. Therefore, the distribution of the contrast agent within the tissues is currently the parameter that most influences contrast.

[0009] Furthermore, it is known that certain pathologies have the side effect of altering the extracellular pH. The extracellular pH is the pH of the environment in which the cells forming tissues are bathed. Warburg demonstrated that tumors, due to their intense metabolism and an inappropriate supply of glucose and oxygen, expel larger quantities of lactate and protons than healthy cells. This results in greater acidity in tumor tissues, with an extracellular pH that can reach 6.4 in certain human cancers such as carcinoma. For comparison, the extracellular pH is approximately 7.4 in healthy tissues. This acidic pH (i.e., lower than normal physiological values) observed around tumor cells is called acidosis.Tissue acidosis is a phenomenon underlying the intense metabolic activity of tumor cells and also results in increased cancer aggressiveness, notably stimulating the production of metastases.

[0010] Tissue acidosis is also encountered during acute infarctions. Indeed, in this disease, the affected areas are acidic due to the accumulation of lactic acid (pH 4.7 to 6.8).

[0011] Thus, as explained above, commercial contrast agents comprising gadolinium complexes are not (or only very slightly) sensitive to pH and therefore cannot reflect tissue acidosis by increasing their relaxivity in tissues exhibiting said acidosis. In other words, these commercial contrast agents, although generally based on a macrocyclic framework and possessing an acid-base function, do not specifically target the pH range between 6.4 and 7.4 and do not exhibit an abrupt change in relaxivity (synonymous with sensitivity) at a pH between 6.4 and 7.4.

[0012] Therefore, it would be particularly beneficial to develop contrast agents comprising a gadolinium complex for medical imaging which be able to precisely and easily locate tissue acidosis on X-rays. Indeed, this would allow, in the field of imaging, and particularly in oncology: - to more easily differentiate a tumor from inflammation (whose extracellular pH is approximately 7.1 to 7.4) or from an infection (whose extracellular pH is approximately 7); - to assess the aggressiveness of a tumor as early as possible.

[0013] The use of these contrast agents would not be limited to imaging for oncology but could also be considered for imaging of acute myocardial infarction or ischemia, or more generally for imaging of any pathology clinically manifesting as localized tissue acidosis.

[0014] To achieve this, this gadolinium complex should ideally have the following characteristics: - a pKa close to 7; - a very large amplitude of relaxivity variation when the extracellular pH is close to the value of said pKa; - a maximum number of chelating functions (i.e. inversely proportional to the number of coordinated water molecules) to avoid the release of gadolinium in vivo.

[0015] The inventors of the present invention have developed new contrast agents comprising at least one gadolinium complex (also referred to as "gadolinium compound" in the context of the disclosure of the present invention) which fully satisfy the criteria detailed above for being able to precisely and easily localize tissue acidosis on medical imaging images.

[0016] Said contrast agents according to the invention equal, or even surpass, the properties of commercial contrast agents, while providing a novel functionality with regard to the localization of tissue acidosis.

[0017] Indeed, the gadolinium complexes comprising the contrast agent according to the invention have the following remarkable characteristics: - their pKa is very close to neutral (7.07 in one of the two examples described below), that is to say, exactly in the targeted area to highlight tissue acidosis. The contrast agents according to the invention therefore have maximum sensitivity in vivo; - a very significant variation in relaxivity, with variations on the order of +200 to +250% (depending on the device frequency) when the pH is lowered from 7.9 to 6.25. The relaxivity at pH 6.25 is higher than that of commercial contrast agents (7.5 mM 1 s⁻¹ vs. 4-4.5 mM 1 s⁻¹), making them more effective contrast agents and therefore usable at lower concentrations. The relaxivity at pH 7.9 is on the other hand lower (2.5 mM 1 s1), lowering the contrast in areas where the pH is physiological; - a reversibility of action: the mechanism involved is a simple protonation and not a complex chemical reaction.

[0018] In other words, the contrast agents according to the invention exhibit a relaxivity that increases considerably under slightly acidic conditions (namely, within a pH range compatible with the phenomenon to be observed, i.e., between 6.4 and 7.4). They thus have the ability to induce a significant increase in contrast in areas of acidosis (i.e., at the tumor site in the case of oncology imaging), without increasing contrast elsewhere. Therefore, the contrast agents according to the invention also offer the advantage, when searching for tumors, of requiring a lower dose while obtaining superior contrast, and thus facilitating easier and more reliable diagnosis.

[0019] Furthermore, the contrast agents according to the invention which have been tested against M21 cell lines do not exhibit cytotoxicity, presumably due to a lack of cell penetration, which is an essential characteristic for an injectable contrast agent.

[0020] The coordination sphere can contain up to nine complexing atoms at pH 7.9. This number is unprecedented in contrast agents known to date. It suggests a very high affinity of gadolinium for the ligand at this pH and therefore a lower risk of gadolinium release, and thus lower toxicity, than with currently used contrast agents.

[0021] Finally, the framework of the gadolinium complexes of the contrast agents according to the invention is perfectly modular, offering the possibility of post-functionalization. This opens up numerous perspectives, both in vectorization, theragnostics, interaction with targets in order to modulate relaxivity, for the optimization of residence time in the blood, or even the addition of functions detectable by tomography for bimodal imaging.

[0022] The present invention thus relates to a contrast agent comprising at least one gadolinium compound in an effective quantity and which is selected from the group consisting of compounds (1) to (12) of the following chemical structures:

[0023] [Chem.l] rv / \ ; N. ,.-x x”7 p* x MHV r >— XX X*

[0024] (1) [Chem.2]

[0025] (2) [Fabric. 3] XX

[0026] (3) [Chem.4] “xx xj px FU / ... \ - R z N éJ>K x and WK y" and 'RR \ X X (4)

[0027] [Chem.5] (5)

[0028] [Chem.6] xxy Xx „ N'C ^x X- TT^ x x^s. ,R–X x” XN” x . $ { X _ YR yy (6)

[0029] [Chem.7] x X X.. ...X R x --y" -y X p( iCldj ^^'""X

[0030] [Fabric. 8] XX

[0031] (8) [Chem.9] R

[0032] (9) [Fabric. 10]

[0033] [Chem. 11] y (11)

[0034] [Chem. 12] (12)

[0035] in which: - x independently represents a hydrogen or an alkyl group in Ci-C2 which is optionally substituted by a hydroxyl, amine, ether group, preferably x represents a hydrogen or a methyl group; - an R is a group chosen from -(CH2)n-G1 to -(CH2)n-G8 in which n is equal to 1 or 2 and the chemical structures of groups G1 to G8 are defined below; - the remaining R groups being chosen independently from among: -(CH2)nA with n equal to 1 or 2 and A is a group chosen from among the following groups: carboxylate, C2-C4 alkynyl, ester, alkylcarboxylate, alkylamide, amide, amine, alkylamine, phosphonate, alkylphosphonate, hydroxyl, alkylhydroxyl, ether, sulfonate, triazole, thiolate, thioether and thiocyanate, or A is a chemical motif configured to vector said gadolinium compound and / or to modulate the physicochemical properties of said gadolinium compound; as well as

[0036] the following groups of chemical structures (13) to (17):

[0037] [Chem. 13] O^OH S>H (13);

[0038] [Chem. 14] I 1 < Y ​​" 0H (14);

[0039] [Chem. 15] O^ÔH (15);

[0040] [Chem. 16] (16);

[0041] [Chem. 17] (17);

[0042] wherein Xn is a hydrogen or a chemical motif configured to vector said gadolinium compound,

[0043] - Y represents, independently of each other, a hydrogen or an alkyl group in C1-C4 which is optionally substituted by at least one group chosen from among the carboxylate, ester, alkylcarboxylate, alkylamide, amide, amine, alkylamine, phosphonate, alkylphosphonate, hydroxyl, alkylhydroxyl, ether, sulfonate, triazole, thiolate, thioether or thiocyanate groups; - Z independently represents a hydrogen, a halogen, a hydroxyl, an ether, an alkyloxy, a cyano, a nitro, a sulfonate, a trifluoromethyl or a C1-C4 alkyl group which is optionally substituted by at least one group chosen from the following groups: carboxylate, ester, alkylcarboxylate, alkylamide, amide, amine, alkylamine, phosphonate, alkylphosphonate, hydroxyl, alkylhydroxyl, ether, sulfonate, triazole, thiolate, thioether or thiocyanate; and groups G1 to G8 respectively have the following chemical structures:

[0044] [Chem. 18] (Gl)

[0045] in which: gl 1 to g 13 independently represent a hydrogen, halogen, hydroxyl, ether, alkyloxy, cyano, nitro, sulfonate, trifluoromethyl or a C1-C4 alkyl group that is optionally substituted by at least one group selected from the following groups: carboxylate, ester, alkylcarboxylate, alkylamide, amide, amine, alkylamine, phosphonate, alkylphosphonate, hydroxyl, alkylhydroxyl, ether, sulfonate, triazole, thiolate, thioether or thiocyanate; g 14 to g 17 independently represent a hydrogen, a methyl or ethyl group;

[0046] [Chem. 19] (G2)

[0047] in which:

[0048] g21 represents a hydrogen, a hydroxyl, or an alkyl group in Ci-C4 which is optionally substituted by a hydroxyl, amine, triazole, ether or amide group; g22 represents CH2, oxygen, nitrogen, sulfur or alkyl group in Ci-C4 optionally substituted by a hydroxyl, amine, triazole, ether or amide group;

[0049] or g21 represents CH2 whose carbon is directly connected to g22 which represents CH,

[0050] g23 to g26 independently represent a hydrogen, a group methyl or ethyl;

[0051] [Chem.20]

[0052] in which:

[0053] g31 represents a hydrogen, a hydroxyl or an alkyl group in CrC4 which is optionally substituted by a hydroxyl, amine, triazole, ether or amide group;

[0054] g32 represents CH, CH2, oxygen, nitrogen, sulfur or an alkyl group in Cr C4 which is optionally substituted by a hydroxyl, amine, triazole, ether or amide group; or g31 represents CH2 whose carbon is directly connected to g32 which represents CH;

[0055] g34 represents a hydrogen, an amine, an imine, a hydroxyl, an alkyl group or acyl in CrC4, said alkyl or acyl group being optionally substituted by a hydroxyl, amine, triazole, ether or amide group;

[0056] g35 represents a hydrogen, a hydroxyl, an alkyl or acyl group in CrC4, said alkyl or acyl group being optionally substituted by a hydroxyl, amine, triazole, ether or amide group; or g34 represents an alkyl or alkylamine group in Ci-C2, one carbon of which is directly connected to g35, which represents an alkyl group in CrC2;

[0057] [Chem.21]

[0058] in which: g41 represents a hydrogen, hydroxyl or alkyl group in C1-C4 which is optionally substituted by a hydroxyl, amine, triazole, ether or amide group; g42 represents CH3, an oxygen, a nitrogen, a sulfur or a alkyl group in C1-C4 which is optionally substituted by a hydroxyl, amine, triazole, ether or amide group; or g41 represents CH2 whose carbon is directly connected, or connected via a methyl group, to g42 which represents CH2;

[0059] g43 represents a hydrogen, an imine, an amine, a hydroxyl, an alkyl group or acyl in C1-C4, said alkyl or acyl group being optionally substituted by a hydroxyl, amine, triazole, ether or amide group;

[0060] g44 represents a hydrogen, a hydroxyl, an alkyl or acyl group in C1-C4, said alkyl or acyl group being optionally substituted by a hydroxyl, amine, triazole, ether or amide group; or g43 represents an alkyl or alkylamine group in Ci-C2, one carbon of which is directly connected to g44, which represents an alkyl group in CrC2.

[0061] g45 represents a hydrogen, a hydroxyl, an alkyl or acyl group in C1-C4, said alkyl or acyl group being optionally substituted by a hydroxyl, amine, ether or amide group; or g44 represents an alkyl or alkylamine group in CrC2, one carbon of which is directly connected to g45, which represents an alkyl group in CrC2;

[0062] [Chem.22] (G5)

[0063] g52 independently represents a hydrogen, halogen, hydroxyl, ether, alkyloxy, cyano, nitro, sulfonate, trifluoromethyl, alkyl or a C1-C4 alkyl group that is optionally substituted by at least one group selected from the following groups: carboxylate, ester, alkylcarboxylate, alkylamide, amide, amine, alkylamine, phosphonate, alkylphosphonate, hydroxyl, alkylhydroxyl, ether, sulfonate, triazole, thiolate, thioether or thiocyanate;

[0064] g51 and g53 independently represent a hydrogen, halogen, hydroxyl, ether, alkyloxy, cyano, nitro, sulfonate, trifluoromethyl or a Ci-C4 alkyl group which is optionally substituted by at least one group selected from the following groups: carboxylate, ester, alkylcarboxylate, alkylamide, amide, amine, alkylamine, phosphonate, alkylphosphonate, hydroxyl, alkylhydroxyl, ether, sulfonate, triazole, thiolate, thioether, or thiocyanate; or g52 is connected to g51 or g53 so as to form a C2-C3 carbon chain; g54 represents a hydrogen, imine, amine, hydroxyl, alkyl or acyl group in CrC4, said alkyl or acyl group being optionally substituted by a hydroxyl, amine, triazole, ether or amide group;

[0065] g55 represents a hydrogen, a hydroxyl, an alkyl or acyl group in CrC4 optionally substituted by a hydroxyl, amine, triazole, ether, amide or alkyl group in Ci-C2 directly connected to g54;

[0066] or g54 represents an alkyl or alkylamine group in Ci-C2 of which one carbon is directly connected to g55 which represents an alkyl group in CrC2;

[0067] [Chem.23] (G6)

[0068] in which: g61 represents an alkyl group in CrC4 which is optionally substituted by a hydroxyl, amine, triazole, ether or amide group; g62 represents an alkyl group in CrC4 which is optionally substituted by a hydroxyl, amine, triazole, ether or amide group;

[0069] or g62 represents CH2 whose carbon is directly connected to g61 which represents CH; g63 to g66 independently represent a hydrogen, a methyl or ethyl group;

[0070] [Chem.24] (G7)

[0071] in which:

[0072] g71 represents a hydrogen, a hydroxyl, an alkyl group in Ci-C4 which is optionally substituted by a hydroxyl, amine, triazole, ether or amide group; g72 represents a CrC4 alkyl group which is optionally substituted by a hydroxyl, amine, triazole, ether or amide group; or g71 represents CH2 whose carbon is directly connected to g72 which represents CH2; g73 represents a hydrogen, an imine, an amine, a hydroxyl, an alkyl or acyl group in CrC4, said alkyl or acyl group being optionally substituted by a hydroxyl, amine, triazole, ether or amide group; g74 represents a hydrogen, a hydroxyl, an alkyl or acyl group in CrC4, said alkyl or acyl group being optionally substituted by a hydroxyl, amine, triazole, ether or amide group;

[0073] or g73 represents an alkyl or alkylamine group in Ci-C2 of which one carbon is directly connected to g74 which represents an alkyl group in CrC2;

[0074] g75 represents a hydrogen, a hydroxyl, an alkyl or acyl group in Ci-C4, said alkyl or acyl group being optionally substituted by a hydroxyl, amine, ether or amide group;

[0075] [Chem.25]

[0076] in which:

[0077] g81 represents an alkyl group in CrC4 which is optionally substituted by a hydroxyl, amine, triazole, ether or amide group;

[0078] g82 represents a hydrogen or an alkyl group in Ci-C4 which is optionally substituted by a hydroxyl, amine, triazole, ether or amide group;

[0079] or g82 represents CH2 whose carbon is directly connected to g81 which represents CH;

[0080] g84 represents a hydrogen, an imine, an amine, a hydroxyl, an alkyl group or acyl in CrC4, said alkyl or acyl group being optionally substituted by a hydroxyl, amine, triazole, ether or amide group;

[0081] g85 represents a hydrogen, a hydroxyl, an alkyl or acyl group in Ci-C4 which is optionally substituted by a hydroxyl, amine, triazole, ether or amide group;

[0082] or g84 represents an alkyl or alkylamine group in Ci-C2 of which one carbon is directly connected to g85 which represents an alkyl group in CrC2.

[0083] Compounds (1) to (12) are gadolinium complexes.

[0084] As used herein, the term "alkyl" refers to linear alkyl groups or branched. The term "alkynyl" refers to linear or branched alkynyl groups.

[0085] These are molecular compounds in which gadolinium and an organic structure are associated, which is also called, in the context of the description of the present invention, "the ligand".

[0086] All groups G1 to G8 contain a hydroxylamine function (or its nitrone tautomer form). This is an essential technical feature of all these compounds (1) to (12) of the contrast agent according to the invention.

[0087] Since the hydroxylamine chemical function is acid-base, it can protonate or deprotonate depending on the pH. It can also isomerize to a zwitterion or to α-aminonitrone in the specific case of α-iminohydroxylamines, depending on the experimental conditions (solvent polarity, presence of ions in solution, etc.). The term hydroxylamine thus refers, in the context of this The invention encompasses all these forms in tautomeric or acid-base equilibrium: hydroxylammonium, hydroxylamine, α-aminonitrone, zwitterion, and deprotonated hydroxylamine. Hydroxylamine can be secondary or tertiary. In all cases, it is an N-hydroxylamine (i.e., substituted at the nitrogen atom, not the oxygen atom).

[0088] When hydroxylamine is in its protonated form, the electrostatic repulsion between ammonium and gadolinium (both positively charged) prevents the arm containing said hydroxylamine from coordinating with gadolinium. When hydroxylamine is in its deprotonated form, it can convert to a nitrone: its negatively charged oxygen atom will coordinate strongly with gadolinium, expelling the water molecules bound to gadolinium. The relaxivity ri depends on the number of water molecules bound to gadolinium. Thus, the relaxivity will be low at physiological pH, but will increase sharply in the case of tissue acidosis. As explained above, the higher the ri, the greater the contrast in medical imaging (e.g., MRI).

[0089] Furthermore, the gadolinium complex advantageously has a pKa between approximately 6 and 8, preferably approximately 7, in order to obtain maximum contrast effect at physiological pH and in the case of mild acidosis (such as around tumor cells). Hydroxylamine is predominantly in protonated form (i.e., "hydroxylammonium") at pH below the pKa and predominantly in non-protonated or zwiterrionic form at pH above the pKa.

[0090] In compounds (1) to (12), the positioning of the hydroxylamine is closely linked to the nature of the chemical bond between the hydroxylamine and the rest of the organic structure (i.e., the rest of the ligand) of these compounds (1) to (12) so as to allow the oxygen of the hydroxylamine in its deprotonated, zwitterionic, or nitrone form to coordinate with gadolinium. The positioning of the hydroxylamine is essential because the Lewis acidity of gadolinium helps to modulate the pKa of the gadolinium complex, which is between 6 and 8, in order to obtain the maximum effect at physiological pH and in the case of acidosis. It is the coordination of the hydroxylamine via the oxygen atom that allows the expulsion of water molecules from the coordination sphere, and thus modulates the relaxivity.

[0091] Groups G1 to G8, as defined above, enhance this effect, i.e., they modulate the number of water molecules to be expelled. This is because they contain an additional complexing group, which is an imine. This complexing group is preferably a pyridine, as is the case for groups G1 and G5.

[0092] Compound (1) is a derivative of cyclene (in other words, a derivative of 1,4,7,10-tetraaza cyclododecane). Compound (3) is a derivative of 1,4,7-triazacyclononane (also known by the abbreviation "TACN"). Compound (5) is a derivative of cyclame. Compound (9) is a derivative of pyclene.

[0093] In compounds (1) to (12) as detailed above, the carbon chains can be functionalized, as can the amines, to modulate the size and blood residence time of the contrast agent according to the invention.

[0094] In preferred embodiments of the invention, with respect to group Gl: - gl1 to gl3 are chosen from hydrogen, C1-C4 alkyl groups and halogens and -gl4 ​​to gl7 are chosen from among the methyl or ethyl groups.

[0095] In even more preferred embodiments of the invention, with regard to group Gl: - gl1 to gl3 are chosen from hydrogen and methyl or ethyl groups and -gl4 to gl7 are chosen from methyl or ethyl groups.

[0096] In a most preferred manner, gl1 to gl3 are hydrogens and gl4 to gl7 are methyl groups.

[0097] In preferred embodiments of the invention, with respect to group G2, g21 is a hydrogen or a methyl group, g22 is CH2 and g23 to g26 are methyl groups.

[0098] In preferred embodiments of the invention, with respect to group G3, g31 is a hydrogen or a methyl group, g32 is CH2, g34 is an imine or an amine, and g35 is a tert-butyl group. The tert-butyl group, lacking a hydrogen on the carbon adjacent to the hydroxylamine, helps to limit the risk of beta-elimination. Beta-elimination would lead to the decomposition of the hydroxylamine.

[0099] In preferred embodiments of the invention, with respect to group G4, g41 is a hydrogen or a methyl group, g42 is a methyl group, g43 is an imine or an amine, g44 is a tert-butyl group and g45 is a hydrogen.

[0100] In preferred embodiments of the invention, with respect to group G5, g51 to g53 are hydrogens, g54 is an imine or an amine, g55 is a tert-butyl group.

[0101] In preferred embodiments of the invention, with respect to group G6, g61 is CH2, g62 is a methyl group and g63 to g66 are methyl groups.

[0102] In preferred embodiments of the invention, with respect to group G7, g71 is a hydrogen or a methyl group, g72 is a methyl group, g73 is an imine or an amine, g74 is a tert-butyl group and g75 is a hydrogen.

[0103] In preferred embodiments of the invention, with respect to group G8, g82 is a hydrogen or a methyl group, g81 is CH2, g84 is an imine or an amine and g85 is a tert-butyl group.

[0104] Preferably, in compounds (1) to (12), an R is a -(CH2)n-Gl group in which n is equal to 1 or 2, preferably equal to 1.

[0105] In a preferred embodiment of the invention, in compounds (1) to (12), an R is a -(CH2)n-Gl group in which n is equal to 1 or 2, preferably equal to 1, and in group G1: - gl1 to gl3 can be chosen from hydrogen, C1-C4 alkyl groups and halogens and - g 14 to g 17 can be chosen from the methyl or ethyl groups.

[0106] In a most preferred embodiment of the invention, in compounds (1) to (12), an R is a -(CH2)n-Gl group in which n is equal to 1 or 2 (preferably n is equal to 1) and in the Gl group gl 1 to gl3 can be hydrogens and gl4 to gl7 can be methyl groups.

[0107] As explained above, compounds (1) to (12) may comprise a group R which is -(CH2)nA with n equal to 1 or 2 (preferably n equals 1) and A is a chemical motif configured to vector said gadolinium compound and / or modulate the physicochemical properties of said gadolinium compound.

[0108] In the context of the present invention, “a chemical motif configured to deliver said gadolinium compound” means a chemical motif that is configured to deliver said gadolinium compound to a specific location in the body (for example, to the surface of cancer cells) after administration of the contrast agent according to the invention to the patient. Thanks to the presence of this chemical delivery motif in the ligand, the gadolinium compound will accumulate at this specific location in the body to increase local contrast and thus facilitate the detection of this specific location.

[0109] Such chemical motifs enabling the vectorization of gadolinium compounds which comprise contrast agents are perfectly known and within the reach of a person skilled in the art.

[0110] By way of example, and without limiting the scope of the invention, the chemical motif configured to deliver the gadolinium compound can be an RGD motif (preferably a cyclo-RGD motif) having an affinity for an integrin (preferably the av

[33] integrin). In other words, it is a chemical motif containing the following sequence: arginine, glycine, and aspartic acid. The av

[33] integrin is the most important protein present on the cell surface during tumor angiogenesis. Its overexpression has been observed in many types of cancer (brain, glioblastoma, melanoma, ovarian, prostate, pancreatic, breast). The RGD motif allows the gadolinium compound to be delivered to tumor cells and to accumulate it in this area to increase contrast and facilitate the detection of said tumor cells.

[0111] An example of an RGD chemical motif may be the following chemical structure motif (26):

[0112] [Chem.26] (26)

[0113] In the context of the present invention, "a chemical motif configured to modulate the physicochemical properties of the gadolinium compound" means a chemical motif that is configured to, for example: - act on the size of said gadolinium compound (in order to increase r2 and to carry out ratiometric measurements); - to achieve the formation of supramolecular structures; - to perform its grafting on supports (for example polymers, particles); - control the solubility and stability of said gadolinium compound in the blood, or - perform a bimodal detection (by positron emission tomography or luminescence).

[0114] Such chemical motifs allowing the modulation of the physico-chemical properties of gadolinium compounds are perfectly known and within the reach of a person skilled in the art.

[0115] By way of example, and without limiting the scope of the invention, the chemical motif configured to modulate the physicochemical properties of the gadolinium compound may be a lipophilic chain designed to promote the formation of micelles, or a polyethylene glycol chain aimed at increasing the residence time of said compound in the blood.

[0116] In preferred embodiments of the invention, in compounds (1) to (12), at least one of the remaining R is a group selected from -(CH2)nA with n equal to 1 or 2 (preferably n equals 1) and A is a chemical motif configured to vector said gadolinium compound and / or modulate the physicochemical properties of said gadolinium compound.

[0117] In preferred embodiments of the invention, in compounds (1) to (12), among the remaining Rs: - an R is a group chosen from -(CH2)nA with n equal to 1 or 2 (preferably n equals 1) and A is a chemical motif configured to vectorize said gadolinium compound and / or modulate the physicochemical properties of said gadolinium compound and - the remaining R(s) is / are chosen from -(CH2)nA with n equal to 1 or 2 (preferably n equals 1) and A is a group chosen from the following groups: carboxylate, C2-C4 alkynyl, ester, alkylcarboxylate, alkylamide, amide, amine, alkylamine, phosphonate, alkylphosphonate, hydroxyl, alkylhydroxyl, ether, sulfonate, triazole, thiolate, thioether and thiocyanate.

[0118] Preferably, the contrast agent comprises at least one compound in macrocycle form. In other words, the contrast agent preferably comprises at least one compound selected from compounds (1), (3), (5), (7) and (9) as defined above.

[0119] Most preferably, the contrast agent comprises at least one compound selected from compounds (1), (3) and (5).

[0120] Preferably, the contrast agent comprises at least compound (1). In other words, the contrast agent comprises at least one derivative of cyclene.

[0121] In embodiments of the invention, the contrast agent comprises at least compound (1) which may have the following technical characteristics 1) to 10), taken alone or in combination therewith: 1) the Xs of said compound (1) independently represent a hydrogen or a methyl group, preferably the Xs are hydrogens; 2) an R in said compound (1) is a (CH2)n-Gl group in which n is equal to 1 or 2 (preferably n is equal to 1); 3) an R is the group -(CH2)n-Gl in which n is equal to 1 or 2 (preferably n is equal to 1) and in which gl 1 to gl3 are chosen from hydrogen, C1-C4 alkyl groups and halogens and g 14 to g 17 are chosen from methyl or ethyl groups; 4) an R is the group -(CH2)n-Gl in which n is equal to 1 or 2 (preferably n is equal to 1) and in which gl 1 to g 13 are chosen from hydrogen and methyl or ethyl groups and g 14 to g 17 are chosen from methyl or ethyl groups; 5) an R is the group -(CH2)n-Gl in which n is equal to 1 or 2 (preferably n is equal to 1) and in which gl1 to g13 are hydrogens and gl4 to gl7 are methyl groups; 6) the remaining R groups are -(CH2)nA with n equal to 1 or 2 (preferably n equals 1) and A is a group chosen from the following: carboxylate, C2-C4 alkynyl, ester, alkylcarboxylate, alkylamide, amide, amine, alkylamine, phosphonate, alkylphosphonate, hydroxyl, alkylhydroxyl, ether, sulfonate, triazole, thiolate, thioether and thiocyanate; 7) at least 2 R of the remaining R are (CH2)nA groups with n equal to 1 or 2 (preferably n equals 1) and A is a carboxylate; 8) the remaining 3 R are all (CH2)nA groups with n equal to 1 or 2 (preferably n equals 1) and A is a carboxylate;

[0122] 9) 2 R of the remaining R are (CH2)nA groups with n equal to 1 or 2 of (preferably n is equal to 1) and A is a carboxylate and the 3rd R of the remaining Rs is a (CH2)nA group with n is equal to 1 or 2 (preferably n is equal to 1) and A is an ethyne;

[0123] 10) an R of the remaining R is a group chosen from -(CH2)nA with n equal to 1 or 2 (preferably n is equal to 1) and A is a chemical motif configured to vector said gadolinium compound and / or modulate the physicochemical properties of said gadolinium compound and the remaining 2 Rs are chosen from -(CH2)nA with n is equal to 1 or 2 (preferably n is equal to 1) and A is a group chosen from the following groups: carboxylate, C2-C4 alkynyl, ester, alkylcarboxylate, alkylamide, amide, amine, alkylamine, phosphonate, alkylphosphonate, hydroxyl, alkylhydroxyl, ether, sulfonate, triazole, thiolate, thioether and thiocyanate, preferably the remaining 2 Rs are chosen from -(CH2)nA with n is equal to 1 or 2 (preferably n is equal to 1) and A is a carboxylate or an ethyne.

[0124] When, in compound (1), one R is the -(CH2)n-Gl group in which n is equal to 1 or 2 (preferably n is equal to 1) and at least two of the remaining Rs are carboxylates, this has the advantage of creating good affinity between the ligand and gadolinium within the gadolinium complex. Furthermore, this provides suitable parameters for medical imaging (in particular magnetic imaging).

[0125] In a preferred embodiment of the invention, the contrast agent comprises at least one gadolinium compound selected from the following gadolinium compounds with chemical structures (A) and (B):

[0126] [Chem.27] (HAS)

[0127] [Chem.28] (B)

[0128] The concentration of at least one gadolinium compound included in the contrast agent (namely at least one of the compounds (1) to (12)) may be between 0.1 and 0.2 mmol / kg of patient weight.

[0129] Preferably, the contrast agent comprises at least one compound (1) to (12) as detailed above in effective quantity and in association with one or more pharmaceutically acceptable excipients, diluents or solvents.

[0130] The invention also relates to a method for acquiring medical imaging images comprising: - the administration of the contrast agent according to the invention and as described above to a patient, - the acquisition of images using a medical imaging technique.

[0131] The contrast agent may be administered intravenously or intramuscularly, preferably intravenously.

[0132] Preferably, the medical imaging technique is a magnetic imaging technique, such as magnetic resonance imaging (MRI).

[0133] Thanks to the contrast agent according to the invention, this acquisition method has the advantage of providing medical imaging images with better contrast than those produced with commercial contrast agents.

[0134] Image acquisition can be performed at the level of one or more organs of the patient.

[0135] These may be organs suspected of containing cancer cells, for example, the breasts, lungs, pancreas, brain, bladder, bones, and prostate. The medical imaging acquisition method according to the invention is particularly suitable and reliable for detecting tumors. It can therefore be used in oncology.

[0136] It can also refer to the heart. The method for acquiring medical imaging images according to the invention is particularly suitable and reliable for imaging acute myocardial infarction or ischemia.

[0137] The invention also relates to a contrast agent according to the invention and as described above for use in the diagnosis of tissue acidosis. This diagnosis can be established by: - the implementation of the medical imaging image acquisition process according to the invention and as described above; - image analysis to detect areas of contrast.

[0138] As explained above, the contrast areas on these images correspond to tissues exhibiting acidosis. These tissues may be tissues affected by a pathology resulting in tissue acidosis, for example, tissues containing cancer cells or heart tissue.

[0139] The invention will be better understood with the aid of the detailed description of experiments carried out with two contrast agents according to the invention.

[0140] [Fig-1] Fig. 1 schematically details all the synthesis steps described above until the 1st gadolinium complex of chemical structure (A) is obtained.

[0141] [Fig.2] The [Fig.2] represents the 1st gadolinium complex of chemical structure (A) depending on whether the pH is lower or higher than the pKa.

[0142] [Fig.3] Fig.3 schematically details all the synthesis steps described above up to obtaining the 2nd gadolinium complex of chemical structure (B).

[0143] EXPERIMENTAL SECTION:

[0144] Experiments were carried out on two gadolinium complexes which may comprise the contrast agents according to the invention.

[0145] The synthesis of these two gadolinium complexes is detailed below.

[0146] Synthesis of the 1α-gadolinium complex:

[0147] The first gadolinium complex having the chemical structure (A) detailed above was synthesized according to the steps detailed below:

[0148] 1 — step: synthesis of 2,3-dimethyl-2,3-dinitrobutane:

[0149] At 0°C, 7.3 mL (0.14 mol) of Br2 were added dropwise over one hour to a 25 mL solution of 2-nitropropane (0.39 mol) in a total of 180 mL of sodium hydroxide (6 mol / L) and ethanol (7:11 v / v). Following this addition, the reaction mixture was stirred at 84°C for 3 hours, then transferred to one liter of ice water. The pale yellow crystals thus formed were recovered by filtration, then recrystallized in methanol to obtain 6.3 g (25% yield) of 2,3-dimethyl-2,3-dinitrobutane in crystal form.

[0150] Characterization of 2,3-dimethyl-2,3-dinitrobutane: ¹³C NMR (400 MHz, CDC13) δ / ppm = 1.73 (s, 12H). ¹³C NMR (100 MHz, CDC13) δ / ppm = 91.4, 23.0. These data correspond to those in the literature.

[0151] 2 — step: synthesis of 2,3-dimethylbutane-2,3-dihydroxylamine hydrosulfate _ l

[0152] A sheet of aluminum was cut and placed in an Erlenmeyer flask. A 40 mL solution of tetrahydrofuran and HgCl2 (0.907 g, 0.33 mmol, 0.23 equivalents) was added to the cut aluminum sheet (1.5 g, 56 mmol, 3.8 equivalents), and the solution was stirred manually at 0°C. After 6 minutes, the solution was extracted, and the resulting amalgam was rinsed with 10 mL of methanol and 10 mL of tetrahydrofuran. Then, 40 mL of tetrahydrofuran and 10 mL of water were added to the amalgam, and the resulting solution turned black and self-heated. 2,3-Dimethyl-2,3-Dinitrobutane (2.62 g, 14.7 mmol, 1 equivalent) was added to 40 mL of this black amalgam solution in tetrahydrofuran at 0°C, then stirred for 2.5 hours while monitoring the release of H2. The resulting mixture was filtered through Celite, rinsed with tetrahydrofuran, and the solvents were evaporated.The compound obtained was solubilized in ethanol and precipitated with sulfuric acid to obtain the 2,3-dimethylbutane-2,3-dihydroxylamine hydrosulfate salt of chemical structure (29) as detailed below with a yield of 55%: .

[0153] [Chem.29] HSOZ H ON H H2N-OH

[0154]

[0155]

[0156]

[0157] Characterization of 2,3-dimethylbutane-2,3-dihydroxylamine hydrosulfate: 'H NMR (400 MHz, DMSO) δ = 1.19 (s, 12H). These data correspond to those in the literature. Step 3: Synthesis of 6-(hydroxymethyl)-2-pyridinecarboxaldehyde: Under an argon atmosphere, a solution of 2,6-pyridinedimethanol and SeO2 in 60 mL of 1,3-dioxane was stirred at 50°C for 23 hours. 100 mL of dichloromethane was added to the solution, which was then filtered through Celite. 6-(Hydroxymethyl)-2-pyridinecarboxaldehyde, with chemical structure (30) as detailed below, was obtained after evaporation of the solvents: [Chem.30]

[0158]

[0159]

[0160]

[0161] (30) Characterization of 6-(hydroxymethyl)-2-pyridinecarboxaldehyde: *H NMR (400 MHz, CDC13) δ / ppm = 10.07 (s, 1H), 7.88 (m, 2H), 7.53 (m, 1H), 4.87 (s, 2H). These data correspond to those in the literature. 4 — step: synthesis of 6-(chloromethyl)pyridine-2-carbaldehyde: Under an argon atmosphere, SOC12 (1.25 mL, 17.2 mmol, 1.2 equivalents) was added dropwise to a solution of 6-(hydroxymethyl)-2-pyridinecarboxaldehyde synthesized in step 3 in 120 mL of dichloromethane at 0°C. After 30 minutes, the resulting mixture (a yellow solution) was brought to room temperature and then kept there overnight. Next, 30 mL of water were added, and the solution was extracted with dichloromethane, then dried over Na2SO4, and the solvents were evaporated. The resulting compound was purified by vacuum chromatography on a dry column (using toluene and diethyl ether as eluents). 6-(chloromethyl)pyridine-2-carbaldehyde with chemical structure (31) as detailed below was obtained in a yield of 40%. [Chem.31]

[0162] Characterization of 6-(chloromethyl)pyridine-2-carbaldehyde: 'H NMR (400 MHz, CDC13) β / ppm = 10.07 (s, 1H), 7.88 (m, 2H), 7.53 (m, 1H), 4.87 (s, 2H). These data correspond to those in the literature.

[0163] 5 — step: synthesis of 2-(chloromethyl)-6-(4,4,5,5-tetramethylimidazolidin-2-y l)pyridine:

[0164] A solution of 2,3-dimethylbutane-2,3-dihydroxylamine hydrosulfate (2nd synthesis step) (0.300 g, 1.22 mmol) in 10 mL of water was added to a solution of 6-(chloromethyl)pyridine-2-carbaldehyde (4th synthesis step) (0.190 g, 1.22 mmol) in 10 mL of methanol under vigorous stirring. Sodium acetate (120 mg, 1.46 mmol) was added to the resulting reaction mixture, and the cloudy yellow solution formed transformed into a white precipitate after 30 minutes, which was kept under stirring overnight at room temperature. The white solid thus obtained was filtered and dried under vacuum to obtain 2-(chloromethyl)-6-(4,4,5,5-tetramethylimidazolidin-2-yl)pyridine of chemical structure (32) as detailed below (0.273 g, yield of 78%):

[0165] [Chem.32] (32)

[0166] Characterization of 2-(chloromethyl)-6-(4,4,5,5-tetramethylimidazolidin-2-yl)pyridine: 7.43 (d, 3JH H= 8Hz, 1H), 4.76 (s, 2H), 4.63 (s, 1H), 1.07 (d, XH = 4Hz, 12H). 13C NMR (125 MHz, DMSO-d6) δ / ppm = 161.9 (Ar), 155.2 (Ar), 137.7 (Ar), 122.6 (Ar), 122.5 (Ar), 91.6 (imidazole), 66.9 (C-quat), 66.8 (C-quat), 47.5 (CH2Cl), 24.5 (CH3), 17.9 (CH3). High-resolution mass spectrometry - electron spray ionization m / z calculated for Ci3H2iO2N3Cl [M+H]+ 286.1317, found at 286.1127. Infra-red spectrum (cm1, pure): 3245, 2984, 1594, 1448, 1377, 1045, 995, 719,580.

[0167] 6 — step: synthesis of 2-(chloromethyl)-6-(l-hydroxy-4,4,5,5-tetramethyl-imida zol-2-yl)pyridine

[0168] Sodium periodate (0.019 g, 0.089 mmol) was added to a solution of 2-(chloromethyl)-6-(4,4,5,5-tetramethylimidazolidin-2-yl)pyridine (0.017 g, 0.059 mmol) (5th synthesis step) in a mixture of 5 mL of dichloromethane, 2,5 mL of ethyl acetate and 5 mL of water. After 5 minutes, the solution turned dark purple. The reaction mixture was stirred for 30 minutes at room temperature while the reaction was monitored by silica plate chromatography. The aqueous phase was extracted with dichloromethane (10 mL). The organic phases were combined and dried with Na2SO4 and the solvents evaporated under vacuum to obtain 2-(chloromethyl)-6-(l-hydroxy-4,4,5,5-tetramethylimidazol-2-yl)pyridine as a purple powder (0.016 g, 88%) with the following chemical structure (33):

[0169] [Chem.33] L +■ ^Z Cl i Ji Xr V x (33)

[0170] Characterization of 2-(chloromethyl)-6-(l-hydroxy-4,4,5,5-tetramethyl-imidazol-2-yl)pyridine: High-resolution mass spectrometry - electron fogging m / z calculated for Ci3Hi8O2N3C1 [M+H]+ 283.1082, found at 283.1081. Infrared spectrum (cm1, pure): 2965, 2918, 2851, 1359, 1087, 705, 643. Electron paramagnetic resonance (EPR) (MeCN): Isotropic 5-line nitroxide signal at g = 2.00, AM = AN2 = 0.7 mT.

[0171] Step 7: Synthesis of 3-oxyl-4,4,5,5-tetramethyl-2-(6-((4,7,10-tris(2-(tert- butoxy)-2-oxoethyl)-l,4,7,10-tetraazacyclododecan-l-yl)methyl)pyridin-2-yl)-4,5-dihy dro- lH-314-imidazol- 1-olate

[0172] Tri-tert-butyl 2,2',2”-(l,4,7,10-tetraazacyclododecane-l,4,7-triyl)triacetate of the following chemical structure (34):

[0173] [Chem.34] Xh K H'" muo2c— / 3—s ca2Su (34)

[0174] (0.071 g, 0138 mmol) was dissolved in 25 mL of anhydrous acetonitrile and the Potassium carbonate (0.038 g, 0.276 mmol) was added. After 5 minutes of stirring, 2-(chloromethyl)-6-(l-hydroxy-4,4,5,5-tetramethylimidazol-2-yl)pyridine (6th synthesis step) (0.038 g, 0.138 mmol) and potassium iodide were added. (0.023 g, 0.138 mmol) were added, and the resulting reaction mixture was stirred for 48 hours under an argon atmosphere. The suspension was filtered through a filter funnel, and the filtrate was diluted in 5 mL of water. This solution was extracted with dichloromethane (3 x 15 mL). The organic phases were combined, dried with Na2SO4 and the solvents evaporated under vacuum to obtain 3-oxyl-4,4,5,5-tetramethyl-2-(6-((4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-l,4,7,10-tetraazacyclododecan-l-yl)methyl)pyridin-2-yl)-4,5-dihydro-lH-314-imidazol-l-olate as a purple solid (0.101 g, 97% yield) and with the following chemical structure (35):

[0175] [Chem.35] (35)

[0176] Characterization of 3-oxyl-4,4,5,5-tetramethyl-2-(6-((4,7,10-tris(2-(tert-butoxy)-2-ox oethyl)-1,4,7,10-tetraazacyclododecan-l-yl)methyl)pyridin-2-yl)-4,5-dihydro-lH-314-imidazol-l-olate: High-resolution mass spectrometry - electron spray ionization m / z calculated for C39H67O8N7 [M+H]+ 761.5046, found at 761.5045. Infrared spectrum (cm', pure): 2975, 2930, 2850, 1724, 1367, 1153, 1101. Electron paramagnetic resonance (EPR) (MeCN): Isotropic 5-line nitroxide signal at g = 2.00, ANi = AN2 = 0.7 mT.

[0177] 8 6016 step: Synthesis of 3-hydroxy-4,4,5,5-tetramethyl-2-(6-((4,7,10-tris(2-(tert- butoxy)-2-oxoethyl)-l,4,7,10-tetraazacyclododecan-l-yl)methyl)pyridin-2-yl)-4,5-d ihydro-1 H-314-imidazol-1 -olate

[0178] The protected ligand 3-oxyl-4,4,5,5-tetramethyl-2-(6-((4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-l-yl)methyl)pyridin-2-yl)-4,5-dihydro-lH-314-imidazol-1-olate (7th synthesis step) (0.101 g, 0.133 mmol) was dissolved in 14 mL of dichloromethane and 2 mL of anhydrous trifluoroacetic acid were added to the reaction mixture to obtain a yellow solution, which was kept under stirring overnight. The trifluoroacetic acid was withdrawn under vacuum to obtain an oily solution, which was The solution was dissolved in dichloromethane and evaporated. This process was repeated three times, also using methanol, to eliminate all traces of trifluoroacetic acid. The oily residue was then dissolved in a minimal amount of methanol and precipitated with the addition of diethyl ether. The resulting solution was decanted, and excess solvent was removed using a Pasteur pipette. The solid thus obtained was dried under vacuum to obtain a compound which was purified by size exclusion chromatography on a Sephadex LH-20 column to obtain 3-hydroxy-4,4,5,5-tetramethyl-2-(6-((4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)methyl)pyridin-2-yl)-4,5-dihydro-1H-314-imidazol-1-olate (0.067 g, 83%) in the form of a yellow powder and of the following chemical structure (36):

[0179] [Chem.36] (36)

[0180] This was ligand 1. Two tautomeric forms are accessible for ligand 1, one showing the α-iminohydroxylamine function (left) and the other the α-aminonitrone function (right). The predominant form depends on the analytical solvent, and the equilibrium is reversible. We will describe only the form observed under our analytical conditions.

[0181] Characterization of the 3-hydroxy-4,4,5,5-tetramethyl-2-(6-((4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-l,4,7,10-tetraazacyclododecan-l-yl)methyl)pyridin-2-yl)-4,5-dihydro-lH-314-imidazol-l-olate: 'H NMR (500 MHz, D2O) ô / ppm = 8.22 (d, 3JH H = 8Hz, 1H, CHpyr), 8.13 (d, 3JH H =8Hz, 1H, CHpyr), 8.04 (t, 3JH H =8Hz, 1H, CHpyr), 4.08 (s, 2H, Ncycien-CH2-Npyr), 3.90 (s, 1H), 3.53-3.30 (br, 6H) 3.25-2.89 (br, 16H), 1.46 (d,3J HH = 6Hz, 12H). 13C NMR (125 MHz, D2O) δ / ppm = 174.4, 169.8, 163.3, 163.1, 162.8, 162.5, 159.9, 140.2, 139.5, 130.1, 125.8, 117.5, 115.2 112.8, 74.4, 66.0, 63.9, 58.2, 57.4, 56.2, 55.8, 53.4, 53.2, 51.6, 51.3, 50.4, 49.0, 48.0, 47.8, 42.3, 21.7, 18.0, 16.8. High-resolution mass spectrometry - ionization by electron fogger m / z calculated for C27H44O7N7 [M+H]+ 578.3297, found at 578.3275. Infrared spectrum (cm1, pure): 2990, 1673, 1399, 1173, 1124, 799, 719.

[0182] Step 9: Synthesis of the 1st gadolinium complex with chemical structure (A):

[0183] The ligand 1 (50 mg, 0.086 mmol) as described above was mixed with a salt gadolinium trifluoromethanesulfonate (52 mg, 0.086 mmol) was dissolved in 10 mL of water at a pH adjusted to 7 by adding a sodium hydroxide solution (0.5 mol / L). The resulting reaction mixture was maintained at 50°C for 48 hours. The complex was then purified by size-exclusion chromatography on a Sephadex LH-20 column to obtain 30 mg of the first gadolinium complex with a yield of 48%.

[0184] Characterization of the 1 a gadolinium complex of chemical structure (A): High-resolution mass spectrometry- ionization by electron spray m / z calculated for C27H41O7N7EU [M+H]+, 728.2277 found at 728.2265. Infrared spectrum (cm1, pure): 3379, 3259, 2980, 2870, 1587, 1448, 1394, 1320, 1239, 1085, 1005, 935, 906, 837.717.

[0185] Fig. 1 schematically details all the synthesis steps described above up to obtaining the first gadolinium complex of chemical structure (A).

[0186] Results obtained with the 1 H gadolinium complex of chemical structure (A)

[0187] The relaxivity of the 1st gadolinium complex was monitored as a function of pH. The relaxivity of this 1st gadolinium complex increases from +200% (at a frequency of 30 MHz) to +250% (at a frequency of 0.11 MHz) when the pH decreases from 7.9 to 6.25.

[0188] This result is explained by the fact that hydroxylamine protonates, decoordinating and leaving space for two water molecules in the coordination sphere. The pKa of the first gadolinium complex was determined from relaxometric data and is 7.07.

[0189] Thus, at a pH lower than this pKa, the hydroxylamine in this first gadolinium complex is in protonated form. The arm containing the hydroxylamine is uncoordinated, thus leaving space for water molecules in the coordination sphere. The value of Lest is high.

[0190] At a pH above this pKa, the hydroxylamine, and more specifically the α-iminohydroxylamine function, is in the zwitterionic form α-aminonitrone. The nitrone arm is coordinated, thus displacing water molecules into the coordination sphere. The ri value is low.

[0191] The [Fig.2] represents the 1st gadolinium complex of chemical structure (A) depending on whether the pH is lower or higher than the pKa.

[0192] The toxicity of the first gadolinium complex was evaluated against the M21 (melanoma) cell line. No toxicity was observed, even after 72 hours of incubation and using a high concentration of 40 pM.

[0193] Synthesis of 2 — gadolinium complex:

[0194] The 2nd gadolinium complex of chemical structure (B) as detailed above was synthesized according to the steps detailed below:

[0195] Synthesis steps 1 to 6 were identical to those of the 1st gadolinium complex.

[0196] 7 — step: synthesis of 3-hydroxy-4,4,5,5-tetramethyl-2-(6-((4,10-tris(2-(tert- butoxy)-2-oxoethyl)-10-prop-2-ynyl-l,4,7,10-tetraazacyclododecan-l-yl)methyl)pyridi n-2-yl)-4,5-dihydro-lH-314-imidazol-l-olate

[0197] Potassium carbonate (378 mg, 2.74 mmol) and potassium iodide (151 mg, 1.00 mmol) were added to a 50 mL solution of acetonitrile containing: - 1,7-bis(tert-butoxycarbonylmethyl)-4-prop-2-ynyl-1,4,7,10-tetreazacyclododecane (400 mg, 0.91 mmol) and whose chemical structure (37) is as follows:

[0198] [Chem.37] , v —CO, ZV / - (37) and of - 2-(chloromethyl)-6-(l-hydroxy-4,4,5,5-tetramethyl-imidazol-2-yl)pyridine (6th step of synthesis of the 1st gadolinium complex) (285 mg, 1.00 mmol).

[0199] The resulting purple reaction mixture was maintained at 60°C overnight. The solution turned yellow, indicating the decomposition of the nitronyl nitroxide radical. Inorganic matter was removed from the solution by filtration, and the solvent was evaporated under reduced pressure. The residues were dissolved in a 3 mol / L sodium hydroxide solution, then extracted three times with 40 mL of dichloromethane and dried with Na₂SO₄. The solvent was evaporated under reduced pressure to obtain 3-hydroxy-4,4,5,5-tetramethyl-2-(6-((4,10-tris(2-(tert-butoxy)-2-oxoethyl)-10-prop-2-ynyl-l,4,7,10-tetraazacyclododecan-l-yl)methyl)py ridin-2-yl)-4,5-dihydro-lH-314-imidazol-l-olate whose chemical structure (38) is as follows:

[0200] [Chem.38] iBuO^C —zs' (38)

[0201] Characterization of 3-hydroxy-4,4,5,5-tetramethyl-2-(6-((4,10-tris(2-(tert-butoxy)-2-oxoethyl)-10-prop-2-ynyl-1,4,7,10-tetraazacyclododecan-l-yl)methyl)pyridin-2-yl)-4,5-dihydro-lH-314-imidazol-1-olate: High-resolution mass spectrometry-spray ionization m / z calculated for C36H59O7N5 [M+H]+ 669.45, found at 669.48. Electron paramagnetic resonance (EPR) (MeCN): Isotropic 5-line nitroxide signal at g = 2.00, AM = 1.0 mT and AN2 = 0.5 mT.

[0202] 8 — step: synthesis of 3-oxyl-4,4,5,5-tetramethyl-2-(6-((4,10-tris(2-(tert-butoxy)-2- oxoethyl)-10-prop-2-ynyl-l,4,7,10-tetraazacyclododecan-l-yl)methyl)pyridin-2-yl)-4,5-dihydro-lH-314-imidazol-1-olate

[0203] The protected ligand 3-hydroxy-4,4,5,5-tetramethyl-2-(6-((4,10-tris(2-(tert-butoxy)-2-oxoethyl)-10-prop-2-ynyl-1,4,7,10-tetraazacyclododecan-l-yl)methyl)pyridin-2-yl)-4,5-dihydro-lH-314-imidazol-1-olate (previous synthesis step) (0.138 g, 0.206 mmol) was dissolved in 20 mL of dichloromethane and 4 mL of anhydrous trifluoroacetic acid were added to the reaction mixture. The resulting yellow solution was kept under stirring overnight and the trifluoroacetic acid was removed under vacuum to obtain an oily solution, which was dissolved in dichloromethane and evaporated. This operation was performed three times and repeated with methanol to eliminate all traces of trifluoroacetic acid. The oily residue was then dissolved in a minimal amount of methanol and precipitated with the addition of diethyl ether. The resulting solution was decanted, and excess solvent was removed using a Pasteur pipette.The solid thus obtained was dried under vacuum to obtain 0.123 g (yield of 98%) of 3-oxyl-4,4,5,5-tetramethyl-2-(6-((4,10-tris(2-(tert-butoxy)-2-oxoethyl)-10-prop-2-ynyl-1,4,7,10-tetraazacyclododecan- l-yl)methyl)pyridin-2-yl)-4,5-dihydro-lH-314-imidazol- 1-olate in the form of a yellow powder and whose chemical structure (39) is as follows: .

[0204] [Chem.39] — -- UjL—' (39)

[0205] This was ligand 2. It contains an alkyne group intended to be post-functionalized by Huigsden cycloaddition. As with ligand 1, two tautomeric forms are accessible for ligand 2, one showing the α-iminohydroxylamine group (left) and the other the α-aminonitrone group (right). The predominant form depends on the analytical solvent, and the equilibrium is reversible. We will describe only the form observed under our analytical conditions.

[0206] Characterization of 3-oxyl-4,4,5,5-tetramethyl-2-(6-((4,10-tris(2-(tert-butoxy)-2-oxoe thyl)-10-prop-2-ynyl-l,4,7,10-tetraazacyclododecan-l-yl)methyl)pyridin-2-yl)-4,5-dihydro-lH-314-imidazol-l-olate: 'H NMR (500 MHz, MeOD) ô / ppm = 8.43 (dd.3 JH H = 8Hz, 1H, CH-pyr), 8.15 (t, 3JH H = 8Hz, 1H, CH-pyr), 7.90 (d, 3JH H =8Hz, 1H, CH-pyr), 4.03 (s, 2H, Ncycien-CH2-Npyr), 3.59-2.71 (br, 23H (CH2-cyclen, CH2-CO2H, CH-alkyne, and CH2-alkyne)), 1.47 (s, 12H, CH3-imidazole). High-resolution mass spectrometry - electron spray ionization m / z calculated for C28H4457N7 [M+H]+ 558.33984, found at 558.33856. Infra-red spectrum (cm1, pure): 3079, 2989, 2924, 2852, 2325, 1668, 1569,1456, 1419, 1401, 1371, 1178, 1125, 997, 875, 832, 798, 719, 701.

[0207] 9 — step: Synthesis of the 2nd gadolinium complex with chemical structure (B):

[0208] The ligand 2 (40 mg, 0.072 mmol) as described above was mixed with a salt gadolinium trifluoromethanesulfonate (43.3 mg, 0.072 mmol) was dissolved in 10 mL of water at a pH adjusted to 7 by adding a sodium hydroxide solution (0.5 mol / L). The resulting reaction mixture was maintained at 50°C for 48 hours. The complex was then purified by size-exclusion chromatography on a Sephadex LH-20 column to obtain 54 mg of the second gadolinium complex with a yield of 93%.

[0209] Fig. 3 schematically details all the synthesis steps described above up to obtaining the 2nd gadolinium complex of chemical structure (B).

[0210] Characterization of the 2 — gadolinium complex of chemical structure (B): High-resolution mass spectrometry - ionization by electron spray m / z calculated for C28H4iGdO7N5 [M+H]+, 713.24 found at 713.21. Infrared spectrum (cm', pure): 3331, 2983, 2911, 2867, 1685, 1594, 1481, 1435, 1395, 1256, 1208, 1169, 1230, 1081, 1035, 860, 836, 800, 724, 640.

[0211] Results obtained with the 2-gadolinium complex of chemical structure (B)

[0212] The relaxivity of the 2nd gadolinium complex was monitored as a function of pH. It also exhibited a significant variation in relaxivity with pH, ​​ri=2.7 mM 1 s 1 at pH 8.5 and l=7.2 mM 1 s 1 at pH=5.8.

[0213] The toxicity of the second gadolinium complex with chemical structure (B) was evaluated against the M21 cell line (melanoma). Very low toxicity (90% survival) was observed, but only at the highest concentration tested (40 pM) and over time exceeding 48 hours.

Claims

Demands

1. Contrast agent, characterized in that it comprises at least one gadolinium compound in an effective amount and which is selected from the group consisting of compounds (1) to (12) of the following chemical structures: [Chem.2] (2) [Chem. 3] [Chem.4] R / \ y X** / X (4) [Chem. 5] (5) [Chem.6] xx x V * «A / X / —X. J | XX Xx X ï (Gd):> x —..-X ,xx' N's 'x R""" yy (6) [Chem.7] [Chem. 8] (8) [Chem.9] R (9) [Chem. 10] [Chem. 11] y (ii) [Chem. 12] (12) in which: - x independently represents a hydrogen or an alkyl group in Ci-C2 which is optionally substituted by a hydroxyl, amine, ether group, preferably x represents a hydrogen or a methyl group; - an R is a group chosen from -(CH2)n-Gl to -(CH2)n-G8 in which n is equal to 1 or 2 and the chemical structures of groups G1 to G8 are defined below; - the remaining Rs being chosen independently of each other from: -(CH2)nA with n equal to 1 or 2 and A is a group selected from the following groups: carboxylate, C2-C4 alkynyl, ester, alkylcarboxylate, alkylamide, amide, amine, alkylamine, phosphonate, alkylphosphonate, hydroxyl, alkylhydroxyl, ether, sulfonate, triazole, thiolate, thioether, and thiocyanate, or A is a chemical motif configured to vector said gadolinium compound and / or to modulate the physicochemical properties of said gadolinium compound; as well as the following groups of chemical structures (13) to (17): [Chem. 13] (13); [Chem. 14] (14); [Chem. 15] (15); [Chem. 16] (16); [Chem. 17] (17); in which Xn is a hydrogen or a chemical motif configured to vector said gadolinium compound, - Y independently represents a hydrogen or an alkyl group in C1-C4 which is optionally substituted by at least one group chosen from among the carboxylate, ester, alkylcarboxylate, alkylamide, amide, amine, alkylamine, phosphonate, alkylphosphonate, hydroxyl, alkylhydroxyl, ether, sulfonate, triazole, thiolate, thioether or thiocyanate groups; - Z independently represents a hydrogen, a halogen, a hydroxyl, an ether, an alkyloxy, a cyano, a nitro, a sulfonate, a trifluoromethyl or a C1-C4 alkyl group which is optionally substituted by at least one group chosen from the following groups: carboxylate, ester, alkylcarboxylate, alkylamide, amide, amine, alkylamine, phosphonate, alkylphosphonate, hydroxyl, alkylhydroxyl, ether, sulfonate, triazole, thiolate, thioether or thiocyanate; and groups G1 to G8 respectively have the following chemical structures: [Chem. 18] (Gl) in which: gll to g 13 independently represent a hydrogen, halogen, hydroxyl, ether, alkyloxy, cyano, nitro, sulfonate, trifluoromethyl or a C1-C4 alkyl group which is optionally substituted by at least one group selected from the following groups: carboxylate, ester, alkylcarboxylate, alkylamide, amide, amine, alkylamine, phosphonate, alkylphosphonate, hydroxyl, alkylhydroxyl, ether, sulfonate, triazole, thiolate, thioether or thiocyanate; g 14 to g 17 independently represent a hydrogen, a methyl or ethyl group; [Chem. 19] (G2) in which: g21 represents a hydrogen, hydroxyl or alkyl group in C1-C4 which is optionally substituted by a hydroxyl, amine, triazole, ether or amide group; g22 represents CH2, oxygen, nitrogen, sulfur or a C1-C4 alkyl group optionally substituted by a hydroxyl, amine, triazole, ether or amide group; or g21 represents CH2, whose carbon is directly connected to g22, which represents CH. g23 to g26 independently represent a hydrogen, a methyl or ethyl group; [Chem.20] (G3) in which: g31 represents a hydrogen, hydroxyl or alkyl group in C1-C4 which is optionally substituted by a hydroxyl, amine, triazole, ether or amide group; g32 represents CH, CH2, oxygen, nitrogen, sulfur or a C1-C4 alkyl group which is optionally substituted by a hydroxyl, amine, triazole, ether or amide group; or g31 represents CH2 whose carbon is directly connected to g32 which represents CH; g34 represents a hydrogen, an amine, an imine, a hydroxyl, a C1-C4 alkyl or acyl group, said alkyl or acyl group being optionally substituted by a hydroxyl, amine, triazole, ether or amide group; g35 represents a hydrogen, hydroxyl, alkyl or acyl group in C1-C4, said alkyl or acyl group being optionally substituted by a hydroxyl, amine, triazole, ether or amide group; or g34 represents a Ci-C2 alkyl or alkylamine group with one carbon directly connected to g35 which represents a CrC2 alkyl group; [Chem.21] in which: g41 represents a hydrogen, hydroxyl or alkyl group in C1-C4 which is optionally substituted by a hydroxyl, amine, triazole, ether or amide group; g42 represents CH3, oxygen, nitrogen, sulfur or a C1-C4 alkyl group which is optionally substituted by a hydroxyl, amine, triazole, ether or amide group; or g41 represents CH2 whose carbon is directly connected, or connected via a methyl group, to g42 which represents CH2; g43 represents a hydrogen, an imine, an amine, a hydroxyl, a C1-C4 alkyl or acyl group, said alkyl or acyl group being optionally substituted by a hydroxyl, amine, triazole, ether or amide group; g44 represents a hydrogen, a hydroxyl, an alkyl or acyl group in C1-C4, said alkyl or acyl group being optionally substituted by a hydroxyl, amine, triazole, ether or amide group; or g43 represents a Ci-C2 alkyl or alkylamine group with one carbon directly connected to g44 which represents a Ci-C2 alkyl group; g45 represents a hydrogen, a hydroxyl, an alkyl or acyl group in C1-C4, said alkyl or acyl group being optionally substituted by a hydroxyl, amine, ether or amide group; or g44 represents an alkyl or alkylamine group in Ci-C2, one carbon of which is directly connected to g45, which represents an alkyl group in CrC2; [Chem.22] 952 (G5) g52 independently represents a hydrogen, halogen, hydroxyl, ether, alkyloxy, cyano, nitro, sulfonate, trifluoromethyl, alkyl or a C1-C4 alkyl group that is optionally substituted by at least one group selected from the following groups: carboxylate, ester, alkylcarboxylate, alkylamide, amide, amine, alkylamine, phosphonate, alkylphosphonate, hydroxyl, alkylhydroxyl, ether, sulfonate, triazole, thiolate, thioether or thiocyanate; g51 and g53 independently represent a hydrogen, halogen, hydroxyl, ether, alkyloxy, cyano, nitro, sulfonate, trifluoromethyl or an alkyl CrC4 group which is optionally substituted by at least one group selected from the following groups: carboxylate, ester, alkylcarboxylate, alkylamide, amide, amine, alkylamine, phosphonate, alkylphosphonate, hydroxyl, alkylhydroxyl, ether, sulfonate, triazole, thiolate, thioether, or thiocyanate; or g52 is connected to g51 or g53 so as to form a C2-C3 carbon chain; g54 represents a hydrogen, an imine, an amine, a hydroxyl, a C1-C4 alkyl or acyl group, said alkyl or acyl group being optionally substituted by a hydroxyl, amine, triazole, ether or amide group; g55 represents a hydrogen, hydroxyl, alkyl or acyl group in C1-C4 optionally substituted by a hydroxyl, amine, triazole, ether, amide or alkyl group in Ci-C2 directly connected to g54; or g54 represents an alkyl or alkylamine group in Ci-C2, one carbon of which is directly connected to g55, which represents an alkyl group in CrC2; [Chem.23] (G6) in which: g61 represents a C1-C4 alkyl group that is optionally substituted by a hydroxyl, amine, triazole, ether or amide group; g62 represents a C1-C4 alkyl group that is optionally substituted by a hydroxyl, amine, triazole, ether or amide group; or g62 represents CH2 whose carbon is directly connected to g61 which represents CH; g63 to g66 independently represent a hydrogen, a methyl or ethyl group; [Chem.24] your (G7) in which: g71 represents a hydrogen, a hydroxyl, an alkyl group in Cr C4 which is optionally substituted by a hydroxyl, amine, triazole, ether or amide group; g72 represents a C1-C4 alkyl group that is optionally substituted by a hydroxyl, amine, triazole, ether or amide group; or g71 represents CH2 whose carbon is directly connected to g72 which represents CH2; g73 represents a hydrogen, an imine, an amine, a hydroxyl, an alkyl or acyl group in CrC4, said alkyl or acyl group being optionally substituted by a hydroxyl, amine, triazole, ether or amide group; g74 represents a hydrogen, hydroxyl, alkyl or acyl group in CrC4, said alkyl or acyl group being optionally substituted by a hydroxyl, amine, triazole, ether or amide group; or g73 represents an alkyl or alkylamine group in CrC2 of which one carbon is directly connected to g74 which represents an alkyl group in Ci-C2; g75 represents a hydrogen, a hydroxyl, an alkyl or acyl group in CrC4, said alkyl or acyl group being optionally substituted by a hydroxyl, amine, ether or amide group; [Chem.25] (G8) in which: g81 represents a Ci-C4 alkyl group that is optionally substituted by a hydroxyl, amine, triazole, ether or amide group; g82 represents a hydrogen or a CrC4 alkyl group that is optionally substituted by a hydroxyl, amine, triazole, ether or amide group; or g82 represents CH2 whose carbon is directly connected to g81 which represents CH; g84 represents a hydrogen, an imine, an amine, a hydroxyl, an alkyl or acyl group in Ci-C4, said alkyl or acyl group being optionally substituted by a hydroxyl, amine, triazole, ether or amide group; g85 represents a hydrogen, a hydroxyl, an alkyl or acyl group in Ci-C4 which is optionally substituted by a hydroxyl, amine, triazole, ether or amide group; or g84 represents an alkyl or alkylamine group in Ci-C2 whose carbon is directly connected to g85 which represents an alkyl group in CrC2.

2. Contrast agent according to claim 1, characterized in that in compounds (1) to (12) an R is a -(CH2)n-Gl group in which n is equal to 1 or 2, preferably n is equal to 1.

3. Contrast agent according to claim 2, characterized in that in group G1gll to g13 are selected from hydrogen, C1-C4 alkyl groups and halogens and g14 to g17 are selected from methyl or ethyl groups.

4. Contrast agent according to claim 3, characterized in that in group G1 gll to gl3 are hydrogens and gl4 to gl7 are methyl groups.

5. Contrast agent according to any one of claims 1 to 4, characterized in that in compounds (1) to (12) among the remaining Rs: - one R is a group selected from -(CH2)nA with n equal to 1 or 2, preferably n equal to 1, and A is a chemical motif configured to vector said gadolinium compound and / or modulate the physicochemical properties of said gadolinium compound, and - the other remaining R(s) is / are selected from -(CH2)nA with n equal to 1 or 2, preferably n equal to 1, and A is a group selected from the following groups: carboxylate, C2-C4 alkynyl ester, alkylcarboxylate, alkylamide, amide, amine, alkylamine, phosphonate, alkylphosphonate, hydroxyl, alkylhydroxyl, ether, sulfonate, triazole, thiolate, thioether, and thiocyanate.

6. Contrast agent according to any one of claims 1 to 5, characterized in that it comprises at least one selected compound among compounds (1), (3), (5), (7) and (9), preferably among compounds (1), (3) and (5).

7. Contrast agent according to any one of claims 1 to 6, characterized in that it comprises at least compound (1).

8. Contrast agent according to claim 7, characterized in that the Xs of said compound (1) independently represent a hydrogen or a methyl group, preferably hydrogens.

9. Contrast agent according to claim 7 or 8, characterized in that in compound (1) an R is a -(CH2)n-Gl group in which n is equal to 1 or 2, preferably n is equal to 1.

10. Contrast agent according to claim 9, characterized in that in group G1gll to g13 are selected from hydrogen, C1-C4 alkyl groups and halogens and g14 to g17 are selected from methyl or ethyl groups.

11. Contrast agent according to claim 10, characterized in that in group G1 gll to gl3 are selected from hydrogen and methyl or ethyl groups and g 14 to g 17 are selected from methyl or ethyl groups.

12. Contrast agent according to claim 11, characterized in that in group G1 gll to gl3 are hydrogens and gl4 to gl7 are methyl groups.

13. Contrast agent according to any one of claims 9 to 12, characterized in that in compound (1) the remaining R groups are -(CH2)nA with n equal to 1 or 2, preferably n equal to 1 and A is a group selected from the following: carboxylate, C2-C4 alkynyl, ester, alkylcarboxylate, alkylamide, amide, amine, alkylamine, phosphonate, alkylphosphonate, hydroxyl, alkylhydroxyl, ether, sulfonate, triazole, thiolate, thioether and thiocyanate.

14. Contrast agent according to claim 13, characterized in that in compound (1) at least 2 of the remaining Rs are (CH2)nA groups with n equal to 1 or 2, preferably n equals 1 and A is a carboxylate.

15. Contrast agent according to claim 14, characterized in that in compound (1) the remaining 3 Rs are all (CH2)nA groups with n equal to 1 or 2, preferably n equals 1 and A is a carboxylate.

16. Contrast agent according to claim 14, characterized in that in compound (1) 2 of the remaining Rs are (CH2)nA groups with n equal to 1 or 2, preferably n equals 1 and A is a carboxylate and the 3rd of the remaining Rs is a (CH2)nA group with n equal to 1 or 2, preferably n equals 1 and A is an ethyne.

17. Contrast agent according to any one of claims 9 to 12, characterized in that in compound (1) one of the remaining Rs is a group selected from -(CH2)nA with n equal to 1 or 2, preferably n equal to 1, and A is a chemical motif configured to vector said gadolinium compound and / or modulate the physicochemical properties of said gadolinium compound, and the other two remaining Rs are selected from -(CH2)nA with n equal to 1 or 2, preferably n equal to 1, and A is a group selected from the following groups: carboxylate, C2-C4 alkynyl, ester, alkylcarboxylate, alkylamide, amide, amine, alkylamine, phosphonate, alkylphosphonate, hydroxyl, alkylhydroxyl, ether, sulfonate, triazole, thiolate, thioether, and thiocyanate, preferably the other two Rs remaining are chosen from -(CH2)nA with n equal to 1 or 2, preferably n equal to 1 and A is a carboxylate or an ethyne.

18. Contrast agent according to claim 7, characterized in that it comprises at least one gadolinium compound selected from the gadolinium compounds of the following chemical structures (A) and (B): [Chem.27] k / \ .X + —YYN ( cô, y jV asc— / —cos (A) [Chem.28]. V. -V' ;n-° NX^^ y—cô2 .XK* Nf" pp / ' (B)

19. A method for acquiring medical imaging images, characterized in that it comprises: - administering a contrast agent according to any one of claims 1 to 18 to a patient, - acquiring images by a medical imaging technique.

20. Contrast agent according to any one of claims 1 to 18 for its use in the diagnosis of tissue acidosis.

Images