DIAGNOSTIC AGENT FOR NUCLEAR MAGNETIC RESONANCE IMAGING (MRI): CARBOHYDRATE DERIVATIVE LABELED WITH STABLE CARBON-13 ISOTOPES FOR THE IN VIVO STUDY OF NORMAL AND PATHOLOGICAL METABOLISM

Abstract

The present invention relates to a deoxyglucose, comprising at least one carbon-13 isotope, as a medicinal product intended for use in a quantitative and / or qualitative diagnostic method for conditions, diseases, pathologies, syndromes, or disorders in the body of a subject, said diagnostic method being in vivo and employing nuclear magnetic resonance, and said carbon-13 isotope not directly bonded to deuterium. The present invention also relates to a composition, chemical formulation, and / or pharmaceutical formulation comprising at least one deoxyglucose according to the invention, as well as a kit comprising, on the one hand, any commercially manufactured form, pharmaceutical formulation suitable for any administration to a subject regardless of the route of administration, containing one or more deoxyglucoses according to the invention. Finally, the present invention relates to a diagnostic method using a composition according to the invention. (Fig. 2)

Description

Title of the invention: Diagnostic agent for nuclear magnetic resonance imaging (MRI): carbohydrate derivative labeled with stable isotopes of carbon 13 for the in vivo study of normal and pathological metabolism.

[0001] This invention relates to the use of 2-deoxyglucose and / or 2-fluoro-2-deoxyglucose molecules (also known by the respective names 2-deoxyglucose, 2-deoxyglucose, 2-deoxyglucose, 2-DG and 2-fluoro-2-deoxyglucose, 2-fluoro-2-deoxyglucose, 2-flu-2-deoxyglucose, fludeoxyglucosi, 2-FDG) labeled with stable carbon isotopes such as carbon-13, as well as their associated derivatives and metabolites, and their uses in the field of nuclear magnetic resonance (NMR) and associated biomedical techniques such as Nuclear Resonance Imaging (MRI), Nuclear Magnetic Resonance Spectroscopy (NMRS), and Nuclear Magnetic Resonance Spectroscopic Imaging (NMRS), coupled or not to other modalities biomedical imaging such as X-ray or computed tomography (CT), ultrasound, positron emission tomography (PET) or any other biomedical imaging modality for the diagnosis or evaluation of states, conditions,of disorders, diseases, pathologies or syndromes in the body of a subject. FIELD OF INVENTION

[0002] The present invention relates to a contrast agent for magnetic resonance imaging (MRI) for the functional exploration of pathological and normal cellular glucose metabolism and its method of detection in living organisms. The contrast agent is deoxyglucose and fluorodeoxyglucose, in which certain carbon-12 atoms are substituted at different positions by carbon-13 atoms, as described herein. The in vivo magnetic resonance imaging method comprises (i) administering one or more agents, the chemical formula of which is detailed herein, to a sample or individual; and (ii) detecting magnetic resonance signals from the sample or individual.The present invention relates to carbon-13 labeled deoxyglucose and fluorodeoxyglucose, kits comprising them and associated uses in magnetic resonance imaging, for use in the quantitative, semi-quantitative and qualitative diagnosis or evaluation of states, conditions, disorders, diseases, pathologies or syndromes in the body of a subject. State of the art

[0003] Fluorine-18 labeled 2-fluoro-2-deoxyglucose (18F-FDG) has been widely used in human medicine for diagnostic purposes for over 30 years. This radioactive drug is injected into humans and detected by Positron Emission Tomography (PET), thus creating an image of the distribution of this product throughout the patient's / subject's whole body. PET is a highly developed medical imaging modality that may or may not be combined with a CT scan. More recently, this imaging modality can also be combined with MRI. Millions of 18F-FDG PET scans are performed worldwide each year.

[0004] The current limitations of using 18F-FDG in a PET scan are as follows: Ionizing radiation from the decay of fluorine-18 exposes patients / subjects receiving the radiation, as well as paramedical and medical staff, and all personnel involved in the procedure. This use of ionizing radiation is particularly harmful to children and pregnant women. Furthermore, it necessitates that this type of examination be performed based on a documented benefit / risk assessment for each examination (the principle of justification, optimization, and limitation in radiation protection). Therefore, the use of this type of examination is not systematic, and the number of examinations for any given patient is limited. This constraint prevents performing as many procedures as necessary for monitoring a condition (remission, relapse), tracking therapeutic treatment, or for the early diagnosis of a disease (exposure to ionizing radiation is not always justified). - The spatial resolution of images from PET is lower than that of other whole-body imaging techniques such as MRI or CT (on the order of 2 to 4 mm). The availability of the most commonly used isotope, fluorine-18 (18F), limits the use of 18F-FDG PET scans. This isotope is produced using a cyclotron, has a half-life of 119 minutes, and must therefore be transported to the nuclear medicine department within hours of its production. In other words, no storage of the radiopharmaceutical is possible. Production is thus carried out daily, several times a day, using radiochemical processes that must be highly reproducible and automated due to the high radioactivity required for the production of the radiotracer. This production takes place at night in a suitable environment. Therefore, providing sterile pharmaceutical forms is a real daily challenge for manufacturers. - A “race against time” due to the isotope's half-life, both for the imaging department and patients, with delays potentially leading to exam cancellations due to insufficient activity. In the event of a prolonged technical incident, exams must be postponed due to a lack of available radioactive tracer. - The cost of equipment, radiation protection requiring significant lead shielding for the attenuation of high energy ionizing radiation (511 keV) throughout the chain from the producer to the imaging service: shielding of buildings, preparation enclosures, equipment for injection. - Very cumbersome legislation to apply for proper management of the risks inherent in the handling of radioactivity in the medical field.

[0005] Despite these limitations, 18F-FDG PET scans are now irreplaceable in the medical management of a wide range of diseases. This examination has demonstrated significant value, particularly in the field of oncology. The interest in this examination stems primarily from the metabolic pathway used in vivo by 18F-FDG. Deoxyglucose and fluorodeoxyglucose are glucose analogs with metabolic impasses that mimic the biodistribution of physiological glucose. These molecules enter cells via the same transporters as glucose; these are transmembrane proteins of the GLUT (Glucose Transporter) family. Many states, conditions, diseases, and / or syndromes lead to increased glucose uptake compared to a normal physiological state. This increased uptake reflects an increased need for glucose to meet additional energy demands.This increased energy requirement is particularly noticeable in cases of neoplasia (cancerous processes with increased cell division) or inflammation. An increase in the GLUT-1 and GLUT-3 isoforms of these transporters has been most frequently reported in this process. After entering the cell, deoxyglucose, 2-fluorodeoxyglucose, and glucose follow the same metabolic pathway, which consists of phosphorylation by a hexokinase, a glycolytic enzyme; this is the first metabolic step of glycolysis. Most often, increased GLUT expression is associated with increased expression of glycolytic enzymes due to an escalation of the glycolytic pathway. Thus, this metabolic shift is exploited and demonstrated through these glucose analogs, deoxyglucose and fluorodeoxyglucose. In order to detect these increases in glucose consumption, particularly in cancerous pathologies. In many states, specific conditions, pathologies, or syndromes, such an increase is observed in numerous locations (cardiac, cerebral, digestive, renal, etc.). Thus, 18F-FDG is taken up by cells via GLUTs and transformed into 18F-FDG-6-phosphate via hexokinase. Due to the absence of the hydroxyl group (-OH) at position 2 of glucose, 18F-FDG-6-phosphate undergoes virtually no further metabolism and is thus trapped in the cell cytosol. An accumulation of this metabolite is then observed, allowing its detection using PET imaging.

[0006] Numerous studies have demonstrated the direct beneficial impacts of 18F-FDG PET scans in the diagnosis and therapeutic monitoring of many neoplastic diseases affecting the lungs, breasts, ovaries, colorecta, esophagus, and lymphomas (non-exhaustive list). Furthermore, more recently, the level of 18F-FDG uptake has emerged as a marker for evaluating early response to antitumor treatment in many cancers. A growing body of research suggests that this examination has reliable prognostic value for predicting the progression of many neoplastic diseases.

[0007] Magnetic resonance imaging (MRI), nuclear magnetic resonance spectroscopy (NMRS), and nuclear magnetic resonance spectroscopy (NMRS) have become indispensable tools for over three decades in a wide variety of medical pathologies and / or syndromes. These are non-invasive techniques that do not use ionizing radiation, the main source of exposure dosimetry for the population. In simplified terms, MRI is based on the detection of nuclear signals following the application of an external magnetic field and specific radiofrequency (RF) waves. The magnetic field allows the alignment of nuclear spins along the axis of this field, thus causing a precessional movement (Larmor precession) whose frequency can be measured. The application of RF pulses of varying intensities, depending on the targeted nucleus (¹³H, ¹³C, etc.), is performed.The external magnetic field strength and the energetic excitation of the atomic nucleus of the targeted molecule allow for the modification of its precessional motions. These pulses are applied transiently and repeatedly from a radio frequency antenna. The abrupt cessation of these pulses causes the nuclei to return to their equilibrium state, previously initiated by the external magnetic field, resulting in the emission of "de-excitation" waves. These secondarily emitted radio frequency waves are described as relaxation waves, which are also detected by an antenna. These interactions are characterized by a relaxation time. These relaxation times depend on the environment of the excited nucleus, that is, the surrounding biological tissues and their viscosity (biological fluids, tissues, or organs). These signals are acquired tomographically, then filtered, transformed (Fourier), and processed by computer to reconstruct a spectrum or image. The nuclei for which such interactions are detectable are those with a non-zero quantum spin value (such as H, C, N, P), that is, a gyromagnetic moment compatible with the detection device (magnetic field and RF pulse). Furthermore, the applied external magnetic field can orient the magnetic nuclear spins in two possible directions: parallel or antiparallel.The net magnetization per unit volume, that is, the amount of signal that can be detected, will be proportional to the difference between these two population states, themselves dependent on their biophysical environment. Thus, proton MRI, classically used in routine clinical practice, produces signals based on the resonance of protons in water molecules; the resulting image is a function of the density of water molecules within a volume of interest.

[0008] The natural isotopic content of carbon 13 (13C) is 1.1% in nature. This relatively low abundance is actually considered a limiting factor for performing MRI / SRMN / ISRMN scans based on the detection of this nucleus. Furthermore, the gyromagnetic moment of carbon-13 is four times lower than that of the proton, which in turn reduces the sensitivity of detectable signals. Another limitation of 13C in MRI / SRMN / ISRMN comes from spin-spin coupling between carbon and neighboring atoms ("J coupling"). For example, a covalent bond between a hydrogen atom and a carbon-13 atom involves sharing electrons between these two atoms. The movement of these electrons within their orbitals will influence the energy level of the nuclear spins, thus modifying the Larmor resonance frequency. However, it is possible to use NMR sequences that overcome this coupling; such sequences are called decoupling sequences. There are many NMR sequences for the detection of 13C nuclei.These sequences define the time windows and the nature of the RF pulses leading to the excitation of atomic nuclei. These sequences can focus the analysis directly on the signals emitted by carbon-13 nuclei, on those emitted by C-H coupling, or even C-C coupling. The most commonly used sequences are (non-exhaustive list): DEPT (Distortionless Enhancement Polarization Transfer), HSQC (Heteronuclear Single Quantum Coherence), ADEQUATE, INADEQUATE (Incredible Natural Abundance Double Quantum Transfer Experiment), WALTZ... .

[0009] Carbon-13, as a stable isotope of carbon-12, has been administered to humans in numerous clinical studies. No clinical studies have yet been conducted with the administration of derivatives described in this document (2-[X-13Cy]deoxyglucose or 2-fluoro-[X-13Cy]deoxyglucose, whose respective abbreviations are nC-DG and 13C-FDG). In particular, no clinical studies have used the molecules 13 13 13 The following are examples: 2-[1-C]deoxyglucose, 2-[U-C6]deoxyglucose, 2-fluoro-[1-C]deoxyglucose, and 2-fluoro-[U-13C6]deoxyglucose. Studies have been conducted with carbon-13 labeled deoxyglucose derivatives combined with deuterium (2H) labeling. An international patent application exists in this field: WO 2012 / 056447 A1. The use of such products relates to the hyperpolarization technique, which is outside the scope of this document. In summary, as we have described, nuclear spins can be oriented parallel and antiparallel within a magnetic field. Under thermodynamic equilibrium conditions, there is an imbalance between these two states due to a non-equivalent energy level. Hyperpolarization accentuates this distributional imbalance between these two states, thus modifying the relaxation times of hyperpolarized molecules, which ultimately increases the amount of signal detected. Hyperpolarization can be summarized as a transfer of polarization to a molecule of biological interest that one wishes to track. Several hyperpolarization methods exist, for example, dynamic nuclear hyperpolarization (DNP) or that involving parahydrogen (para-2H). Generally, hyperpolarization requires the heating and / or microwave irradiation of transient chemical complexes (substances not labeled with carbon-13) which allows the transfer of polarization to the 13C-labeled molecule of interest. These chemical complexes are most often administered along with the biological molecule of interest in order to maintain the hyperpolar state in vivo.However, this hyperpolar state cannot be maintained for more than ten minutes at best (most often just a few minutes), so the signal must be detected during this time window. However, such a short delay does not allow for the identification of biological processes of interest whose kinetics extend beyond this short time window. Consequently, only biological processes with rapid kinetics or partial biological processes (i.e., their early phase not yet fully developed in vivo) can benefit from this technique. For 18F-FDG, the biodistribution phase, which allows for the reliable study of glucose metabolism, requires a delay of 30 minutes before images with useful clinical value can be acquired. This delay is among the recommendations of numerous learned societies for this type of examination worldwide. This delay includes the biodistribution phase, that is, the distribution phase. In the body, the molecule is transported via glucose transporters and undergoes biochemical transformation by hexokinase. In this case, hyperpolarization has very limited clinical relevance based on current knowledge. Therefore, the implementation of hyperpolarization techniques, compared to the use of non-hyperpolarized substrates, differs for those skilled in the art.

[0010] Thus, apart from hyperpolarization, an alternative way to increase the detection sensitivity of 13C is to increase the quantity of carbon-13 atoms present in a given volume and thereby increase its natural abundance. This increase can be achieved on the molecule of biological interest itself by substituting all the carbon-12 atoms with carbon-13 atoms. The second level is to administer higher quantities of the molecules of biological interest. This point is most often considered by those skilled in the art as a definitive limit for carbon-13 imaging, which explains why no study to date has considered the molecules described in this patent as in vivo diagnostic agents.Indeed, it is commonly reported in numerous studies using carbon-13 labeled molecules that the amount of molecule administered is too large, leading to biological disturbances that no longer reflect the physiological and / or pathological processes being studied. This administered quantity would thus disrupt the biochemical processes being investigated, creating an unusable artifact for diagnosis. Clearly, this assumption depends on the organ being visualized and the biochemical process being studied using the molecule of interest. For example, it has been described that glucose concentration in the brain is strictly linear and proportional to that of the plasma for concentrations up to 30 mmol / L.However, since nC-DG and 13C-FDG accumulate in cells, this "natural" accumulation helps to limit the quantities needed to obtain a signal with clinically relevant sensitivity. These factors form the basis of the present invention. Furthermore, recent technological innovations in MRI and ISMRN, in terms of magnetic fields (increased magnetic field strength for heavy clinical equipment), antennas (structure, surface area, impedance, etc.), computer processing (reconstruction, signal filtering, deconvolution, etc.), and atomic excitation sequences (ultrafast sequences, spin decoupling, etc.), also contribute to increased detection sensitivity.Thus, the method according to the invention makes it possible to avoid both hyperpolarization, currently considered the reference technique in imaging 13C-labeled substrates, and the large quantities required as suggested in the majority of scientific articles in the field.

[0011] Thus, the present invention takes advantage of the cellular accumulation capacity due to the metabolic deadlock of the deoxyglucose and fluorodeoxyglucose substrates. According to particular embodiments of the invention, it can also take advantage of the addition of numerous stable 13C isotopes within these chemical structures in varying proportions without resorting to hyperpolarization. Furthermore, the substitution of the entire carbon skeleton by 13C atoms increases the detection sensitivity of the method at the cost of a multiplication of resonance lines. The molecules [U-13C6]-deoxyglucose and 2-fluoro-[U-13C6]-2-deoxyglucose allow both improved sensitivity and the possibility of using variable detection NMR sequences (direct 13C, heteronuclear 13C-'H, homonuclear 13C-13C with or without prior uncoupling).These two molecules benefit from the least complex synthetic route due to the substitution of all carbon atoms, compared to the other derivatives described in this document where specific positions of the carbon skeleton have been substituted by carbon 13. The other molecules of major interest are [l-13C]-deoxy-glucose and 2-fluoro-[l-13C]deoxyglucose due to the adjacent position of the 13C atom relative to the oxygen atom, as well as [6-13C]-deoxy-glucose and 2-fluoro-[6-13C]deoxy-glucose due to the position of the carbon 13 atom outside the chemical ring in the hemiacetal form of the molecule.

[0012] The field of the invention is to provide non-radioactive, non-hyperpolarized, carbon-13 labeled compounds enabling the diagnosis or evaluation of states, conditions, disorders, diseases, pathologies or syndromes in the body of a subject to be carried out in a clear, rapid and safe manner by means of MRI, SRMN, ISRMN, PET-MRI techniques based on the direct or indirect detection of signals from the 13C nucleus by means of nuclear magnetic resonance.

[0013] Regarding the issue of the mass density of the 13C-DG and 13C-FDG molecules as described below, necessary for obtaining satisfactory signals, which, from the perspective of a person skilled in the art, would be an insurmountable difficulty for the intended applications, the inventor surprisingly found that this difficulty could be resolved. Cellular glucose transport is ensured by a family of proteins described under the term GLUT (Glucose Transporter). For example, the GLUT-1 transporter is the predominant transporter at the blood-brain barrier (The glucose transporter of the human brain and blood-brain barrier, Ann Neurol, 1988, 24(6):757-64). Several studies have shown that the intra- and extracellular cerebral glucose concentration is finely regulated very rapidly, thus maintaining a stable and constant energy supply. Gruetter et al. (Steady-state Cerebral glucose concentrations and transport in the human brain, Journal of Neurochemistry, 1998, 70(1):397-408) show that there is a linear relationship between blood glucose and cerebrospinal fluid glucose (glucose concentration in the central nervous system) over a wide range of plasma glucose concentrations from 4 to 30 mM. Thus, the intracerebral glucose concentration follows blood glucose in parallel via a non-saturable transport mechanism. This observation implies that there is no real competition between glucose and its analogs (as described in this document) for these transporters as long as the sum of their respective concentrations does not exceed 30 mM. Glucose transport to the central nervous system can be described using the Michaelis-Menten model.This model has been validated in animal models and indicates that the limiting factor for glucose entry lies not in the transporters themselves, but in the capillary permeability of the endothelial cells of the blood-brain barrier. This model suggests that the extra- and intracerebral glucose concentrations are the same and that the GLUT transporters on both sides of the endothelial capillary cells have the same Michaelis-Menten transport kinetics with a maximum unidirectional velocity. Furthermore, these transporters do not appear to be the limiting factor for glycolysis as long as the glucose concentration does not fall to the order of magnitude of the hexokinase Km, which appears to be around 50 pM (Transport of glucose from blood to brain, Physiol Rev, 1979, 59(2):305-52), a level significantly lower than cerebral glucose concentrations.In the healthy brain, the phosphorylation of glucose or its analogs is most often considered the rate-limiting step in the accumulation of the phosphorylation product, 2-FDG-6-Phosphate or DG-6-Phosphate. Glucose analogs can compete with glucose as a substrate for hexokinase. Therefore, it is recommended to fast for 4 to 6 hours before the injection of 18F-FDG for a PET scan. Hexokinase exists in four isoforms, each with specific kinetics and tissue distribution (Isozyme studies of several enzymes of carbohydrate metabolism in human adult and fetal tissues, tumor tissues, and cell cultures, 1978, Cancer Res, 38, 1323-28). Isotypes I and II (HKI and HKII, respectively) are primarily expressed in the central nervous system. Mutzi et al.(Kinetic characterization of hexokinase isoenzymes from glioma cells: implications for FDG imaging of human brain tumors, Nucl Med Biol, 2001, 28(2):107-16) compared the in vitro Km values ​​of HK I and HK II for glucose and 18F-FDG using three different methods. For HK I, a Km of 39 pM was reported for glucose, and for 18F-FDG, the value was between 55 and 77 pM. For HK II, the Km value for glucose was between 129 and 137 pM, and between . 166 and 177 for 18F-FDG. Thus, these reminders, and the fact that the rate-limiting step in the accumulation of glucose and its analogs is indeed the phosphorylation step, which is directly dependent on hexokinase, demonstrate that administering glucose analogs labeled with carbon-13 in a concentration range between micromolar and millimolar is perfectly capable of providing valuable diagnostic information for functional explorations used to evaluate states, conditions, disorders, diseases, pathologies, or syndromes in a subject's body. This possibility has been detailed at the brain level; the same applies to many other organs.Thus, the described approach demonstrates the feasibility of developing a non-radioactive diagnostic imaging agent capable of detecting metabolic abnormalities within cells, tissues, or organs in a manner similar to 18F-FDG, which is already widely used in another imaging modality. The invention provides an innovative solution to a medical need in the field of non-radioactive metabolic imaging, applicable to a range of medical specialties such as oncology, neurology, psychiatry, infectious diseases, and biological processes such as inflammation in its broadest sense. Summary of the invention

[0014] The present invention thus relates to a deoxyglucose, comprising at least one isotope of carbon-13, as a medicinal product intended for use in a quantitative and / or qualitative diagnostic method for conditions, diseases, pathologies, syndromes, or disorders in the body of a subject, said diagnostic method being in vivo and associated with nuclear magnetic resonance spectroscopic imaging. This deoxyglucose is particular in that said isotope of carbon-13 is not directly bonded to a deuterium atom.

[0015] This deoxy-glucose is much easier to manufacture, since it only requires one type of minor isotope in nature.

[0016] According to other characteristics: - said nuclear magnetic resonance spectroscopic imaging can use a direct detection sequence of the carbon-13 isotope, and / or a heteronuclear detection sequence of the carbon-13 - hydrogen-1 bond; these arrangements make it possible to overcome hyperpolarization, which leaves too little observation time available, and allow observation at much longer times, on the order of half an hour to several hours, - said diagnostic method may be for a disease characterized by abnormally high glucose consumption by cells, in particularly in the fields of oncology, cardiology, neurology, and infectious or inflammatory diseases; such characteristics can be particularly well observed thanks to deoxyglucose according to the invention, - said deoxyglucose may be a fluorodeoxyglucose, allowing for better affinity with respect to the transporters and enzymes involved in its metabolism, in which the fluorine atoms present are fluorine-19, which has the advantage of not being radioactive, - The carbon 13 atom can be located in position 6, which has the advantage of a single bond with another carbon and a position of the carbon 13 atom outside the chemical ring in the hemiacetal form of the molecule, or in position 1, which has the advantage of a single bond with another additional carbon and the adjacent position of the carbon 13 atom relative to the oxygen atom, which allows this carbon 13 atom not to be subject to phosphorylation, thus allowing easier detection, - the six carbon atoms can be carbon 13, thus multiplying the resonance lines and increasing the sensitivity of the detection, while simplifying the synthesis of the molecule, and said nuclear magnetic resonance spectroscopic imaging can further use a homonuclear detection sequence of the carbon 13 -carbon 13 bond, allowing a complementary signal, improving the identification capacity of deoxy-glucose.

[0017] The present invention further relates to a composition, chemical formulation and / or galenic formulation comprising at least one deoxy-glucose according to the invention.

[0018] According to a particular embodiment, the dosage of said deoxy-glucose can be between 0.001g / kg and 0.3g / kg, sufficient for the vast majority of the diagnoses sought, preferably between 0.025g / kg and 0.1g / kg, constituting the range of the best ratios between the reliability of the diagnosis and the acceptance of the product by the tissues.

[0019] The present invention further relates to a kit comprising, on the one hand, any commercially manufactured form, galenic formulation favorable to any administration in a subject regardless of the route of administration, containing one or more deoxy-glucoses according to the invention, and on the other hand, instructions for its use.

[0020] The present invention finally relates to a diagnostic method using a composition according to the invention, and comprising the following steps: - the administration to a subject of a quantity of said composition, whether single or repeated, - excitation by nuclear magnetic resonance using a direct detection sequence of the carbon-13 isotope, and / or a heteronuclear detection sequence of the carbon-13 - hydrogen bond - signal detection and reconstruction of a spectrum or image.

[0021] According to an alternative embodiment of the invention, said diagnostic method may use a composition according to the invention in which the deoxyglucose may be a fluorodeoxyglucose, with a fluorine-18 atom, and further comprise a PET scan due to the labeling with the 18F isotope. The invention thus makes it possible to perform a first scan shortly after administration, based on the detection of the fluorine-18 atom, and a second scan a few hours later, when the fluorine-18 has largely decayed, thanks to carbon-13 and / or its bonding with hydrogen-1.

[0022] According to a preferred embodiment of the invention, said diagnostic method may aim to assess a state, condition or disease during and / or after the administration to a subject of a therapeutic agent or modulator.

[0023] Thus, this invention represents an alternative to 18F-FDG PET scans, thereby reducing the need for hybrid PET-CT or PET-MRI imaging devices, since the invention allows for anatomical and functional imaging of the uptake, retention, and distribution of the described compounds using adapted conventional MRI / MRS / MRS devices. Therefore, the present invention reduces the cost of this type of medical imaging.

[0024] The invention will be better understood in light of the detailed description below, as well as the drawings, in which: - Fig. 1 represents glucose according to the Fischer projection, - Fig. 2 represents an example of deoxyglucose according to the invention, - Figures 3 and 4 represent two examples of fluorodeoxyglucose according to the invention, - Figs. 5 and 6 represent two examples of deoxyglucoses according to the invention according to the Haworth projection.

[0025] Against all expectations, the inventor found that an in vivo imaging diagnostic method based on the use of carbon-13 labeled compounds derived from deoxy-glucose and fluorodeoxy-glucose using nuclear magnetic resonance gives much better results than expected.

[0026] Thus, according to a first of its aspects, the present invention relates to 2-deoxy-glucose comprising at least one carbon 13 atom in its chemical structure.

[0027] Thus, according to another of its aspects, the present invention relates to 2-fluoro-2-deoxy-glucose comprising at least one carbon atom 13.

[0028] According to another aspect of it, the present invention relates to 2-fluor-2-deoxy-glucose which comprises 2 carbon 13 atoms in its chemical structure (adjacent or not).

[0029] According to another aspect of it, the present invention relates to 2-fluoro-2-deoxy-glucose which comprises 2 carbon 13 atoms in its chemical structure (adjacent or not).

[0030] According to another aspect of it, the present invention relates to 2-deoxyglucose which comprises 1 to 6 carbon 13 atoms in its chemical structure.

[0031] According to another aspect of it, the present invention relates to 2-fluoro-2-deoxy-glucose which comprises 1 to 6 carbon 13 atoms in its chemical structure.

[0032] In the present invention, the said carbon-13 atom is also called the stable isotope or stable isotope of carbon; it is a stable isotope of carbon-12, the most abundant atom naturally.

[0033] According to another aspect of the present invention, the stable isotope carbon-13 is an atom whose atomic orbitals are sp3 hybridized and whose bonding with neighboring atoms is via sigma bonds or any other covalent or non-covalent bond. According to another aspect, the stable isotope carbon-13 is an atom whose atomic orbitals are sp2 hybridized and whose bonding with neighboring atoms is via pi bonds or any other covalent or non-covalent bond. According to yet another aspect, the stable isotope carbon-13 is an atom whose atomic orbitals are sp hybridized and whose bonding with neighboring atoms is via pi, sigma, or any other covalent or non-covalent bond.

[0034] In the present invention, the term deoxy-glucose refers to all isomers including all natural or synthetic structural isomers, all natural or synthetic stereochemical isomers, all natural or synthetic conformational isomers of glucose in which a hydroxyl group is replaced by a hydrogen atom.

[0035] In the present invention, the term fluoro-deoxy-glucose refers to the set of isomers including all natural or synthetic structural isomers, all natural or synthetic stereochemical isomers, all natural or synthetic conformational isomers of glucose in which a hydroxyl group is replaced by a fluorine atom (18F or 19F).

[0036] In the context of the present invention, fluorodeoxyglucose is considered to be a special case of a deoxyglucose, and to be part of the large family of deoxyglucoses.

[0037] Thus, the deoxyglucose mentioned in the present invention refers individually to all of the following isomers: 2-deoxyglucose, 3-deoxyglucose, 4-deoxyglucose, 5-deoxyglucose, or 6-deoxyglucose. The 2-deoxyglucose molecule is preferred given that its affinity for hexokinase is the highest compared to the other isomers (3-deoxyglucose, 4-deoxyglucose, etc.). Similarly, the term fluoro-deoxy-glucose cited in the present invention refers individually to all of the following isomers: 1-fluoro-l-deoxy-glucose, 2-fluoro-l-deoxy-glucose, 3-fluoro-l-deoxy-glucose, 3-fluoro-l-deoxy-glucose, 4-fluoro-l-deoxy-glucose, 5-fluoro-l-deoxy-glucose, 6-fluoro-l-deoxy-glucose; l-fluoro-2-deoxy-glucose, 2-fluoro-2-deoxy-glucose, 3-fluoro-2-deoxy-glucose, 4-fluoro-2-deoxy-glucose, 5-fluoro-2-deoxy-glucose, 6-fluoro-2-deoxy-glucose;l-fluoro-3-deoxy-glucose, 2-fluoro-3-deoxy-glucose, 3-fluoro-3-deoxy-glucose, 4-fluoro-3-deoxy-glucose, 5-fluoro-3-deoxy-glucose, 6-fluoro-3-deoxy-glucose ; l-fluoro-4-deoxy-glucose, 2-fluoro-4-deoxy-glucose, 3-fluoro-4-deoxy-glucose, 3-fluoro-4-deoxy-glucose, 4-fluoro-4-deoxy-glucose, 5-fluoro-4-deoxy-glucose, 6-fluoro-4-deoxy-glucose ; l-fluoro-5-deoxy-glucose, 2-fluoro-5-deoxy-glucose, 3-fluoro-5-deoxy-glucose, 4-fluoro-5-deoxy-glucose, 5-fluoro-5-deoxy-glucose, 6-fluoro-5-deoxy-glucose ; l-fluoro-6-deoxy-glucose, 2-fluoro-6-deoxy-glucose, 3-fluoro-6-deoxy-glucose, 4-fluoro-6-deoxy-glucose, 5-fluoro-6-deoxy-glucose, 6-fluoro-6-deoxy-glucose. ;

[0038] Selon un autre de ses aspects, l’invention concerne tout isomère du deoxy-glucose dans une forme cyclisée (par exemple forme hémiacétal cyclique) ou linéaire.

[0039] According to another aspect of it, the invention relates to any isomer of fluorodeoxyglucose in a cyclized form (for example cyclic hemiacetal form) or linear form.

[0040] According to another aspect of it, the invention relates to all possible stereoisomers of deoxy-glucose (in a cyclic or linear form) including in particular D-deoxy-glucose, L-deoxy-glucose and all possible epimers, enantiomers, diastereomers and anomers (α-deoxy-glucose or [3-deoxy-glucose].

[0041] According to another aspect of it, the invention relates to all possible stereoisomers of fluoro-deoxy-glucose (in a cyclic or linear form) including in particular D-fluoro-deoxy-glucose, L-fluoro-deoxy-glucose and all possible enantiomers, diastereomers and anomers (α-fluoro-deoxy-glucose or [3-fluoro-deoxy-glucose).

[0042] According to another aspect of it, the invention relates to the compound whose derivatives are deoxyglucose or fluorodeoxyglucose (as described herein), which is glucose. The term glucose refers to any isomer (natural or chemically synthesized), any stereoisomer (natural or chemically synthesized), any diastereoisomer (natural or chemically synthesized), any conformational isomer (natural or from chemical synthesis) of 6-(hydroxymethyl)oxane-2,3,4,5-tetrol. Thus, the present invention relates to any isomer of glucose in its cyclic or linear hemiacetal form including any stereoisomer of glucose (including D-glucose, L-glucose), any epimer, diastereomer, any enantiomer and all anomers of glucose (α-glucose, α-glucose).

[0043] According to another aspect of the invention, it relates to the isotopic labeling of molecules and their derivatives described in this document; the term isotopic labeling refers to any atom whose nucleus has an atomic mass different from that of the same element and whose natural abundance is the highest. Due to a change in the number of neutrons within this atomic nucleus, the atomic mass differs among the isotopes of the same element. The sum of the number of neutrons and protons in the nucleus represents the atomic mass. Carbon-12 has 6 protons and 6 neutrons in its nucleus and a natural abundance of approximately 98.93%. Carbon-13 is a stable isotope of carbon-12; it has 6 protons and 7 neutrons in its nucleus and a natural abundance of approximately 1%.

[0044] According to another aspect, the invention relates to isotopic labeling, which refers to the carbon-13 atom, which has 7 neutrons and 6 protons. This labeling applies to all the described deoxyglucose and fluorodeoxyglucose molecules and their derivatives.

[0045] According to another aspect of it, the invention relates to the isotopic labeling of deoxy-glucose by fluorine 19 (comprising 10 neutrons and 9 protons) whose natural abundance is 100%.

[0046] According to another aspect of it, the invention relates to the isotopic labeling of deoxyglucose by radioactive fluorine 18 (comprising 9 neutrons and 9 protons) used in PET imaging.

[0047] According to another aspect of it, the invention relates to all the isotopic labels of the deoxy-glucose and fluoro-deoxy-glucose compounds and their derivatives described in this document obtained according to techniques known to those skilled in the art, such as the synthesis of compounds from the present invention from reagents already labeled, enriched in isotopes of interest or without labeling.

[0048] According to another aspect thereof, concerning deoxyglucose, fluorodeoxyglucose, their derivatives and associated metabolites comprising in their chemical structure at least one isotopic marker in the present invention, this isotopic marker shall be understood as the presence of a specific isotopic element whose presence is greater than the natural abundance of that same element. This remark This principle is valid for both carbon-13 relative to carbon-12 and fluorine-18 relative to fluorine-19. Thus, labeling with the carbon-13 isotope corresponds to an enrichment of the molecule by this isotope of the aforementioned compounds (deoxyglucose, fluorodeoxyglucose, their derivatives, and associated metabolites) at one or more specific positions within their chemical structure and in a proportion ranging from 1.1% to 100%. Similarly, labeling with the fluorine-18 isotope corresponds to an enrichment of the aforementioned compounds (deoxyglucose, fluorodeoxyglucose, their derivatives, and associated metabolites) at one or more specific positions within their chemical structure and in a proportion ranging from 0.001% to 100%. Therefore, a compound or composition resulting from the invention can have different degrees of isotopic enrichment.

[0049] According to another aspect of the invention, the invention relates to the following molecules for compounds or substances derived from fluoro-deoxyglucose (non-exhaustive list due to the possibilities of positional permutations between the isotopic markings of carbon 13 and fluorine): 1-fluoro-2-[U-13C6]deoxyglucose, 2-fluoro-2-[U-13C6]deoxyglucose, 3-fluoro-2-[U-13C6]deoxyglucose, 4-fluoro-2-[U-13C6]deoxyglucose, 5-fluoro-2-[U-13C6]deoxyglucose and 6-fluoro-2-[U-13C6]deoxyglucose; example of derivatives of 2-fluoro-2-deoxyglucose: 2-fluoro-2-[1-13C]deoxyglucose, 2-fluoro-2-[2-13C]deoxy-glucose, 2-fluoro-2-[3-13C]deoxy-glucose, 2-fluoro-2-[4-13C]deoxy-glucose, 2-fluoro-2-[5-13C]deoxy-glucose, 2-fluoro-2-[6-13C]deoxy-glucose, 2-fluoro-2-[ 1,2-13C2]deoxy-glucose, 2-fluoro-2-[1,3-13C2]deoxy-glucose, 2-fluoro-2-[1,4-13C2]deoxy-glucose, 2-fluoro-2-[1,5-13C2]deoxy-glucose, 2-fluoro-2-[1,6-13C2]deoxy-glucose, 2-fluoro-2-[2,3-13C2]deoxy-glucose, 2-fluoro-2-[2,4-13C2]deoxy-glucose, 2-fluoro-2-[2,5-13C2]deoxy-glucose, 2-fluoro-2-[2,6-13C2]deoxy-glucose, 2-fluoro-2-[3,4-13C2]deoxy-glucose, 2-fluoro-2-[3,5-13C2]deoxy-glucose, 2-fluoro-2-[3,6-13C2]deoxy-glucose, 2-fluoro-2-[4,5-13C2]deoxy-glucose, 2-fluoro-2-[4,6-13C2]deoxy-glucose, 2-fluoro-2-[5,6-13C2]deoxy-glucose, 2-fluoro-2-[l,2,3-13C3]deoxy-glucose, 2-fluoro-2-[ 1,2,4- 13C3]deoxy-glucose, 2-fluoro-2-[ 1,2,5- 13C3]deoxy-glucose, 2-fluoro-2-[ 1,2,6- 13C3]deoxy-glucose, 2-fluoro-2-[1,3,4- 13C3]deoxy-glucose, 2-fluoro-2-[l,3,5-13C3]deoxy-glucose, 2-fluoro-2-[l,3,6-13C3]deoxy-glucose, 2-fluoro-2-[ 1,4,5- 13C3]deoxy-glucose, 2-fluoro-2-[ 1,4,6- 13C3]deoxy-glucose, 2-fluoro-2-[l,5,6-13C3]deoxy-glucose, 2-fluoro-2-[2,3,4-13C3]deoxy-glucose, 2-fluoro-2-[2,3,5-13C3]deoxy-glucose, 2-fluoro-2-[2,3,6-13C3]deoxy-glucose, 2-fluoro-2-[2,4,5- 13C3]deoxy-glucose, 2-fluoro-2-[2,4,6- 13C3]deoxy-glucose, 2-fluoro-2- , [2,5,6-13C3]deoxy-glucose, 2-fluoro-2-[3,4,5-13C3]deoxy-glucose, 2-fluoro-2-[3,4,6-13C3]deoxy-glucose, 2-fluoro-2-[3,5,6-13C3]deoxy-glucose, 2-fluoro-2-[4,5,6-13C3]deoxy-glucose, 2-fluoro-2-[l,2,3,4-13C4]deoxy-glucose, 2-fluoro-2-[l,2,3,5-13C4]deoxy-glucose, 2-fluoro-2-[l,2,3,6-13C4]deoxy-glucose, 2-fluoro-2-[l,2,4,5-13C4]deoxy-glucose, 2-fluoro-2-[l,2,4,6-13C4]deoxy-glucose, 2-fluoro-2-[l,2,5,6-13C4]deoxy-glucose, 2-fluoro-2-[l,3,4,5-13C4]deoxy-glucose, 2-fluoro-2-[l,3,4,6-13C4]deoxy-glucose, 2-fluoro-2-[l,4,5,6-13C4]deoxy-glucose, 2-fluoro-2-[l,3,5,6-13C4]deoxy-glucose, 2-fluoro-2-[2,3,4,5-13C4]deoxy-glucose, 2-fluoro-2-[2,3,4,6-13C4]deoxy-glucose, 2-fluoro-2-[3,4,5,6-13C4]deoxy-glucose, 2-fluoro-2-[2,3,5,6-13C4]deoxy-glucose, 2-fluoro-2-[2,4,5,6-13C4]deoxy-glucose, 2-fluoro-2-[l,2,3,4,5-13C5]deoxy-glucose, 2-fluoro-2-[2,3,4,5,6-13C5]deoxy-glucose, 2-fluoro-2-[ 1,3,4,5,6-13C5]deoxy-glucose, 2-fluoro-2-[ 1,2,4,5,6-13C5]deoxy-glucose, 2-fluoro-2-[ 1,2,3,5,6-13C5]deoxy-glucose,2-fluoro-2-[ 1,2,3,4,6-13C5]deoxy-glucose, 2-fluoro-2-[1,2,3,4,5,6-13C5]deoxy-glucose corresponding to 2-fluoro-2-[ U-13C6]deoxy-glucose). ,

[0050] According to another aspect of the invention, the invention relates to the molecules described below for compounds or substances derived from deoxyglucose (this list is not exhaustive due to the possibilities of permutation of the carbon-13 isotope). 2-[1-13C]deoxyglucose, 13 13 13 2-[2- C]deoxy-glucose, 2-[3- C]deoxy-glucose-glucose, 2-[4- C]deoxy-glucose-glucose, 2-[5- C]deoxy-glucose, 2-[6- C]deoxy-glucose, 2-[l,2- C2]deoxy-glucose, 2-[l,3-13C2]deoxy-glucose, 2-[l,4-13C2]deoxy-glucose, 2-[l,5-13C2]deoxy-glucose, 2-[l,6-13C2]deoxy-glucose, 2-[2,3-13C2]deoxy-glucose, 2-[2,4-13C2]deoxy-glucose, 2-[2,5-13C2]deoxy-glucose, 2-[2,6-13C2]deoxy-glucose, 2-[3,4-13C2]deoxy-glucose, 2-[3,5-13C2]deoxy-glucose, 2-[3,6-13C2]deoxy-glucose, 2-[4,5-13C2]deoxy-glucose, 2-[4,6-13C2]-2-deoxy-glucose, 2-[5,6-13C2]deoxy-glucose, 2-[l,2,3-13C3]deoxy-glucose, 2-[ 1,2,4-13C3]deoxy-glucose, 2-[ 1,2,5-13C3]deoxy-glucose, 2-[ 1,2,6-13C3]deoxy-glucose, 2-[l,3,4-13C3]deoxy-glucose, 2-[l,3,5-13C3]deoxy-glucose, 2-[l,3,6-13C3]deoxy-glucose, 2-[l,4,5-13C3]deoxy-glucose, 2-[l,4,6-13C3]deoxy-glucose, 2-[l,5,6-13C3]deoxy-glucose, 2-[2,3,4-13C3]deoxy-glucose, 2-[2,3,5-13C3]deoxy-glucose, 2-[2,3,6-13C3]deoxy-glucose, 2-[2,4,5-13C3]deoxy-glucose, 2-[2,4,6-13C3]deoxy-glucose, 2-[2,5,6-13C3]deoxy-glucose, 2-[3,4,5-13C3]deoxy-glucose, 2-[3,4,6-13C3]deoxy-glucose, 2-[3,5,6-13C3]deoxy-glucose, 2-[4,5,6-13C3]deoxy-glucose, 2-[l,2,3,4-13C4]deoxy-glucose, 2-[l,2,3,5-13C4]deoxy-glucose, 2-[l,2,3,6-13C4]deoxy-glucose, 2_[l,2,4,5-13C4]deoxy-glucose, 2-[l,2,4,6-13C4]deoxy-glucose, 2-[l,2,5,6-13C4]deoxy-glucose, 2-[l,3,4,5-13C4]deoxy-glucose, 2-[l,3,4,6-13C4]deoxy-glucose, 2-[l,4,5,6-13C4]deoxy-glucose, 2- , [l,3,5,6-13C4]deoxy-glucose, 2-[2,3,4,5-13C4]deoxy-glucose, 2-[2,3,4,6-13C4]deoxy-glucose, 2-[2,3,5,6-13C4]deoxy-glucose, 2-[2,4,5,6-13C4]deoxy-glucose, 2-[3,4,5,6-13C4]deoxy-glucose, 2-[l,2,3,4,5-13C5]deoxy-glucose, 2-[2,3,4,5,6-13C5]deoxy-glucose, 2-[l,3,4,5,6-13C5]deoxy-glucose, 2-[l,2,4,5,6-13C5]deoxy-glucose, 2-[l,2,3,5,6-13C5]deoxy-glucose, 2-[l,2,3,4,6-13C5]deoxy-glucose, 2-[l,2,3,4,5,6-13C6]deoxy-glucose également décrit par le terme 2-[U-13C6]deoxy-glucose.

[0051] In another aspect of the invention, the invention relates to the performance of diagnoses or evaluations of states, conditions, disorders, diseases, pathologies or syndromes in the body of a subject based on the first-pass effect, retention or fixation of one of the compounds, their derivatives and / or their associated metabolites by nuclear magnetic resonance using MRI, SRMN, ISRMN type devices regardless of the protocol or equipment including in the case of hybrid type equipment (heavy equipment of clinical MRI / SRMN / ISRMN type, PET / MRI, PET / SRMN, PET / ISRMN, vertical NMR spectrometer, etc.).

[0052] According to another aspect, the invention relates to performing diagnoses or assessments of states, conditions, disorders, diseases, pathologies, or syndromes in a subject's body based on the first-pass effect; this involves the distribution of one of the compounds of the invention, their derivatives, and / or their associated metabolites within a very short time from the administration of said compounds, i.e., less than thirty seconds, which is less than the time required for recirculation and, in all cases, before reaching a target organ for the second time via vascular recirculation. The time of the first-pass effect is thus considered to be that preceding the recirculation of the compounds, their derivatives, and / or their associated metabolites.

[0053] According to another aspect, the invention relates to performing diagnoses or assessments of states, conditions, disorders, diseases, pathologies, or syndromes in a subject's body based on the binding or retention of the compounds of the invention, their derivatives, and / or their associated metabolites. This includes the distribution of one of the aforementioned compounds in the tissue, organ, biological compartment of interest, and / or surrounding tissues at any time after administration, provided that a signal is detectable for one of the compounds of the invention, as well as their derivatives and associated metabolites.The difference in signal distribution observed within different tissues or organs stems from a contrast between different levels of retention within the cells composing the tissue or organ. This retention level corresponds, on the one hand, to cell density and, on the other hand, to the level of intracellular accumulation, itself dependent on the type of membrane transporters and hexokinase activity. The detection of signals from one or more of these... several compounds of the invention, their derivatives and associated metabolites can be carried out for as long as necessary at any time after administration of said compounds.

[0054] According to another aspect of it, the invention relates, with regard to said diagnosis, evaluation of states, conditions, disorders, diseases, pathologies or syndromes in the body of a subject, to the quantitative, semi-quantitative or qualitative assessment of the fixation or retention of compounds derived from deoxy-glucose or fluoro-deoxy-glucose comprising at least one carbon atom 13 as described in the present invention.

[0055] As previously stated, NMR signals from an atomic nucleus require that its spin quantum number be non-zero, which is the case for 13C (value Yi). Thus, the carbon-13 nucleus is able to "resonate" when an external magnetic field is applied. Therefore, in another aspect, the invention relates to the detection of signals from one of the compounds described in the present invention, as well as their derivatives and associated metabolites, via NMR sequences based on the direct or indirect detection of the carbon-13 nucleus(es) using methods known to those skilled in the art, such as spin-decoupling sequences, homonuclear or heteronuclear sequences, single-quantum sequences, double-quantum sequences, etc.The detection of NMR signals of the described compounds and their associated derivatives and / or metabolites is carried out within a magnetic field, using a transmitting and / or receiving antenna, adapted excitation / emission NMR sequence(s) and the necessary computer post-processing (filtering, transformation, reconstruction).

[0056] In some of its aspects, the invention relates to the diagnosis or evaluation of states, conditions, disorders, diseases, pathologies, or syndromes in the body of a subject using the described compounds and their associated derivatives and / or metabolites according to an NMR / MRI / SIRMN type detection method; said diagnoses, evaluations of states, conditions, disorders, diseases, pathologies, or syndromes in the body of a subject are selected from:

[0057] The diagnosis or evaluation of states, conditions, disorders, diseases, pathologies, or syndromes in the body of a subject related to oncology and / or neoplastic processes, including but not limited to: evaluation or characterization of a tumor mass (benign or malignant), evaluation of the degree of differentiation of a tumor mass, characterization of a tumor mass (establishment of a grade, for example), determination of tissue penetration into adjacent tissues, monitoring of a therapeutic method (pharmacological, for example) on the tumor mass, evaluation of a distant tumor mass, evaluation of a systemic tumor mass, characterization or evaluation lymphatic nodules, recurrent or remission disease, metabolism, pre- and post-external, internal or targeted radiotherapy monitoring, cancers of the central nervous system, head and neck, brain cancer, thyroid cancer, carcinomatous processes, lung cancer, small cell lung cancer, lymphoma, myeloma, melanoma, breast cancer, esophageal cancer, colorectal carcinoma, pancreatic carcinoma, hepatobiliary carcinoma, gynecological cancer, cervical cancer, uterine cancer, ovarian cancer, endometrial cancer, genitourinary cancer, sarcomas, gastrointestinal tumors, stromal tumors, neuroendocrine tumors, gastrinomas, liver metastases, pancreatic metastases, astrocytomas, glioblastoma, carcinoma of unknown origin, carcinoid tumor, childhood cancer, bladder carcinoma, gallbladder carcinoma, tumor hypoxia assessment, evaluation of angiogenesis, bone metastases, evaluation of angiogenic therapy,metastases from lymph nodes, bone lesions, cholangiocarcinoma, functional study of brown fat, characterization of pulmonary nodules, ganglioglioma, gliosis, high and low grade glioma, prostate cancer, kidney cancer, testicular cancer, cancer of the genitourinary tract, hepatobiliary tumor, pancreatic tumor, benign tumor, adrenal gland hypertrophy;

[0058] The diagnosis or evaluation of states, conditions, disorders, diseases, pathologies, or syndromes in the body of a subject related to the field of neurology, including but not limited to: movement disorders, apoplexy, epilepsy, stroke, childhood epilepsy, temporal lobe epilepsy, dementia, familial or non-familial Alzheimer's disease, amyloid angiopathy, Levy body dementia, frontotemporal degeneration, memory and / or cognitive impairment of the MCI (mild cognitive impairment) type, typical and atypical Parkinson's disease, brain development disorders, central nervous system tumors, cerebral blood flow assessment, interictal imaging, ictal imaging, spasm, infantile spasms, Lennox-Gastaut syndrome, general condition assessment, cerebral metabolism assessment, epileptic seizures, neurodegenerative diseases, hypometabolism frontal lobe, multiple sclerosis, multiple system sclerosis,Tourette syndrome, myasthenia gravis, sleep disorders, narcolepsy, addiction;

[0059] Diagnoses or assessments of states, conditions, disorders, diseases, pathologies or syndromes in the body of a subject in connection with the field of psychiatry including but not limited to: affective disorders, bipolar disorders, depression, acute delusional episode, substance abuse, alcohol abuse, cocaine abuse, anxiety disorders, personality disorder, schizophrenia, schizoaffective disorders, social phobia, post-traumatic stress, obsessive-compulsive disorder;

[0060] The diagnosis or evaluation of states, conditions, disorders, diseases, pathologies or syndromes in the body of a subject related to the vascular and cardiology fields, including but not limited to: evaluation of myocardial perfusion, myocardial viability, cardiac metabolism, hypertension, myocardial neurotransmission, coronary reserve, quantification of cardiac output, myocardial infarction, postoperative aortic remodeling including transplantation, atherosclerosis, coronary pathologies, coronary viability, cardiac involvement in endocrine pathologies, monitoring of cell transplantation at the cardiac level, any cardiomyopathy, pediatric cardiac monitoring, myocardial perfusion under pharmacological stress, heart transplantation, valvular pathologies, cardiac ischemia, plasma volume, vascular permeability,of any cardiac syndrome (e.g., Takotsubo syndrome), angiography;

[0061] The diagnosis or evaluation of states, conditions, disorders, diseases, pathologies or syndromes in the body of a subject related to the infectious or inflammatory domain, including but not limited to: pediatric infections, cardiorespiratory infection, fever of unknown origin, soft tissue infection, inflammatory reaction related to the presence of foreign bodies, infection and / or inflammation in immunocompromised patients, infection in the context of a malignant pathology, inflammation in children, colitis, Crohn's disease, musculoskeletal inflammation and associated inflammatory processes, infection on a prosthesis or implant, osteomyelitis, sarcoidosis, vascular infection, vasculitis, vulnerable atherosclerotic plaques, rheumatoid arthritis, local or systemic autoimmune disease, differentiation between inflammation and malignancy, fever, parasitic infection, pyogenic infection, viral infection, fungal infection,bacterial infection;

[0062] Diagnoses or evaluations of states, conditions, disorders, diseases, pathologies or syndromes in the body of a subject in connection with the renal domain including but not limited to: Alport syndrome, renography, captopril renography, renal stenosis, renal transplantation;

[0063] The diagnosis or evaluation of states, conditions, disorders, diseases, pathologies or syndromes in the body of a subject in relation to the general field including but not limited to are: monitoring and / or localization over time of any normal or abnormal metabolism, monitoring and / or localization over time of any normal or abnormal metabolism following a pharmacological intervention, interventional imaging regardless of the field of intervention, interventional neuroradiology, hemorrhagic pathology, head trauma, hemorrhagic or non-hemorrhagic stroke, interventional cardioradiology;

[0064] In some aspects, the present invention relates to carbon-13 labeled compounds derived from deoxyglucose and / or fluorodeoxyglucose and their associated derivatives and metabolites described herein and used in drug development, therapeutic monitoring, and related applications, including but not limited to: cytotoxic agents, cytostatic agents, anticancer agents, anti-angiogenic agents, anti-tyrosine kinase agents, treatment plan evaluation, therapeutic reassessment, determination of response to a pharmacological agent, growth factor inhibitors, signal transduction inhibitors, antihypertensive agents, antibiotic agents, antifungal agents, antioxidant agents, antipsychotics, the effect of pharmacological and non-pharmacological agents on aerobic and anaerobic glycolysis, gene therapy,Cell therapy (labeled and unlabeled cells).

[0065] In some aspects, the present invention relates to carbon-13 labeled compounds derived from deoxyglucose and / or fluorodeoxyglucose and their associated derivatives and metabolites described herein and used for the diagnosis or evaluation of states, conditions, disorders, diseases, pathologies, or syndromes in the body of a subject for which the biomarker of uptake, i.e., the level of uptake of said compounds, may be higher or lower in the volume of interest compared to the surrounding tissues. For example, malignant tumors are characterized by a higher level of uptake than the surrounding tissues, while cerebral epileptic foci are characterized by a lower level of uptake than the surrounding tissues.

[0066] In another aspect of it, the present invention relates to the performance of said diagnoses or evaluations of states, conditions, disorders, diseases, pathologies or syndromes in the body of a subject using biomarkers such as the level of fixation of carbon-13 labeled compounds derived from deoxy-glucose and / or fluorodeoxyglucose and their associated derivatives and metabolites described in this document.

[0067] In some of its aspects, the present invention relates to the use of the described carbon-13 labeled compounds derived from deoxyglucose and / or fluorodeoxyglucose and their associated derivatives and metabolites in a mass weight between 0.0001g / kg and 1g / kg.

[0068] In some aspects of the invention, the use of the described carbon-13 labeled compounds derived from deoxyglucose and / or fluorodeoxyglucose and their associated derivatives and metabolites includes their use in isolation but also with any substance outside the scope of this patent.

[0069] In another aspect, the invention relates to a method for diagnosing or evaluating states, conditions, disorders, diseases, pathologies, or syndromes in the body of a subject; this method comprises: - The administration to a subject of a quantity of one or more of the described compounds labeled with carbon-13 derived from deoxyglucose and / or fluorodeoxyglucose and their associated derivatives and metabolites - Detection of the signal associated with one or more administered compounds and / or their derivatives and associated metabolites - The detection of the signal associated with these compounds from the invention and their associated derivatives and metabolites is based on the nuclear magnetic resonance of carbon 13 using MRI / NMRS / NMR / PET-MRI type devices, each of these devices comprising the entire detection chain necessary for the acquisition of signals (external magnetic fields, adapted excitation NMR sequence, transmitting and / or receiving antenna, computer processing, reconstruction of a spectrum or an image)

[0070] This results in the possibility of establishing a diagnosis or an evaluation of states, conditions, disorders, diseases, pathologies or syndromes in the body of a subject.

[0071] In another aspect, the method of the invention includes detection and / or tracking by means of nuclear magnetic resonance such as 1TRM, 1TSRMN, SRMN, PET-MRI regardless of the excitation / reception sequence, the type of radio frequency antenna, the computer processing of the signal, the type of clinical equipment.

[0072] In another aspect of it, the method resulting from the invention relates to subjects to whom compounds described in the present invention have been administered, i.e. carbon-13 labeled compounds derived from deoxyglucose and / or fluorodeoxyglucose and their associated derivatives and metabolites, in a single or repeated manner.

[0073] In another aspect, the method resulting from the invention relates to the establishment of diagnoses or the evaluation of states, conditions, disorders, diseases, pathologies or syndromes in the body of a subject during or after the administration to a subject of one or more pharmacologically active or inactive agents.

[0074] In another aspect, the method resulting from the invention relates to the establishment of a diagnosis or the evaluation of states, conditions, disorders, diseases, pathologies or syndromes in the body of a subject during or after the administration to a subject of one or more compounds described in the present invention, i.e. labeled with carbon 13 derived from deoxy-glucose and / or fluorodeoxy-glucose and their associated derivatives and metabolites.

[0075] In another aspect, the method resulting from the invention relates to the establishment of a diagnosis or the evaluation of states, conditions, disorders, diseases, pathologies or syndromes in the body of a subject in the fields of oncology, neurology, psychiatry, cardiology and the vascular field, infection, drug development, therapeutic monitoring and their applications, the renal field and the general field as described above.

[0076] In another aspect of it, the method of the invention relates to compounds described in the present invention, i.e. labeled with carbon 13 derived from deoxyglucose and / or fluoro-deoxy-glucose comprising at least one carbon 13 atom and their associated derivatives and metabolites.

[0077] The invention also relates to kits comprising at least one compound described in the present invention, i.e. derived from deoxyglucose and / or fluorodeoxyglucose comprising at least one carbon atom 13 and their associated derivatives and metabolites intended to be administered accompanied by instructions for use.

[0078] According to some of its aspects, the kit or kits resulting from the invention are used for establishing a diagnosis or evaluating states, conditions, disorders, diseases, pathologies or syndromes in the body of a subject.

[0079] In another aspect of it, the invention relates to a composition comprising at least one other additional compound also derived from the present invention, i.e. from deoxy-glucose and / or fluoro-deoxy-glucose comprising at least one carbon atom 13 and their associated derivatives and metabolites.

[0080] In another aspect, the invention relates to a composition or formulation containing at least one fluorinated derivative of deoxyglucose comprising at least one carbon-13 atom and their associated derivatives and metabolites. In another aspect, said fluorinated derivative of deoxyglucose is fluorodeoxyglucose with 18F and / or 19F as the fluorine atom and their associated derivatives and metabolites.

[0081] In another aspect, the invention relates to a composition or formulation comprising at least one compound described in the present invention, i.e., derived from deoxyglucose and / or fluorodeoxyglucose comprising at least one carbon atom 13, and their derivatives and metabolites associated or mixed with acceptable adjuvant(s), excipient(s), or active pharmaceutical ingredient(s). These substances must be "pharmaceutical" acceptable in the sense of being compatible with all the substances present in the composition and with the container in which they are placed (vial, glass, syringe, plastic, etc.).

[0082] In another aspect, the invention relates to any composition administrable to a subject, including any composition administrable by oral, rectal, nasal, transdermal route, The invention relates to oral, sublingual, vaginal, and parenteral administration (including intramuscular, intravenous, subcutaneous, and intradermal routes). It also relates to implantable compositions. The compositions resulting from the invention can be prepared by recognized methods in the pharmaceutical field. Such a method includes all steps of combining deoxyglucose and / or fluorodeoxyglucose comprising at least one carbon atom 13 and their associated derivatives and metabolites with any associated substance of the excipient or formulation agent type used in the pharmaceutical arts, including but not limited to stabilizing, antimicrobial, preservative, disintegrating, diluting, lubricating, coloring, flavoring, antioxidant, preservative, filler, solvating, and any carrier.

[0083] In another aspect, the invention relates to any composition intended for oral (per os) administration in the form of tablets, capsules, tablets, dragees, caplets, powders, granules, solutions, suspensions, emulsions or any other pharmaceutical form intended for this route of administration.

[0084] In another aspect, the invention relates to any composition intended for parenteral administration in the form of powder or lyophilized powder to be reconstituted, solution, suspension, colloidal suspension, emulsion or any other galenic form intended for this route of administration.

[0085] In another aspect, the invention relates to any composition intended for rectal administration in the form of a suppository, emulsion, gel or any galenic form intended for this route of administration.

[0086] In another aspect, the invention comprises a described composition associated with a presentation including a notice with the indications indicated in this document and instructions for use.

[0087] In another aspect, the invention relates to parenteral administration of a composition comprising a sterile aqueous or non-aqueous vehicle. The compositions or formulations may be presented in unit (single-dose) or multiple (multidose) form, in a vial or ampoule format, in dry form (i.e., lyophilized, requiring reconstitution prior to administration) or in liquid form. Compositions or formulations intended for nasal or pulmonary administration include formulations intended to be inhaled as fine or very fine particles of the nebulized or aerosol type, obtained using aerosol generators, nebulizers, or pressurized or unpressurized carrier gas.

[0088] In another aspect, the invention relates to the composition described in the document, whether or not associated with other diagnostic agents, including but not limited to physiological saline (0.9% NaCl), and buffers (phosphate, acetate). for example), to diagnostic agents used in medical imaging such as iodinated contrast agents, gadolinium chelates, ultrasound contrast agents, radiopharmaceuticals.

[0089] In another aspect, the invention relates to the establishment of a diagnosis or the evaluation of states, conditions, disorders, diseases, pathologies or syndromes in the body of a subject using a composition or formulation from this document in the fields of application already mentioned, namely oncology, neurology, psychiatry, cardiology, the vascular field, infectious diseases, inflammation, the development of new molecules, therapeutic monitoring, the renal and urological field, pneumology and all the general field applications described above.

[0090] According to another aspect, this invention relates to additional conditions, states, diseases, or syndromes that can be diagnosed or assessed by means of a method and / or composition of the invention, including conditions, states, diseases, or syndromes conventionally diagnosed or assessed by 18F-FDG PET scans. Insofar as the method and possible compositions of the invention do not result in exposure to ionizing radiation due to radioactive decay, the method, compositions, and indications of the invention can be used to diagnose and / or assess conditions, states, diseases, or syndromes in populations vulnerable to this type of ionizing radiation, such as children and pregnant women.Furthermore, this absence of exposure to ionizing radiation allows for repeated use of the method and composition described in this document within a short period of time for all conditions, states, diseases, or syndromes mentioned in the document.

[0091] According to another aspect of it, the method described in the present invention is applied using MRI / MRS / MRS / PET-MRI type devices via compositions derived from deoxyglucose and / or fluorodeoxyglucose comprising at least one carbon atom 13 and their associated derivatives and metabolites.

[0092] According to another aspect, the method described in the present invention is applicable using MRI / MRS / MRS-type devices via compositions derived from deoxyglucose and / or fluorodeoxyglucose comprising at least one carbon-13 atom and their associated derivatives and metabolites. Thus, this invention represents an alternative to 18F-FDG PET scanning, thereby reducing the need for hybrid PET-CT or PET-MRI imaging devices, insofar as the invention allows for anatomical and functional imaging of the uptake, retention, and distribution of the described compounds using devices conventional MRI / MRS / MRS-type scanners are adapted. Thus, the present invention makes it possible to reduce the cost of this type of medical imaging.

[0093] According to another aspect, the method and compositions resulting from the invention offer, for the first time, the possibility of reducing the costs of medical imaging by allowing the combination of diagnostic tracers, particularly fluorine-18 labeled radiopharmaceuticals. An increasing number of fluorine-18 labeled radiopharmaceuticals have received marketing authorization in recent years. Thus, in many clinical cases, functional explorations in addition to 18F-FDG are necessary, requiring two separate examinations with two distinct radioactive tracers (since the nature of the radiation is identical, it is impossible to simultaneously detect two fluorine-18 labeled molecules). The complementarity of these examinations lies in the fact that each tracer explores a metabolic pathway of interest.However, since these radioactive tracers expose patients to ionizing radiation, their use must be evaluated according to a benefit / risk assessment with regard to patient radiation protection. The present invention thus makes it possible to obtain this type of information at a lower cost in terms of irradiation (combining a non-radioactive composition from the invention and a radioactive tracer labeled with fluorine-18), and in terms of examination cost, since the PET-MRI device allows for imaging of this combination in a single scan, thus avoiding the need to perform the examination twice for each tracer. Finally, the benefit of performing the functional exploration of two metabolic pathways simultaneously using the same device increases diagnostic precision and acuity, accelerates medical and therapeutic management, and reduces the time imaging equipment is occupied.

[0094] According to another aspect, the method and compositions of the invention offer, for the first time, the possibility of comparing two methods for evaluating in vivo glucose consumption using two complementary techniques with the same carbohydrate analog. The compositions of the invention make it possible to perform, on the same patient, on the same day, a PET scan due to labeling with the 18F isotope and an MRI / MRS / MRMS scan due to labeling with the 13C isotope. This allows for the evaluation of the late retention of the same molecule via the 13C isotope, given the short half-life of 18F, which is 119 minutes. This direct comparison on the same day, in the same patient, for a precise volume of interest represents a major diagnostic advantage for the medical management of subjects / patients. This comparison is all the more valuable as it can be performed using a single hybrid PET-MRI biomedical device.

[0095] The terms "diagnosis or evaluation of states, conditions, disorders, diseases, pathologies, or syndromes in the body of a subject" shall be understood to mean any functional exploration methodology contributing to the identification, recognition, or contribution of knowledge in the evaluation of states, conditions, disorders, diseases, pathologies, or syndromes in any subject or mammal (including brain exploration). A diagnosis performed according to the present invention by means of a composition comprising deoxyglucose and / or fluorodeoxyglucose comprising at least one carbon atom 13 and their associated derivatives and metabolites includes, but is not limited to, a quantitative, semi-quantitative, or overall assessment for the purpose of diagnosis or evaluation (level of retention or fixation of the SUV type, Standard Uptake Value, or equivalent) of states, conditions, disorders, diseases,of pathologies or syndromes in a subject's body; for the purpose of predicting states, conditions, disorders, diseases, pathologies, or syndromes in a subject's body; for the purpose of evaluating a subject's genetic predisposition to a state, condition, disorder, disease, pathology, or syndrome in a subject's body; for the purpose of evaluating the effectiveness of pharmacological or non-pharmacological treatment administered to a subject (continuously or discontinuously); for the purpose of quantitative, semi-quantitative, or qualitative evaluation of neuronal functions in general in a healthy subject or a subject suffering from a state, condition, disorder, disease, pathology, or syndrome in a subject's body; for the purpose of diagnosis or quantitative, semi-quantitative, or qualitative evaluation of a state, condition, disorder, or disease.of a pathology or syndrome in the psychiatric, neurodegenerative, or neurochemical domain; for the purpose of evaluating a pharmacological and non-pharmacological therapeutic agent; for the purpose of evaluating the effectiveness of a treatment; for the purpose of characterizing a mass, tumor, cyst, granuloma, lymph node, vascular anomaly, or the function of an organ or blood vessel; for the purpose of quantification at the cerebral, renal, hepatic, or any other organ level; for the purpose of evaluating the degree of anesthesia or comatose state; for the purpose of evaluating and / or characterizing a cerebral region following a stroke, cerebral ischemia, or cerebral hypoxia; for the purpose of evaluation in the field of cardiology, including the evaluation or characterization of cardiac regions.

[0096] The terms “monitoring” and “therapeutic follow-up” in this document refer to the detection and quantitative, semi-quantitative, or evaluative assessment of the level of The fixation of deoxyglucose and / or fluorodeoxyglucose comprising at least one carbon-13 atom and their associated derivatives and metabolites described in the present invention. This monitoring is performed using any invasive or non-invasive imaging device (including interventional imaging) based on MRI, including but not limited to MRI, SRMN, ISRMN, PET-MRI, and any other hybrid imaging modality.

[0097] According to another aspect of the invention, the invention relates to detection methods using MRI / MRS / MRI-SENS / PET-MRI devices. Detection by this type of device is performed using doubly tuned 13C / ¹H transmitting and / or receiving antenna(s) or separate antennas for each channel. Antenna combinations capable of decoupling the signals from the ¹³C and ¹H nuclei during signal acquisition are also possible. Specific absorption, i.e., the energy level deposited in the tissues, can vary but must remain as low as possible. All kinds of antennas can be used to implement the invention, such as surface antennas, birdcage antennas, saddle antennas, and any other possible combination.

[0098] Thus, the advantage of the present invention lies in exploiting both the benefits of the metabolic dead end of deoxyglucose and fluorodeoxyglucose (which promotes their cellular accumulation) combined with the presence of carbon-13 isotopes within the molecule, thereby quantitatively compensating for the low detection sensitivity of this isotope in MRI / SMR / SMRS. To date, none of the molecules described in the following claims have been used in humans. The central molecule for this invention is 2-[U-13C6]deoxyglucose and 2-fluoro-[U-13C6]deoxyglucose, as these are the two molecules that allow both maximum accumulation in cells and the best increase in the signal-to-noise ratio due to the substitution of all carbon-12s by carbon-13s.Thus the present invention shows that carbon-13 imaging using the compounds described in this document is possible without recourse to hyperpolarization techniques.

Claims

Demands

1. Fluoro-deoxy-glucose intended for use in an in vivo diagnostic method implementing nuclear magnetic resonance, in particular in a method for quantitative and / or qualitative assessment of states, diseases, pathologies, syndromes or disorders, characterized in that said fluorodeoxy-glucose comprises at least one carbon-13 isotope.

2. Fluoro-deoxy-glucose according to any one of the preceding claims, characterized in that the fluorine atoms present are fluorine 19 for all possible stereochemical configurations.

3. Fluoro-deoxy-glucose according to any one of the preceding claims, characterized in that at least one isotope of carbon 13 is located in position 6 or 1.

4. Fluoro-deoxy-glucose according to any one of the preceding claims, characterized in that the six carbon atoms are carbon 13.

5. Fluoro-deoxy-glucose according to any one of the preceding claims, characterized in that said nuclear magnetic resonance uses a direct carbon-13 isotope detection sequence and / or a heteronuclear carbon-13-hydrogen bond detection sequence.

6. Fluoro-deoxy-glucose according to the preceding claim, characterized in that said nuclear magnetic resonance further uses a homonuclear carbon 13-carbon 13 bond detection sequence.

7. Fluoro-deoxy-glucose according to any one of the preceding claims, characterized in that said fluoro-deoxy glucose is a 2-fluoro-2-deoxyglucose which comprises 1 to 6 carbon 13 atoms, adjacent or not when there are two or more, in its chemical structure.

8. Composition comprising a fluorodeoxyglucose according to any one of the preceding claims, intended for use in an in vivo diagnostic method implementing nuclear magnetic resonance, in particular in a method for the quantitative and / or qualitative assessment of states, diseases, pathologies, syndromes or disorders.

9. Composition for use in an in vivo diagnostic method employing nuclear magnetic resonance, in particular in a quantitative and / or qualitative assessment method states, diseases, pathologies, syndromes or disorders according to the preceding claim in which the dosage of said fluorodeoxyglucose is between 0.0001g / kg and 0.3g / kg, preferably between 0.025g / kg and 0.1g / kg.

10. Kit (or kit) comprising fluorodeoxyglucose according to any one of claims 1 to 7 or a composition according to any one of claims 8 or 9, for use of said fluorodeoxyglucose or of said composition in an in vivo diagnostic method implementing nuclear magnetic resonance in particular in a method for quantitative and / or qualitative assessment of states, diseases, pathologies, syndromes or disorders.