FR2989085A1 - RADIOTRACTERS, METHODS OF PREPARATION AND APPLICATIONS - Google Patents

Abstract

The present invention relates to novel radiotracers of formula (III): said compounds of formula (III) being capable of being obtained from new complexing agents of formula (II), themselves capable of being obtained from new precursors of formula (I), as well as their methods of preparation. The invention also relates to a kit that can be used in a hospital environment. Finally, the invention relates to compounds of formula (III) for their use as a diagnostic radiotracer, and more particularly for their use as a non-targeting radiotracer for medical imaging or as an integrated targeting radiotracer, as well as their use as a medicament, and more particularly for targeted radiotherapeutic treatments using bifunctional chelating agents.

Description

The present invention relates to new radiotracers of formula (III), obtainable from new complexing agents of formula (II), themselves obtainable from new precursors of formula (I), and as their preparation processes. The invention also relates to a kit that can be used in a hospital environment. Finally, the invention relates to compounds of formula (III) for their use as a diagnostic radiotracer, and more particularly for their use as a non-targeting radiotracer for medical imaging or as an integrated targeting radiotracer, as well as their use as a medicament, and more particularly for targeted radiotherapeutic treatments using bifunctional chelating agents.

Knowledge of the functioning of living organisms is conditioned by the development of non-invasive exploration methods. Artificial radioactivity provides medical imaging tools that visualize chemical and biological phenomena within organisms. Since then, the development of radiotracers (or radio-pharmaceuticals) has become a highly studied area of medical research. This is according to the official definition of drugs for diagnostic, prognostic or even therapeutic purposes that emit radioactive waves. Radiotracers contain one or more radioactive isotopes (or radioisotopes), radionuclides (or metal radioelements), incorporated for medical purposes, and a vector (a molecule or supramolecular group with biological activity on living organisms).

Nuclear medicine is currently used in three major medical fields: functional imaging (or scintigraphy), radiotherapy, and radioimmunology. Used in imaging, it allows to visualize the presence or absence of the target in the body, for example a tumor cell, or to note an anatomical anomaly (1231 or Tc04- for example to monitor the size of the thyroid gland, Spencer R. et al., Clinical Nuclear Medicine, 1997. 22 (8): pp. 519-522, Arnold, JE et al., Journal of Nuclear Medicine, 1976. 17 (4): 261-267). Thanks to an external acquisition device (f3-imager, y-camera, scanner), the radiation emitted by the radionuclide can be recorded and, after computer processing, an image in two or three dimensions makes it possible to visualize the concentration levels. radiotracers. Nuclear imaging is a so-called functional or dynamic imaging method. It allows, for example, to visualize in real time the blood flows (intracerebral, cardiac ...), thus making it possible to prevent the appearance of infarction (Iida, H. et al., European Journal of Nuclear Medicine and Molecular Imaging , 2008. 35 (5): 896-905) and to study certain degenerative diseases such as Alzheimer's disease (Hanyu, H., et al., Journal of the Neurological Science, 2010. 290 (1): 96-101) or Parkinson's (Stoessl, A., Neurotherapeutics, 2011. 8 (1): 72-81). It is a valuable tool in the study of certain metabolisms and is also used to evaluate the response to chemotherapy (Cachin, F. et al., Bull Cancer, 2006. 93: 1191). Isotope imaging is commonly used in the pharmaceutical industry to provide evidence of concepts of new drugs in the preclinical phase, or to evaluate dosages in the clinical phase (Wong, DF, J. Nucl Med, 2008. 49 (6 ): 26N-28, Hwang, D.R., et al., J. Nucl Med, 2008. 49 (6): 24N-25). By selecting a radiotracer with a high affinity for a chosen target, this target can be highlighted on a 2D or 3D image of the patient. The huge advantage of imaging techniques involving a radiotracer, called internal, compared to conventional imaging techniques (RX ...), called external, is their very high sensitivity. Indeed, quantities of radiotracers of the nanogram order are detectable. The first scintigraphies were developed using emitters y. In fact, the emitted radiation has the essential characteristics for imaging: weak TEL (Linear Energy Transfer) which limits the destructive effect of the radiation, high penetrating power in order to detect the radiation outside the body, and an energy of between 100 and 400 keV (ideally 150 keV). Three methods are used depending on the two-dimensional or three-dimensional nature of the desired images: 2D images are obtained using a y-camera located above the patient. Radiation from radiotracers is collected through a collimator by a thallium doped sodium iodide crystal which has a high sensitivity to radiation. A computer device then makes it possible to obtain the 2D image of the area observed. This technique allows the acquisition of dynamic images and can be used to visualize flows or study metabolisms.

The TEMP (Monophotonic Emission Tomography) or SPECT (Single Photon Emission Computed Tomography) method consists in applying the scanner technique coupled to the use of one or more y-cameras. These revolve around the patient and regularly perform a 2D acquisition, all of these acquisitions is then treated by a computer algorithm to obtain a 3D reconstruction which the specialist can extract the 2D sections necessary to formulate its diagnosis. The PET (Positron Emission Tomography) or PET (Positron Emission Tomography) method, analogous to the TEMP method, allows, using a ring of y-cameras, to selectively detect antiparallel photons of annihilation. (y-511 keV) from the interaction with surrounding electrons of positrons emitted by a 13+ emitting radionuclide. The three-dimensional signal gives, after computer processing, a 3D image. The use of radionuclides emitting more ionizing radiation can also destroy the cells located in the vicinity of the radiotracer. This is the principle of directed radiotherapy. There are four types of radiotherapy: - Metabolic radiotherapy that uses a marked molecule participating in the metabolism as in the case of 131I. Iodine is directly assimilated at the level of the thyroid gland and will allow the treatment of thyroid cancer (Parthasarathy, K.

L. et al., Journal of Nuclear Medicine Technology, 2002. 30 (4): p. 165-171). Local radiotherapy which involves injecting the radiotracer directly at the target for a very localized effect. This is a preferred technique for the treatment of rheumatoid arthritis by injection into the joint (Liepe, K. et al., Aimais of Nuclear Medicine, 2011. 25 (5): 317-323; Biomedical Imaging and Intervention Journal, 2007. 3 (4): 1). - Radioimmunotherapy consists of reaching the target via a labeled antibody targeting a particular antigen. It may be for example an antigen expressed on the surface of tumor cells. This technique has the advantage of being very accurate because of the high specificity of the antibodies (Schubiger, PA et al., Bioconjugate Chemistry, 1996. 7 (2): pp. 165-179; Perkins, AC, Biomedical Imaging and Intervention Journal, 2005: 2), but has limitations related to both the slow diffusion of antibodies to their biological target, and the heterogeneity of antibody labeling related to non-regiospecific bioconjugation of surface lysine residues. - Vectorized radiotherapy is the most widespread. It consists in using a structure serving as a vector that will ensure the specificity of the tracer for the target. This structure can have multiple forms: a chemical compound such as a peptide (GarcïaGarayoa, E. et al., Nuclear Science and Techniques, 2007. 18 (2): 88-100) or a structure resulting from a particular formulation known as a liposome (Bao, A., et al., J Nucl Med, 2003. 44 (12): 1992-1999).

Finally, radioimmunology consists of using antibodies labeled with a radioactive tracer to perform immunological assays. It is the extreme sensitivity of nuclear medicine that is used here. It makes it possible to assay compounds at much lower concentrations than by conventional techniques.

Each field of application requires radionuclides with different physicochemical properties. The choice of a radionuclide must also take into account its chemical properties. The marking must indeed be fast, be carried out in one step, and be quantitative. Indeed, the low half-life of the radionuclides used in imaging prohibits any long-term synthesis. For diagnostic and functional imaging scintigraphy applications, the most widely used radionuclide is 99mTe (more than 85% of current routine examinations), which has all the characteristics of the ideal radionuclide in terms of cost, availability, half life and energy. The 99mTc has many advantages: it is a transmitter with radiochemical characteristics ideal for imaging (period: 6 hours, energy y: 155 keV), which is available as a portable generator, at a very low cost. affordable. Radiotracers obtained by complexing the radionuclide can be classified into several categories as shown in Figure L Metallic tracers Metal-essential complexes Bifunctional complexes Non-target targets (Integrated complexes) Flow tracers Metabolic anatomical flow tracers (non-specific) Diagram 1: The Different categories of radiotracers obtained by complexation of a radioelement There are two main categories of radiotracers prepared by complexation. "Metal-essential" complexes and bifunctional complexes. - The metal-essential complexes: In this first type of radiotracers, the metal occupies a central position. It is complexed by a chelating agent that can improve its stability in vivo and / or confer an affinity for a particular tissue.

Targeting metal-essential complexes: When the chelating agent is functionalized by chemical groups playing a role in its specific interaction with a biological target, we speak of integrated complexes. In these structures, the metal plays the dual role of radionuclide and structuring agent for the radiotracer. In the absence of metal, the structure usually has little affinity for the target. When the metal is complexed, the functional groups carried by the chelating agent adopt a spatial arrangement adapted to the recognition by the target. The chelating metal structure is therefore included in the target structure. Various radiotracers of this type have been studied with rather variable results. The most visual example of this approach is in the field of steroids. Several studies have been carried out with the aim of developing mimes of steroids in order to visualize the tumor cells that overexpress their receptors. In these studies, the steroid mimics are obtained as NS / NS-type mixed complexes shown in Scheme 2 (Hom, RK et al., The Journal of Organic Chemistry, 1997, 62 (18): 6290-6297). Chi, DY et al., Journal of Medicinal Chemistry, 1994. 37 (7): 928-937).

Diagram 2: Integrated approach: natural progesterone (left) and mime progesterone (right) The dual role of metal can be observed since without it, the two parts of the structure would not be interdependent. If the radiotracer obtained on paper has a structure very close to that of progesterone, the reality is quite different. This molecule whose structure differs too much from progesterone has little affinity for the receptor (103 times less active than the natural steroid).

Other integrated radiotracers are obtained by direct complexation of the metal by the biological molecule. It is the functional groups of the molecule used that ensure the complexation: it is not necessary to modify the molecule chemically. For example, in the case of peptide labeling, it is the free chelating groups of the side chains of the amino acids which complex the radionuclide. One example is the 99mTc labeling of peptides such as adrenomedullin, a 52 amino acid long vasodilator peptide whose structure comprises a chain of 5 amino acids forming a ring through a disulfide bridge. Affinity tests carried out after deletion of this cycle show that the latter is essential for the affinity of the peptide for its receptor. Under direct labeling conditions, in a reducing medium, the disulfide bridge is broken, but yet the affinity of the labeled peptide is still high. This is because the thiols released by the bridge reduction act in the chelation of the metal, thereby reforming the cycle with little effect on affinity (Fu, Y. et al., European Journal of Pharmacology , 2009. 617: 118-123). Another example is the labeling of monoclonal antibodies by 99mTc (Goldenberg, D. et al., Cancer, 2000. 89 (104): 104-155, Dias, CR et al., Brazilian Archives of Biology and Technology, 2005. 48: 29-35). The main drawback of this method is that it is generally impossible to know the exact structure of the complex that is formed (in general, different complexation sites are possible). In some cases, up to 20% of the labeling is nonspecific, i.e. it does not correspond to an insertion of the metal at the desired site and leads to by-products which can accumulate in the liver or impair tracer efficacy (John, E. et al., Journal of Nuclear Medicine, 1994. 35 (5): 876-881). In addition, insertion of the radionuclide into the modified vector structure generally results in loss of affinity. By way of example, the direct labeling of the α-melanocyte stimulating hormone α-MSH has resulted in a strong structural change, particularly at the level of the sequence recognized by the biological receptors (Scheme 3). Thus labeled, MSH has been found to have a reduced affinity to 1% of free hormone affinity (Giblin, MF et al., Proceedings of the National Academy of Sciences, 1998. 95 (22): p. 12814-12818).

Figure 3: Radiolabeling leads to strong structural changes in α-MSH. Left: structure of the a-MSH, right: Re-MSH Other radiotracers gave much more conclusive results. For example, a pseudopeptide cyclic compound having the tripeptide motif RGD (Scheme 4 (a)) can be mentioned. This motif is recognized by the integrin avp, which is overexpressed at the level of cancer cells. In this structure it is the metal, here the technetium, which ensures the cyclization. Its role in the three-dimensional structure obtained is therefore essential. The affinity of this cyclic compound for integrin was found to be very interesting (IC 50 = 60 nm) (Aufort, M., et al., Synthesis and biochemical evaluation of a cyclic RGD oxorhenium complex as new ligand of av / 33 European Journal of Medicinal Chemistry, 2009. 44 (9): 3394-3401, Aufort, M. et al., European Journal of Medicinal Chemistry, 2011. 46 (5): 1779-1788). Cyclophilin hCyp-18 chelating agents (Scheme 4 (b)) which have a protein affinity comparable to that previously observed in the case of unlabeled inhibitors have also been developed (Clavaud, C. et al., ChemBioChem). , 2006. 7 (9): pp. 1352-1355, Clavaud, C. et al., ChemBioChem, 2008. 9 (11): pp. 1823-1829, Clavaud, C. et al., Bioconjugate Chemistry, 2006. 17 (3): 807-814) .15 NH2 + H2N HN NH CN / Re-S (a) HN N NO2 (b) Scheme 4: Examples of metal-essential complexes developed in the laboratory: (a) mime cyclic pseudopeptide RGD; b) linear chelating agent of cyclophilin hCyp-18 The development of targeted "metal-essential" complexes is an elegant approach which is hitting for the time being with certain limits related to the chemistry used in syntheses, the losses of affinity induced by the presence of the metal that deforms the structure in a manner that is difficult to predict, and the introduction of the metal core (TcO 3 + for example) which modifies the hydrophilicity of the compound and therefore its biodistribution. Non-target metal-essential complexes: In the complexes of this category, the role of the chelating agent is not to confer targeting properties on the radiotracer but to ensure a high stability in the biological medium. The biodistribution of the complex thus formed is related to its physicochemical properties (size, charge, lipophilicity, etc.) rather than to a structural affinity for the target. Among these complexes, metabolic flux tracers will be accumulated and will allow to visualize certain metabolic functions in the body. Others are simply transported by the circulating medium and make it possible to visualize flows (cerebral irrigation, intracardiac flows ...): they are anatomical flow tracers. Among the anatomical flow tracers, mention may be made of Myoview or 99mTcTetrofosmin (Fragasso, G. et al., The International Journal of Cardiovascular Imaging, 2002. 18 (1): 31-40; T. et al., European Journal of Nuclear Medicine and Molecular Imaging, 2003. (5): 798-799, Jain, D. et al., Journal of Nuclear Cardiology, 2009. 16 (4): 540-7. 548) and Cardiolite or 99mTc-Sestamibi (Maddahi, J. et al., The American Journal of Cardiology, 1991. 67 (14): 27D-34D, Ito, Y. et al., European Journal of Nuclear Medicine and Molecular Imaging, 2003. 30 (2): 281287) which target the heart (Diagram 5 (a) and (b)) and are frequently used in cardiac examinations. After injection, the patient is exercised and imaging allows the activity of both cardiac ventricles to be visualized for abnormality (Shaw, LJ et al., Journal of Nuclear Medicine, 2003. 44 (2): pp. 134-139). The complex [99mTc0 (MAG3)] - (Scheme 5 (c)) has a very strong accumulation in the kidneys and is extremely reduced in the liver (Vivier, P.-H. et al., Am. J. Roentgenol., 2009. 193 (4): pp. W361-). It is used to demonstrate renal insufficiency (Palmer, MR et al., Nuclear Medicine Communications, 2011. 32 (8): 738-744, 10.1097 / MNM.0b013e328347e958) based on local variations its biodistribution (Taylor, A. et al., Urology, 2010. 76 (6): 1512-1516).

The tracers used to visualize cerebral perfusion have a more complex function because they aim to cross the blood-brain barrier without being backscattered thereafter. This is achieved by two non-directed radiotracers: Ceretec (99mTc-HMPAO, Ogasawara, K. et al., AJNR Am., J. Neuroradiol., 1999. 20 (4): 626-628; , A. et al., Clinical Nuclear Medicine, 1989. 14 (7): pp. 482-483) and Neurolite (99mTc-EDC) (Scheme 5 (d) and (e)). In the case of Neurolite, it has been shown that an enzymatic mechanism causes the hydrolysis of one of the ester groups of the LL form of the complex making it sufficiently hydrophilic not to be backscattered across the blood-brain barrier. (Dilworth, JR et al., Chemical Society Reviews, 1998. 27 (1): 4355, Walovitch, R. et al., Journal of Cerebral Blood Flow Metabolism, 1994. 1994 (S4-11): p.

S4-11). As for Ceretec, it is a chemical reaction with cerebral glutathione that increases its hydrophilicity and blocks backscattering (Neirinckx, RD et al., J. Cereb, Blood Flow Metab., 1988. 8 (S1): P. S4- S12).

R, R R R 0, P 0, p. ## STR1 ## wherein R (CH 2 CH 2 OCH 2 CH 3) (C (Me 2) 0 MeO (Me 2) C] S, N, C (Wle 2) 0 MeO (Me 2) C --- / C Me0 (Me2) C) C (Me2) 0Me Tc S / 0 \ CO2H (a) (b) (c) TC I IO I,,,, EtO CN / N CO2Et Tc 3 / ## STR2 ##

(d) (e) Figure 5: Some examples of undirected radiotracers: (a) Ceretec (99mTc-HMPAO), (b) Neurolite (99mTc-EDC), (c) Mioview (99mTc-Tetrofosmin), (d) Cardiolite (99mTcSestamibi), (e) [99mTc0 (MAG3)] -, (f) 67Ga-Citrate. A final example of this family of radiotracers is 67Ga-Citrate (Scheme 5 (0) which allows imaging of infectious foci (Hughes, DK, Journal of Nuclear Medicine Technology, 2003. 31 (4): 196-201 Ercan, MT et al., Nuclear Medicine and Biology, 1993. (7): 881-887) Its mode of action is different since it relies on a transchelement of gallium to transferrin expressed at the level of Thus, it is not the citrate complex that is observed but the 67 Ga-transferrin complex (Nanni, C. et al., Journal of Nuclear Medicine, 2010. 51 (12): 1932-1936; Goldsmith, SJ et al., Seminars in Nuclear Medicine, 2009. 39 (1): 2-10.) This type of radiotracers represents most of the tracers currently on the market.The so-called metabolic flow tracers involve a molecule intended to be metabolized by the body (peptide ...) which is marked by a radioelement.If the metabolism of these compounds is accentuated or r Duit at pathologies, they can be used to prepare tracers. This is the case of 18F-labeled Fluorodesoxyglucose. Tumor cells metabolize much more glucose than quiescent cells to ensure their growth. [18F] -FDG is therefore very often used in PET imaging for the detection of tumors.20 D Bifunctional complexes This is the approach that is currently the most widespread for the development of new imaging agents. It is often called the BiFunctional Chelating Agent (BFCA) approach. Its principle consists of linking a molecule with proven affinity for the chosen target (targeting molecule or vector) to a radionuclide complexing motif via a linker of variable size and type (Scheme 6). Radionuclide Targeting Molecule Complexing Structure Scheme 6 Principle of the bifunctional approach The choice of the targeting molecule is varied: it may be an antibody or simply a fragment, a peptide or non-peptide chelating agent. The presence of a linker of variable size makes it possible to separate the two parts of the radiotracer and thus minimize the interference of the chelating structure on the affinity of the target molecule for its substrate. In addition, the choice of the structure of the linker (PEG, polylysine, etc.) can guide the mode of elimination of the compound to the kidneys or improve its solubility and biodistribution, thus modifying its pharmacokinetics (Liu, S. et al. , Chemical Reviews, 1999. 99 (9): 2235-2268). An example of use of metabolizable linker has been described in the literature. This approach allows for increased removal of the circulating medium compound (Smith-Jones, P.M. et al., Nuclear Medicine and Biology, 1997. 24 (8): 761-769). Among the disadvantages of this approach, the large size of the compounds obtained is troublesome since it increases the probability of generating an immune response of the body. On the other hand, these tracers can target only membrane receptors or circulating proteins because their size strongly limits their passage in the intracellular medium (Hom, RK et al., Nuclear Medicine and Biology, 1997. 24 (6): p 485-498). It is also necessary to identify on the vector a site where the linker can be fixed without altering its affinity. The choice of this site can be guided by molecular modeling or structure-activity relationship studies, but must take into account the chemical feasibility of this fixation and its regioselectivity. Finally, the availability of vector molecules may prove to be an obstacle to the development of these approaches and require, for example, the development of new synthetic routes.

Another limitation of the use of this type of compound lies in their application for the production of kits used in hospitals. In contrast to a "metal-essential" complex where the chelating agent can be introduced in large amounts since it has no target affinity in the absence of metal, a large excess of unlabeled functional chelating agent may enter compete with the tracer and decrease its effectiveness. It is then essential to improve the marking conditions to tend towards a stoichiometric performance. Despite the relative ease of labeling with technetium, the design of tracers remains empirical since it is relatively difficult to predict their behavior in vivo. The development of a tracer for use in humans is therefore often a long and expensive optimization. The development of tracers in vivo requires the isotopic labeling of a biological molecule (peptides, proteins, liposomes, small nonpeptide molecules, etc.) having a marked affinity for the target to be imaged and which will play the role of vector. This labeling may sometimes be accomplished by isotopic substitution or direct labeling using the natural ability of the molecule to complex the radioelement. The addition of these complexing structures to a biological molecule most often requires a rather long development linked to the unpredictability of the behavior of these conjugates in vivo. Molecular engineering to refine the tracer structure very often requires complete resynthesis, resulting in high cost and development time. Other studies have also shown that the best ligand of a biological target (better results in vitro) is not always the best tracer in vivo. The transition to the animal model indeed requires taking into account the criteria of biodistribution, excretion, metabolism. The development of combinatorial chemistry tracers requires the selection of structures and chemistry compatible with this approach. In practice, it will therefore be necessary to use, for example, peptide synthesis, which makes it possible to rapidly and efficiently prepare solid support compound libraries or so-called "click chemistry" reactions (Mincit, TL et al., ChemMedChem, 2009. 4 (4): pp. 529-539, Mincit, TL et al., Journal of the American Chemical Society, 2006. 128 (47): 15096-15097) which allow in a single step of conjugate two molecules. This second possibility is currently in full swing because it has a real potential because of its simplicity of use and its performance (Moses, J. et al., Chemical Society Reviews, 2007. 36: pp. 1249-1262; Tron, GC et al., Medicinal Research Reviews, 2008. 28 (2): 278-308). Radiotracers in which the radioelement is introduced via click chemistry have already been described, including 8F (Hausner, SH et al., Journal of Medicinal Chemistry, 2008. 51 (19): 5901-5904; Hong, V et al., Bioconjugate Chemistry, 2010. 21 (10): pp. 1912-1916, Ross, TL et al., Bioconjugate Chemistry, 2008. 19 (12): pp. 2462-2470) for PET. The objective set by the inventors is the development of new radiotracers that can be used as medicaments for medical imaging or radiotherapy applications. They have thus demonstrated specific structures based on triazole, having particularly attractive biodistribution properties and significantly improved compared to complexes without N2S2 and N3S triazole groups. In addition, the structures identified have the advantage of being easily synthesizable by a direct, simple and versatile combinatorial approach: chemistry-click. This technique thus makes it possible to optimize the tracers by combinatorial chemistry for various applications: preparation of tracers on solid support or in solution, under various conditions, compatible with numerous chemical functions. The inventors have been particularly interested in the preparation of integrated and bifunctional technetium tracers using a combinatorial approach. Indeed, technetium appears, both on its radiochemical properties and by its ease of use, as an "ideal radioisotope" for diagnostic imaging.

The complexes intended to be used in medical imaging, their preparation from a chelating agent had to be performed efficiently (quantitative complexation), fast (a single step, with a reaction time low at the time scale 99mTc (6.02 h), if possible without requiring additional purification) and simple enough to be used in hospital by a physician-manipulator.

The resolved complexes had to be usable in vivo, and therefore necessarily have a high stability in biological medium. The structures chosen should therefore be as stable as possible with regard to demetallation or oxidation. In particular the exchange reactions of chelating agents with endogenous glutathione or cysteine should be minimized. Indeed, circulating fluids, and especially blood, contain glutathione at fairly variable concentrations (approximately 250 nM on average but 2 to 3 mM at the brain level for example (Samuelsson, M. et al., Neuropeptides, 2011. 45: pp. 287-292).

The structures of the chelating agents candidates had to present a maximum of sites allowing to introduce a functionalization allowing to orient their bioactivity. It is at these sites that it will be possible to chemically modify, during a new synthesis, the starting platform to transform it into an integrated tracer or link it to a biological molecule in the case of a bifunctional approach, without affect its chelating properties. The choice of these sites and the methods of functionalization are often determined empirically. In this context, it was desirable that one or more of these sites allow the implementation of combinatorial chemistry in order to consider the simple and fast preparation of chemical libraries of functionalized chelating agents.

In the development of the basic structure used for the development of the chelating agent family of the invention, two types of complexes described in the literature have been more particularly studied: Triazole-technetium tricarbonyl complexes: Since a few years ago, technetium tricarbonyl complexes involving a tridentate chelating agent having within its structure one or more 1,2,3-triazole rings directly involved in the complexation of technetium have been developed (Mindt, TL et al., Journal of the American Chemical Society, 2006. 128 (47): 1509615097; Struthers, H. et al., Chemistry - A European Journal, 2008. 14 (20): 6173-6183; Mindt, TL et al. ChemMedChem, 2009. 4 (4): 529-539) (Scheme 7). These complexes are formed quantitatively and do not require purification. In addition, the 1,2,3-triazole ring is introduced by a click chemistry reaction, the copper catalysed Holesen dipolar cycloaddition. This strategy makes it possible to introduce at the level of the triazole ring a wide variety of substituents via combinatorial methods. However, obtaining these complexes of Tc (I) requires delicate conditions including handling under an atmosphere of carbon monoxide or precursors of carbon monoxide released by heating (Journal of the American Chemical Society, 2001, 123 (13) : pp. 3135-3136; Dalton Transactions 2007 (17), 1651-1660).

## STR2 ## ## STR2 ## ## STR2 ## li ,, Tc ', 0 Ph \ f \ YES.' ## EQU1 ##, ## STR1 ## ## STR2 ## FIG. 7: Tc-Tricarbonyl complexes with triazole chelating agents Tc (V) -N3S complexes with pyridyl or imidazolyl nucleus: This second type of complexes groups together complexes of Tc (V) ## STR1 ## containing N3S tetradentate chelating agents in which one of the metal chelating nitrogen atoms belongs to a pyridyl or imidazoyl heteroaromatic ring (Scheme 8) (Rajagopalan, R. et al., Bioconjugate Chemistry, 1997. 8 (3)). These complexes are obtained with excellent yields (greater than 90%) and are particularly stable in competition tests with cysteine (less than 10% degradation after 24 hours). has the advantage over the heart technetium tricarbonyl to be obtained very easily by reducing sodium pertechnetate in the presence of the chelating agent.

Finally, the structure of these complexes is more rigid and more varied than the tetricarbonyl complexes, thus making it possible to envisage various approaches of functionalization via combinatorial methods. ## STR1 ## Scheme 8: 99mTc-N3S complex with a pyridyl or imidazoyl nucleus The inventors have now discovered a basic structure combining the properties of these two types of complexes: they are complexes of N3X-type metal radioelements in which X = N, O, S in which a 1,2,3-triazole nucleus directly participates in the complexation via nitrogen 3. Obtaining this triazole nucleus by click chemistry makes it easy to introduce diversity into this position by combinatorial chemistry during Subsequently, the subject of the present invention is the precursor compounds corresponding to the following formula (I): (I) in which: the unit A is chosen among the groups of formula: R 3 .54 or OR OR OR OR or R 6 OH R 6 R 6 R 6 R 6 R 6 SH 6 R 7 R 6 R 6 R 6 R 6 R 6 SH 6 R 7 B is chosen from the groups of formula: R 4 0 3 4 % 1 CH or OR or R5, OR RK Where n is 0 or 1, R 1, R 2, R 3, R 4, R 5, R 6 and R 7, which may be identical or different, are chosen from H, an alkyl, alkoxy, aryl, aralkyl, heteroalkyl, heteroaryl or heteroaralkyl radical; saturated or unsaturated mono- or polycyclic hydrocarbon or heterocarbon group, a mono- or polysaccharide, or an amine derivative of mono- or polysaccharides, a polyether such as polyethylene glycol oxide (PEG) or polypropylene glycol (PPG) a polyamide, said radicals and / or groups being optionally substituted by one or more hydroxyl groups, acids, amines, aminoalkyls, amino acids, thiols, thioalkyls, urethanes, ureas, halogens, or an LV group in which L is a spacer arm ( or linker) and V is a vector, and with the proviso that: V is unit A represents the following acetylenic group: R3 R4 V or unit B represents one of the following acetylenic groups: R4 'H OR of the present invention, by: - Alkyl: a linear or branched saturated hydrocarbon aliphatic group, preferably having 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. The term "branched" means that at least one lower alkyl group such as methyl or ethyl is carried by a linear alkyl chain. As an alkyl group, there may be mentioned, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl and n-pentyl groups. Alkoxy: an O-alkyl group in which the alkyl group can have the same meaning as that indicated above. By way of example of alkoxy groups, mention may especially be made of methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy and pentoxy groups. Aryl: any functional group or substituent derived from at least one aromatic ring; an aromatic ring corresponds to any planar mono- or polycyclic group comprising a delocalized system in which each atom of the cycle comprises an orbital p, said orbital p overlapping each other. Among such aryl groups, there may be mentioned phenyl, benzyl, benzylcyclobutene, pentalene, naphthalene, benzylphenyl, and anthracene groups. The aryl groups of the invention preferably comprise 1 to 12 carbon atoms, and more preferably 5 or 6 carbon atoms. Aralkyl: any group derived from an alkyl group as defined above in which a hydrogen atom is replaced by an aryl group. - Heteroaryl: any functional group or substituent derived from at least one aromatic ring as defined above and containing at least one heteroatom selected from P, S, and N; among the heteroaryl groups, mention may be made of furan, pyridine, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyrazine, pyrimidine, pyridazine, benzofuran, isobenzofuran, indole, isoindole, benzothiophene, benzo [ c] thiophene, benzimidazole, indazole, benzoxazole, benzisoxazole, benzothiazole, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, purine, and acridine. Saturated or unsaturated mono- or polycyclic hydrocarbon or heterocarbon group: any functional group or substituent derived from a non-aromatic ring comprising at least 10 3 carbon atoms, and preferably 1 to 12 carbon atoms, optionally optionally comprising one or more heteroatoms selected from P, S, O and N. Among such groups, there may be mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the cyclohexyl group being preferred. Among the monosaccharides which can be used according to the present invention, mention may be made of: glucose, lactose, fructose, mannose, galactose, ribose, maltose, sucrose. One can also mention open-chain monosaccharides. Amino derivatives of sugars include glucosamine and galactosamine. Among the polysaccharides that may be used according to the present invention, there may be mentioned chains consisting of several monosaccharide units, for example: sucrose, maltose and lactobionic acid. When polyether, such as polyethylene glycol oxide (PEG) or polypropylene glycol (PPG) is used, it advantageously comprises from 30 to 100 EG or PG units, and preferably from 50 to 60 units. When speaking of polyamide, it advantageously comprises 30 to 100 monomeric units. According to one advantageous embodiment, the precursor compounds of the invention correspond to the following formula (IA): (TA) in which the unit A is chosen from the groups of formula: OR OR 5 or or R 6 R 6 OH The present invention also relates to compounds, also known as chelating agents, obtainable from a compound of formula (I) according to the invention, and corresponding to the following formula (II): ## STR2 ## (II) wherein n, Rh, R2, R3, R4, R5, and R7 are as defined above, and: the unit A 'is selected from the groups of foimule: R3 \) ziz "4 N NN Y or R6 or 1 ::%; \ or R6 OR R6 OR R6 ,,) i1 / 44 OR R6 R5 ~ NH2 R6 0 OH 0 R7 - Unit B 'is selected from groups of formula: NV OR NV Y Il / NN Wherein Y is selected from alkyl, alkoxy, aryl, aralkyl, heteroalkyl, heteroaryl, heteroaralkyl, saturated mono- or polycyclic hydrocarbon or heterocarbon o u unsaturated, a mono- or a polysaccharide, or an amine derivative of mono- or polysaccharides, a polyether such as polyethylene glycol oxide (PEG) or polypropylene glycol (PPG), a polyamine, a polythioether, a polyester said radicals and / or groups being optionally substituted by one or more hydroxyl, acid, amine, aminoalkyl, amino acid, thiol, thioalkyl, urethane, urea, halogen groups, or an LV group in which L is a spacer arm (or linker) and V is a vector as defined above, and with the proviso that:, / is the unit A 'represents the following triazole group: R3) 1.111 "N" II NNY, / is the unit B' represents one triazole groups according to a preferred embodiment, the chelating agents of the invention have the following formula (IIA) A'-NH NH (IIA) in which n, R1, R2, R3, R4, R5, R6 and R7 are as previously defined, and the unit A 'is chosen from the groups of formula: OR OR OR SH 5 R6 R5b. Or more preferably, the chelating agents of the invention have the following formula (IIB): R5 R6 (IIB) in which n, R1, R2, R3 , R4, R5, R.6 and Y are as defined above. The method for preparing a compound of formula (II) according to the invention by click chemistry by 1,3-dipolar cycloaddition between the azide and the alkyne function of the compound of formula (I) (cycloaddition of Huisgen) is also part of of the invention. More specifically, this process consists in the reaction of a compound of formula (I) according to the invention with an organic azide of type Y-N3, the latter being able to be generated in situ from sodium azide and from a sodium azide. Y-Hal halide in which Hal represents a halogen atom, and Y is as defined above, said reaction being carried out in the presence of copper (Organic Letters 2004, 6 (22): 3897-3899; Medicinal Chemistry Letters 2008, 18 (3): 1195-1198). Preferably, the Hal halogen atom is the bromine atom. The invention therefore relates to a radiotracer capable of being obtained from a compound of formula (II) according to the invention, and corresponding to the following formula (III): (III) in which n, R1, R2, R3 , R4, R5, R6 and Y are as defined above, and: - M is a metal radioelement, - n 'and n ", identical or different, are equal to 0 or 1. When one of the radicals R 1, R 2 , R3, R4, R5, R6 or Y is an LV group in which L is a spacer arm (or linker) and V is a vector: the spacer arm (or linker) L is preferably selected from an aliphatic or aromatic polycarbonate chain substituted or unsubstituted, a polyether such as polyethylene oxide (PEG), a polyamine, a polylysine, a dendrimer, a polypeptide, a structured linear or cyclic peptide platform of the RAFT type (Reversible Addition-Fragmentation Chain Transfer), a polysaccharide, a phospholipid, a nucleic acid or a peptide nucleic acid (PNA ), and the vector V is a biologically active molecule, such as: a peptide or a peptide derivative, and in particular pseudopeptides, peptidomimetic compounds or else peptide and pseudopeptide polymers, a protein, a nucleic acid, a liposome, an oligonucleotide modified or unmodified DNA or RNA, a nucleotide, a nucleoside, a aptamer, or a modified or unmodified peptide nucleic acid (PNA), a vitamin, a steroid, a phospholipid, a receptor of the central nervous system, a polyamine, a polyester, a polythioether, a substituted or unsubstituted aliphatic, aromatic or heteroaromatic polymer. Advantageously, the spacer arm (or linker) L is a peptide or a peptide derivative preferably having 1 to 12 amino acid residues, a polyether such as polyethylene glycol oxide (PEG) or polypropylene glycol (PPG). preferably having 1 to 40 EG or PG units, a polyamine preferably having 1 to 20 monomeric units, a mono- or polysaccharide preferably having 1 to 20 saccharide units. Particularly advantageously, the metal radioelement M is selected from among 94mTc, gTc, 99mTc, 1Re, 186Re, 187Re and 188Re, and n and n are equal to 1. The metal radioelement M may also be selected from 67Ga. or 68Ga, and in this case n and n 'are equal to 0. The process for preparing a compound of formula (III) is also part of the invention, said process being carried out by reaction of a compound of formula ( II) according to the invention with a metal radioelement in oxide form, in the presence of a base, such as tin chloride or sodium hydrosulfite. The metal radioelement in oxide form may advantageously be sodium pertechnetate (TcO4, Na) or sodium perrhenate (ReO4-, Na). Another subject of the invention relates to a kit consisting of: a container comprising a compound of formula (II) according to the invention and a reducing agent such as tin chloride or sodium hydrosulfite, and - a generator portable device comprising a metal radioelement solution, preferably selected from 94mTc, 99gTc, 99mTc, 185Re, 186Re, 187Re and 188Re, said metal radioelement being in oxide form, and - a container comprising a base, such as triethylamine in a suitable solvent or buffer, to bring the pH of the final mixture back to a value between 7.2 and 7.6. Advantageously, the compound of formula (II) is present in the container in the form of amorphous or crystalline powder, or optionally in the form of an oil. A final subject of the invention relates to a compound of formula (III) according to the invention for its use in vivo as a diagnostic radiotracer. The compound of formula (III) according to the invention can be used in vivo as a contrast agent for the diagnosis, in particular by medical imaging by MonoPhotonic Emission Tomography (TEMP) or by Positron Emission Tomography (PET). The compound of formula (II) may also be used as a radio-therapeutic agent for targeted radiotherapy of various pathologies, or as a potential therapeutic agent. The invention relates more particularly to the compound of formula (III) for its use as a non-targeting radiotracer, for example as a radiotracer of circulatory and metabolic flux, or as a tissue marker, and in particular for the molecular imaging of cardiac and renal functions. , hepatic, sanguine, cerebral. The compound of formula (III) according to the invention may also be used as a medicament, and more particularly: as an integrated targeting radiotherapeutic agent, for example for the treatment of cancers, neurodegenerative diseases, pathologies of the central nervous system, atherosclerosis and thrombosis, cardiovascular diseases, hepatic, renal or cardiac pathologies, hypoxia or inflammation, or - as a bifunctional radiotherapeutic agent for targeted radiotherapy treatments, such as metabolic radiotherapy, local radiotherapy, vector radiotherapy, radioimmunotherapy and radioimmunology, for example for the treatment of cancers, neurodegenerative diseases, diseases of the central nervous system, atherosclerosis and thrombosis, hypoxia, inflammation , cardiovascular diseases, or liver, kidney or heart diseases. The metal radioelement M is preferably selected from 94mTc and 99mTc for radio-diagnostic applications, 185Re and 187Re for pharmaceutical applications, and 1g6Re and 188Re for radiotherapy applications. In addition to the foregoing, the invention also comprises other arrangements which will become apparent from the additional description which follows, which relates to examples showing the advantageous properties of the compounds of the invention, as well as to the accompanying figures in FIG. which: FIG. 1 represents the radiochromatograms showing the stability of TriaS-99mTe (99mTe-1) in an acidic medium under the precipitation conditions of the plasma proteins; FIG. 2 shows the radiochromatograms of TriaS-99mTc (99mTe-1) after incubation in murine plasma at 37 ° C, - Figure 3 represents the kinetics of degradation in murine plasma (nanomolar concentration, 37 ° C, 6h) of a radiotracer according to the invention (99mTe-1: -) and two references (N2S2, 99mTc-13: A and N3S, 99mTc-14: Figure 4 shows the evolution of the percentage of residual complex after 2 hours of incubation in murine plasma when the initial proportion of complex varies, - the F Fig. 5 shows the biodistribution observed for Trias-99mTc (a) and 99mTc-reduced (^) 2h after injection in mice (n = 3), - Fig. 6 is a visualization at f3-imager using radiation 0 - minority associated with the decay of 99mTc. Left: sac sac sacrificed 2h after injection of TriaS-99mTc - Right: mouse section after injection of a tracer with significant residual accumulation in the organs of the gastrointestinal tract, Figure 7 is a radio-HPLC analysis of urine of healthy mice collected 2 h after injection, FIG. 8 represents the radio-HPLC profile of the complex TriaS-99 (m + g) Te after 2 h of incubation in healthy mouse urine at 37 ° C., FIG. 9 is a radiochromatogram studying the stability of TriaS99mTe in murine blood (37 ° C, 2h); Figure 10 shows the HPLC and radio-HPLC chromatograms of: A: compounds 51a and 99mTc-51a; B: 51b and 99mTc-51b compounds; C: 53 and 99mTc-53 compounds. EXPERIMENTAL PART: Various chelating agents containing a triazole unit and meeting the definition of the compounds of formula (II) of the invention were synthesized from precursors of formula (I). Among these chelating agents, one has been used for producing a radiotracer which meets the definition of the compounds of formula (III). This compound was then studied in vitro and in vivo, then its potential for the production of tracers illustrated by an application to the 433 integrin imaging. I / PROCEDURES FOR THE 1.3-DIPOLAR CYCLOADDITION OF HUISGEN FROM PRECURSOR FORMULA (I) The formation of triazoles via the cycloaddition of Huisgen can be carried out under a wide variety of conditions. In the present case, two types of conditions have been implemented.

A protocol 1 made in a DMSO / water (9/1) mixture forming benzyl azide in situ from benzyl bromide and sodium azide was carried out. The catalyst used is CuSO 4, 5H 2 O in the presence of sodium ascorbate (Procedure 1, Scheme 9) (Feldmann, AK et al., Organic Letters, 2004. 6 (22): 3897-3899; al.

Bioorganic & Medicinal Chemistry Letters, 2008. 18 (3): p. 1195-1198). H (1.0 equiv) (1.0 equiv.) NaN3 (1.4 equiv.) CuSO4.5H2O (0.2 equiv.) Sodium ascorbate (1.2 equiv.) L-Proline (0.2 equiv.) Na2CO3 (0.2 equiv.) DMSO: H2O ( 9: 1) 60 ° C Scheme 9: Huisgen # 1 cycloaddition procedure: DMSO / H 2 O (9/1), 60 ° C.

Protocol 1: The alkyne (1.0 equiv.) Is dissolved in the minimum of an EtOH / H 2 O mixture (7/3). L-Proline (0.2 equiv.), Sodium carbonate (0.2 equiv.), Benzyl bromide (1.0 equiv.), Sodium ascorbate (0.2 equiv., Molar aqueous solution), CuSO4.5H2O (0.2 equiv.) equiv., molar aqueous solution) and sodium azide (1.4 equiv.) are added to the mixture which becomes pale green. The mixture is stirred in the microwave (300W, 80 ° C) in a sealed flask for 30 minutes. The solvent is then removed under reduced pressure and the brown solution obtained is taken up in ethyl acetate and then washed with a saturated solution of NaCl. The organic phases are combined, dried over anhydrous sodium sulphate and the solvent is evaporated under reduced pressure to yield the desired compound.

Protocol 2 using microwaves in sealed vial (300W, 80 ° C, 30 min) to significantly reduce reaction times (Klein, M. et al., Organic & Biomolecular Chemistry, 2009. 7 (17): 3421-3429) has also been implemented (Scheme 10). In addition, this reaction is carried out in a mixture EtOH: H 2 O (7: 3) allowing a good solubilization of the reagents and a much more effective treatment.

HR (1.0 equiv) (1.2 equiv) NaN3 (1.4 equiv.) CuSO4.5H2O (0.2 equiv) sodium ascorbate (0.2 equiv) L-Proline (0.2 equiv.) Na2CO3 (0.2 equiv) EtOH: H2O ( 7: 3) MW, 300W, 80 ° C, 30 min NN Scheme 10: Huisgen No. 2 Cycloaddition Procedure: EtOH / H2O (7/3), MW, 300W, 80 ° C, 30 min.

Protocol 2 The alkyne (1.0 equiv.) Is dissolved in the minimum of EtOH / H 2 O (7/3). L-Proline (0.2 equiv.), Sodium carbonate (0.2 equiv.), Benzyl bromide (1.0 equiv.), Sodium ascorbate (0.2 equiv., Molar aqueous solution), CuSO4.5H2O (0.2 equiv.) equiv., molar aqueous solution) and sodium azide (1.4 equiv.) are added to the mixture which becomes pale green. The mixture is stirred in the microwave (300W, 80 ° C) in a sealed flask for 30 minutes. The solvent is then removed under reduced pressure and the brown solution obtained is taken up in ethyl acetate and then washed with a saturated solution of NaCl. The organic phases are combined, dried over anhydrous sodium sulphate and the solvent is evaporated under reduced pressure to yield the desired compound.

In both protocols, the formation of triazole is still the penultimate step in the synthesis of chelating agents. The compound is then deprotected with a TFA / TIPS / water mixture without prior purification in order to reveal the protected chelating polar functions. Once deprotected, the compound is then purified by semi-preparative RP-HPLC.

II / SYNTHESES OF THE CHELATING AGENTS OF FORMULA (II) Twelve chelating agents of foimule (II) (1 - 12) subdivided into two series: series A and series B, and two non-triazole reference chelating agents, respectively of N2S2 type (13) ) and N3 S (14) were synthesized.

Table I: Series A ,, o N o, ..--- \ os .....'...,), o ......-- \ Al \ -Ph -., -. , .......,. SH NH2 NHAc N H N N H N N N, A A, A 0, 0, 0, 0, SH OH 0 OH Series B 0 1 -..., / HO /., ... B1 HS / HO -. 0 / --- NH N li r N-- N HN - 1 Ph- / 0, ....., NH o ## STR1 ## Synthesis of Chelating Agents ## STR1 ## The six chelating agents of formula (II) of series A can be separated into two categories: on the one hand diamine-triazole (1 and 2) or triamide-triazole (3) chelating agents obtained by a double peptidic coupling and which constitute the Al series, on the other hand three amide-amine-triazole chelating agents (4-6) forming the A2 series (Table I).

Al series (chelating agents 1-3): The syntheses of the chelating agents 1 and 2 are carried out in 4 steps by a double peptide coupling followed by a Huisgen cycloaddition reaction. Compound 3 is obtained directly from compound 2 by acylation in order to study the effect of a triamide chelating agent on the complexation of technetium (Scheme 11). ## STR2 ## Scheme 11: Synthesis of Al Series Chelating Agents: (a) TrtOH, TFA, rt, 3h, 92%; (b) BoeG1yOH, DCC, DIPEA, THF, rt, 24h, 64%; (c) 1) DCM / TFA (2/1), 0 ° C, 1.5h, 2) 15, DCC, DIPEA, DCM, rt, 24% 50%; (d) CuAAC procedure # 1, 38%; (e) TFA / TIPS / H20 (95 / 2.5 / 2.5), rt, 2h; (f) 1) DCM / TFA (2/1), rt, 1H, 2) BocGlyOH, DCC, DIPEA, DMF, rt, 48h, 73%; (g) CuAAC procedure # 2, 78%; (h) (AcO) 20, DIPEA, rt, 2h, 93%. Triphenylmethanol (5.2 g, 20.0 mmol) is dissolved in 60 mL of TFA and mercaptoacetic acid (1.39 mL, 20.0 mmol, 1.0 equiv) is added. After stirring for 3 hours at room temperature under an argon atmosphere, the TFA is removed under reduced pressure. Toluene was chased 3 times on the resulting orange solid resulting in 15 as a white solid (6.12 g, 18.3 mmol, 92%). 1 H NMR (CDCl3, 250 MHz): 7.31 (m, 15H, Trt), 3.05 (s, 2H, CH2); 13 C NMR (CDCl 3, 62.5 MHz):? 176.0 (CO), 143.9 (C, Ph), 129.7 (C, mea Trt), 128.2 (C, ortho Trt), 127.1 (C, para Trt), 67.3 (C, Trt), 34.6 (CH2).

Boc-Glycine (2.63 g, 15.0 mmol) is dissolved in 20 mL of THF. Propargylamine (960 μL, 15.0 mmol, 1.0 equiv) is added, followed by DIPEA (3.9 mL, 22.5 mmol, 1.5 equiv) and DCC (3.71 g, 18.0 mmol, 1.2 equiv.), Then the whole is stirred at room temperature overnight. After filtration of the precipitate, the solvent is evaporated under reduced pressure. The product is dissolved in DCM and washed with 10% citric acid solution (3 times) and with saturated NaCl solution. The organic phases are grouped together, dried over anhydrous sodium sulphate, filtered and the solvent is evaporated under pressure, and the organic phases are combined and dried over anhydrous sodium sulphate, filtered and the solvent is evaporated under pressure. scaled down. Purification by flash chromatography (eluent: hexane / AcOEt 6/4, Rf = 0.37) gave compound 16 (2.04 g, 9.62 mmol, 64%). NMR (CDCl3, 250 MHz): 6.41 (s, 1H, N-CO), 5.30 (s, 1H, NH-000), 4.08 (dd, J = 5.2, J '= 2.5, 2H, CH2-C), 3.82 (d, J = 5.8, 211, CH 2 -CO), 2.24 (t, J = 2.5, 1H, CE-CH), 1.46 (s, 9H, Bac); 13C NMR (CDCl3, 62.5 MHz): 8169.3 (CO amide), 79.3 (C, Bac), 77.4 (CECH), 71.9 (CECH), 29.2 (CH2-CECH), 28.4 (CH3, Boc). Compound 16 (950 mg, 4.5 mmol) is deprotected with 30 ml of a DCM / TFA mixture (2/1) for 1 h 30 at 0 ° C. After evaporation of the solvent, toluene is removed 3 times. The deprotected reagent was dried under reduced pressure and added to 20 mL of DCM containing compound 15 (1.503 g, 4.5 mmol, 1.0 equiv), DIPEA (4.7 mL, 27.0 mmol, 6.0 equiv) and DCC (1.114 g). 5.4 mmol, 1.2 equiv.). The mixture is stirred overnight at room temperature. After filtration of the precipitate, the filtrate is washed with a solution of 10% citric acid 3 times and with a saturated solution of NaCl. The organic phases are combined, dried over anhydrous sodium sulphate and filtered. The solvent is removed under reduced pressure and the oil obtained is purified by flash chromatography (eluent: hexane / AcOEt 4/6) to give compound 17 in the form of a brown solid (0.963 g, 2.25 mmol, 50%) . 1H NMR (CDCl3, 250 MHz): 7.27 (m, 15H, Trt), 3.99 (s, 2H, CH2-CEC), 3.59 (s, 2H, N-CH2-CO), 3.17 (s, 2H, S-CH 2 -CO), 2.15 (s, 1H, CECH); NMR (CDCl3, 62.5 MHz):? 169.1, 168.0 (2 CO), 143.8 (C, Trt), 129.4, 128.2, 128.0 (CH, Trt), 77.2 (CECH), 71.8 (C-CH), 43.5? (CH2-N), 35.5 (CH2-S), 29.1 (CH2-CEC). Compound 17 (214 mg, 0.5 mmol) is dissolved in 2.5 mL of DMSO / water (9/1) and L-proline (11.5 mg, 0.1 mmol, 0.2 equiv.), Benzyl bromide (59.4 μL, 0.5). mmol, 1.0 equiv.), sodium carbonate (63.6 mg, 0.6 mmol, 1.2 equiv.), sodium ascorbate (50 μM of 1M solution, 0.1 equiv.), CuSO 4 · 5H 2 O (25 μL of 1M solution). , 0.1 equiv.) And sodium azide (39.0 mg, 0.6 mmol, 1.2 equiv) are added according to the cycloaddition procedure No. 1 to give compound 18 as a brown solid (107 mg, 0.19). mmol, 38%). 1H NMR (d6-DMSO, 250 MHz): 8.34 (t, J = 5.5, 1H, NH-CO), 8.17 (t = 5.7, 1H, NH-CO), 7.92 (s, 1H, CH); triazole), 7.32 (m, 20H, CH Trt + Ph), 5.54 (s, 2H, CH2-Ph), 4.26 (d, J = 5.5, 2H, N-CH2-00), 3.58 (d, J = 5.5). , 2H, N-CH 2 -C = C), 2.83 (s, 2H, S-CH 2 -C 2); 13 C NMR (CDCl 3, 62.5 MHz):? 169.01 168.0 (CO, amide), 143.7 (C, triazole), 129.4-127.8 (CH Ar, Trt + Ph), 127.0 (CH, triazole), 71.6 (C, Trt) , 60.3 (CH2, Bn), 35.4 (CH2-CC), 33.8 (N-CH2-CO), 29.0 (S-CH2-00); ES (positive mode): m / z = 562.2 (MF11, 54%), 584.2 (MNa ±, 100%), 600.1 (MI ({, 21%).

Compound 18 is deprotected with a TFA / TIPS / water mixture (95 / 2.5 / 2.5) for 2 hours at room temperature. The solvent is evaporated under reduced pressure and the product is taken up in a water / ACN mixture (4/1) and purified by semi-preparative RP-HPLC (tR-17.4 min) to yield compound 1 (3.0 mg). Analytical RP-HPLC: tR = 14.6 min (purity = 99%); NMR (CDCl3, 250 MHz): S 7.45 (s, 1H, CH-NN = N), 7.39 (m, 2H, NH-CO), 7.25 (m, 5H, CH Ar), 5.50 (s, 2H, CH2Ph), 4.51 (d, .1 = 5.5 Hz, 2H, C112-CC), 3.95 (d, J = 5.5 Hz, 2H, N-CH2-CO), 3.27 (d, J = 9.0 Hz, 2H, S). -CH2-00). ; 13C NMR (CDCl3, 62.5 MHz): 6168.5, 167.6 (CO), 145.1 (C, triazole), 144.0, 129.1, 128.8, 128.1 (CH Ar), 123.0 (CH triazole), 65.9 (CH2 Bn), 40.0 ( CH2, Gly). MALDI / TOF: m / z = 319.9 (MH +, 100%).

Compound 16 (424.2 mg, 2.0 mmol, 1.0 equiv.) Is deprotected with a 1/1 TFA / DCM solution (5 mL) for 1 h at room temperature. After evaporation under reduced pressure, toluene is removed on the product to yield a red oil. After dissolution in DCM, the solution is neutralized by addition of triethylamine and the solvent is evaporated to yield a yellow oil which is used without purification. This oil is taken up in 20 ml of dry DMF, the Boc-Gly-OH (350 mg, 2.0 mmol, 1.0 equiv) is added then the pH is adjusted to 8 by addition of DIPEA. DIPEA (420 .1.1. 2.4 mmol, 1.2 equiv.) Is added followed by DCC (0.454 g, 2.2 mmol, 1.1 equiv.). The mixture is stirred for 2 days at room temperature. After filtration of the precipitate, the solvent is removed under reduced pressure. The product obtained is dissolved in DCM is washed with a 10% citric acid solution three times, and with a saturated solution of NaCl. The organic phases are combined, dried over anhydrous sodium sulphate and the solvent is evaporated under reduced pressure. The product is precipitated in hexane at 0 ° C and the compound 19 is obtained by filtration in the form of a white solid (390 mg, 1.45 mmol, 73%). 1H NMR (CDCl3, 250 MHz): S 7.15 (s, 1H, NH-CO), 7.07 (s, 1H, NH-CO), 5.44 (s, 1H, NH Boc), 4.04 (m, 4H, CH2 Gly) + CH2C .-- C), 3.85 (d, J = 5.7, 2H, BocN-CH2), 2.20 (t, 1H, J = 2.5, C- = CH), 1.46 (s, 9H, Boc); 13C NMR (CDCl3, 62.5 MHz): S 170.5 (N-COO), 168.7 (N-CO), 71.5 (C-CH), 43.1 (CH2 Gly), 29.2 (CH2-CC), 28.4 (CH3 Bac) .

Compound 19 (161.5 mg, 0.6 mmol) is dissolved in 4 mL of EtOH / water 7/3 and treated with L-proline (11.5 mg, 0.1 mmol, 0.2 equiv), Na 2 SO 4 (10.6 mg, 0.1 mmol, 0.2 equiv), benzyl bromide (59.4 μL, 0.5 mmol, 1.0 equiv), sodium ascorbate (39.6 mg, 0.2 mmol, 0.2 equiv), CuSO4.5H2O (100 μL of 1M solution, 0.2 equiv. ), and sodium azide (45.5 mg, 0.7 mmol, 1.4 equiv.) according to the cycloaddition procedure No. 2 to give 20 as a yellow oil (45.5 mg, 0.39 mmol, 78%). 111 NMR (CDCl3, 250 MHz): δ 7.82 (s, 1H, CH triazole), 7.54 (s, 2H, NH-CO), 7.33 (m, 5H, Ph), 5.77 (s, 1H, NH-000) , 5.44 (s, 2H, CH2 Bn), 4.43 (s, 2H, CH2-CC), 3.94 (s, 2H, CH2 Gly), 3.78 (d, J = 4.3, 2H, CH2 Gly), 1.39 (s, 9H, Boc); 13C NMR (CDCl3, 62.5 MHz): 8170.3, 169.2 (CO amide), 134.3 (C, triazole), 129.0-128.1 (CH Ar, Bn), 80.0 (C, tBu), 54.2 (CH2, Bn), 49.1 (N-CH2-CO), 44.2 (CH2-C = C), 42.8 (N-CH2-CO), 28.2 (CH3, tBu). The compound is treated with 10 ml of a TFA / TIPS / water mixture (95 / 2.5 / 2.5) for 2 hours at room temperature and the solvent is then evaporated off under reduced pressure. The product is dissolved in 5 mL of an ACN / water mixture (1/4) and purified by semi-preparative RP-HPLC (tR = 15.0 min) to yield 9.2 mg of compound 2. Analytical RP-HPLC: tR = 14.4 min, purity = 99%; 111 NMR (CDCl3, 250 MHz): δ 7.69 (s, 1H, CH triazole), 7.37 (m, 5H, Ar Bn), 5.50 (s, 2H, CH2 Bn), 4.40 (s, 2H, CH2), 3.87 (s, 2H, CH 2 Gly), 3.72 (s, 2H, CH 2 Gly); 13C NMR (CDCl3, 623 MHz): 3 182.8 (CO), 155.1 (CH triazole), 128.4, 127.8, 127.4 (Ar CH), 46.6 (CH2 Gly), 40.3 (CH2-C = C); MALDI / TOF: m / z = 303.2 (MH +, 100%). Compound 2 (4.6 mg, 0.015 mmol) is dissolved in 200 μl of dry DCM and treated successively with DIPEA (15.6 μM, 0.090 mmol, 6.0 equiv) and acetic anhydride (4.25 μL, 0.045 mmol, 3.0 equiv.). The mixture is stirred for 2 hours at room temperature. After evaporation of the solvent under reduced pressure, compound 3 is obtained in the form of a white solid (4.8 mg, 13.9 mmol, 93%). Analytical RP-HPLC: tR = 17.3 min, purity = 100%; NMR (CD3CN, 250 MHz): S, 7.67 (s, 2H, 2 NH-CO), 7.25 (m, 5H, Ph), 6.83 (s, 1H, CH triazole), 5.48 (s, 2H, Bn), 4.58 (m, 2H, CH 2 -C = C), 2.02 (s, 3H, CH 3); 13C NMR (CDCl3, 62.5 MHz): 8168.9 (CO), 154.9 (C, triazole), 131.4, 128.4, 127.4 (CH Ar), 123.9 (CH triazole), 39.2 (CH2 Gly), 22.4 (CH3 Ac); ES / MS (positive mode): m / z = 345.3 (MH +, 100%), 367.3 (MNa +, 25%), 383.2 (MK +, 7%).

Series A2 (chelating agents 4 -6): The amine-amide-triazole type A2 (4 to 6) chelating agents are obtained in three steps from bromoacetyl bromide. After a first acylation reaction in the presence of propargylamine, the variable pattern of these chelating agents is fixed by alkylation (slow reaction requiring heating at 50 ° C) (Scheme 12). Example 12: Synthesis of chelating agents 4-6: (a) TrtOH, TFA, rt, 2h, 86%; (b) Propargylamine, Cs 2 CO 3, DCM, 0 ° C, 30 min, quant. ; (c) 2-aminophenol, Cs 2 CO 3, DMF, 50 ° C, 7, 38%; (d) CuAAC Procedure No. 1, 24%, (e) tert-butylglycine hydrochloride, Cs 2 CO 3, DMF, 50 ° C, 3%, 19%; CuAAC, Procedure No. 1, 63%; (g) TFA / TIPS / H20 (95 / 2.5 / 2.5), rt, 2h; (h) 21, Na2CO3, DMF, 50 ° C, 24h, 48%; (i) CuAAC, Procedure # 2, 54%.

The cysteamine chloride (4.99 g, 44.0 mmol, 1.1 equiv) is treated with triphenylmethanol (10.41 g, 40.0 mmol) in TFA (100 mL) at room temperature for 2 h. An intense orange color is formed. TFA is removed under reduced pressure and 100 mL of water and then 50 mL of DCM are added. A saturated solution of NaHCO 3 is added until pH 7, a white precipitate is formed. After filtration, the white solid is dried under reduced pressure to yield 21 (15.45 g, 34.5 mmol, 86%). NMR (CDCl3, 250 MHz): 7.24 (m, 15H, Trt), 4.24 (s, 3H, NH3), 2.47 (d, J 5.5, 2H, CH2-N), 2.35 (d, J = 5.5, C1-12-S); 13C NMR (CD30D, 62.5 MHz): 145.4 (C, Ar Trt), 130.4; 128.9, 127.8 (CH, Ar Trt), 68.0 (C, Trt), 39.4 (CH2, N-CH2-CH2-S), 30.3 (CH2, N-CH2-CH2-S). Propargylamine (320 μL, 5.0 mmol) is dissolved in 10 mL dry DCM at 0 ° C.

Cesium chloride (3.258 g, 10.0 mmol, 2.0 equiv) and bromoacetyl bromide (436 μL, 5.0 mmol) are added and the mixture is stirred for 30 min at 0 ° C. After filtration, the solvent is evaporated under reduced pressure and the compound is isolated quantitatively without purification. 1H NMR (CDCl3, 250 MHz): 6.70 (s, 1H, NH-00), 4.09 (dd, J = 2.5, J '= - 5.0, 2H, CH2CEC), 2.27 (t, J = 2.5, 1H); , CECH); 13C NMR (CDCl3, 62.5 MHz): 167.0 (CO), 77.9 (CECH), 72.6 (C = CH), 30.2 (CH2-C = C), 27.7 (CH2-CO). Compound 22 (5.0 mmol) is dissolved in 10 ml of DMF and cesium carbonate (1.629 g, 5.0 mmol, 1.0 equiv) and then 2-aminophenol (0.546 g, 5.0 mmol, 1.0 equiv) are added. . The mixture is stirred at 50 ° C for 7 days. After filtration, the solvent is evaporated under reduced pressure and the product obtained is purified by flash chromatography (eluent: hexane / AcOEt 6/4, Rf = 0.12) to yield 23 (0.387 g, 1.9 mmol, 38%): 1H NMR (CDCl3, 250 MHz): 8.0 (s, 1H, OH), 7.25 (s, 1H, NH amide), 6.81 (m, 2H, CH arom), 6.68 (m, 1H, CH arom), 6.48 ( m, 1H, CH arom), 4.06 (dd, J - 5.5 Hz, J '- 2.5 Hz, 2H, CH2-CEC), 3.83 (s, 2H, CH2C0), 2.18 (t, J = 2.5 Hz, 1H; C = CH); NMR (CDCl3, 62.5 MHz): 171.6 (CO); 143.9 (CarOH), 136.1 (CA, NH), 121.0-111.5 (CH arom), 79.0 (CECH), 71.6 (C = CH), 48.8 (C-CO), 36.7 (CH2-CEC). Compound 23 (0.102 g, 0.5 mmol) is dissolved in 2 mL of DMSO / water (9/1). L-proline (11.5 mg, 0.1 mmol, 0.2 equiv), Na2CO3 (63.6 mg, 0.6 mmol, 1.2 equiv), benzyl bromide (59.4 μl, 0.5 mmol, 1.0 equiv.), Sodium ascorbate (100 μl of 1M solution, 0.2 equiv.), CuSO4.5H2O (100 μl of 1M solution, 0.2 equiv), and sodium azide (39.0 mg, 0.6 mmol, 1.2 equiv) are added successively and the mixture is stirred overnight at. 65 ° C under argon according to the cycloaddition procedure No. 1 to give compound 4 (39 mg, 0.12 mmol, 24%). Analytical RP-HPLC: tR = 19.4 min, purity = 93%; 1 H NMR (CDCl3, 250 MHz): 7.81 (s, 1H amide), 7.46 (s, 1H, CH triazole), 7.28 (m, 5H, Ar Bn), 6.89 (m, 4H, CH Ar), 5.42. (s, 2H, CH 2 Bn), 4.35 (s, 2H, CH 2 -C CC), 4.08 (s, 2H, CH 2 CO), 2.20 (s, 1H, NH amine); 13C NMR (CDCl3, 62.5 MHz): 171.8 (CO), 137.9 (CH-CC, triazole), 136.9 (COR), 136.4 (CNH), 134.4 (C, Ph), 129.2-125.9 (CH Bn), 123.3 (CH-C = CH, triazole), 122.5 - 116.3 (CH phenol), 59.3 (CH2 Bn), 57.6 (CCO), 32.0 (CH2triazole); MALDI / TOF: m / z = 338.2 (Mr1 +, 100%). Compound 22 (875 mg, 5.0 mmol) is dissolved in 20 ml of DMF and cesium carbonate (3.258 g, 10.0 mmol, 2.0 equiv) and then tert-butylglycine (1.006 g, 6.0 mmol, 1.2 equiv. ) are added. The whole is stirred for 3 days at 50 ° C. After filtration, the solvent is removed under reduced pressure. The product obtained is taken up in DCM and washed with a 10% citric acid solution 3 times and then with a saturated solution of NaCl. The organic phases are combined and dried over anhydrous sodium sulphate. After filtration, the solvent is evaporated under reduced pressure. The product is taken up in DCM and purified by flash chromatography (eluent hexane / AcOEt 4/6) to yield compound 24 (256 mg, 1.13 mmol, 19%). 1 H NMR (CDCl 3, 250 MHz): δ 3.99 (2H, dd, J = 5.75 Hz, J = 3.25 Hz 2 H, CH 2 -C CC), 3.89 (d, J = 5.25 Hz, 2H, CH 2 -CON), 3.24 (s, 2H, CH 2 CO 2), 2.17 (t, J 2.5 Hz, 1H, CECH), 1.39 (s, 9H, tBu); 13C NMR (CDCl3, 623 MHz):? 171.2 (CO-N), 161.2 (C0-O), 81.8 (C, tBu), 79.6 (CHC), 71.3 (CECH), 52.1 (C-CON), 51.6 ( C-COO), 28.6 (C-CEC), 28.0 (CH, tBu). Compound 24 (113 mg, 0.5 mmol) is dissolved in 2 mL of DMSO / water (9/1). L-proline (11.5 mg, 0.1 mmol, 0.2 equiv), Na2CO3 (63.6 mg, 0.6 mmol, 1.2 equiv), benzyl bromide (59.4 μL, 0.5 mmol, 1.0 equiv), sodium ascorbate (100 μL of 1M solution, 0.2 equiv.), CuSO4.5H2O (100 RL of 1M solution, 0.2 equiv) and sodium azide (39.0 mg, 0.6 mmol, 1.2 equiv) are added successively according to the procedure of Cycloaddition No. 2 to give compound 25 (113 mg, 0.314 mmol, 63%). 1 H NMR (CDCl3, 250 MHz): δ 8.11 (s, 1H, NH-CO), 7.44 (s, 1H, CH triazole), 7.35 (m, 5H, Ph), 5.49 (s, 2H, CH 2 Ph), 4.52 (d, J = 5.8, 2H, CH2-CEC), 3.29 (s, 2H, CH2), 2.93 (s, 2H, CH2-CO2tBu), 2.02 (s, 1H, NH amine), 1.48 (s, 9H). , tBu); 13C NMR (CDCl3, 62.5 MHz): 166.2, 164.8 (CO), 132.0-126.5 (CH Ar, Bn), 122.3 (CH, triazole), 80.2 (C, tBu), 61.7 (CH2, Bn), 36.1 ( CH2C = C), 28.2 (CH3, tBu).

Compound 25 is deprotected with a solution of TFA / TIPS / water (95 / 2.5 / 2.5) at room temperature for 2 hours. After evaporation of the solvent under reduced pressure, the solid obtained is dissolved in a water / ACN mixture (4/1) and purified by semi-preparative RP-HPLC (tR = 14.6 min) to yield compound 5 (7.1 mg). Analytical RP-HPLC: tR = 14.3 min (purity = 97%); 1H NMR (CDCl3, 250 MHz): S 7.35 (m, 5H, Ph), 5.48 (s, 2H, CH2Ph), 4.47 (s, 2H, CH2-C = C), 4.25 (s, 2H, CH2 Gly) 3.81 (s, 2H, CH2C00); 13C NMR (CDCl3, 62.5 MHz): 163.4, 162.0 (2 CO), 129.5, 128.4, 127.3 (CH Ar), 121.5 (CH triazole), 53.2 (CH2Ph), 51.8 (CH2-CO-N), 48.9 ( CH2-CO2H), 42.0 (CH2-C = C); MALDI / TOF: m / z = 304.1 (MH +, 100%). Compound 22 (5.0 mmol, 1.0 equiv.) Is dissolved in 20 ml of DMF and treated with NaCO3 (1.06 g, 10.0 mmol, 2.0 equiv). After stirring for 10 min at room temperature, compound 21 (2.58 g, 6.0 mmol, 1.2 equiv) is added. The mixture is stirred for 24 hours at room temperature, then the reaction medium is filtered and the DMF is evaporated under reduced pressure to give a colorless oil. After purification by flash chromatography, compound 26 (0.986 g, 2.38 mmol, 48%) is obtained. 1H NMR (CDCl3, 250 MHz): 6.60 (s, 1H, NH-CO), 7.23 (m, 15H, Trt), 3.99 (dd, J = 5.5, J '= 2.5, 2H, CH2-C = - C), 3.10 (s, 2H, N-CH 2 -CO), 2.42 (m, 2H, N-CH 2 -CH 2 -S), 2.36 (m, 2H, N-CH 2 -CH 2 -S), 2.11 (t, J = 2.5, 1H, C = CH), 1.79 (s, 1H, NH-Trt); 13 C NMR (CDCl 3, 62.5 MHz): 6170.7 (CO), 144.7 (C, Trt), 126.8-129.6 (CH, Trt), 79.4 (C, C = CH), 71.5 (CH, C = -CH), 66.9 (C, Trt), 51.4 (N-Cl-12-CC), 48.3 (S-CH2-CH2-N), 32.0 (CH2-C = C), 28.8 (S-CH2-CH2-N). Compound 26 (248.7 mg, 0.6 mmol, 1.2 equiv) is dissolved in 2.5 mL of EtOH / water (7: 3). L-proline (11.5 mg, 0.1 mmol, 0.2 equiv), Na2CO3 (10.6 mg, 0.1 mmol, 0.2 equiv), benzyl bromide (59.4 0.5 mmol, 1.0 equiv), sodium ascorbate (39.6 mg, 0.2 mmol, 0.2 equiv /), CuSO 4, 5H 2 O (100 μl of 1M solution, 0.2 equiv) and sodium azide (45.5 mg, 0.7 mmol, 1.4 equiv.) are introduced successively according to the cycloaddition procedure. # 2. The resulting brown oil is precipitated in hexane at 0 ° C to yield compound 27 as a brown solid (176 mg, 0.32 mmol, 54%). 1H NMR (CDCl3, 250 MHz): 7.81 (s, 1H, CH triazole), 7.35 (m, 15H, Trt), 5.37 (s, 2H, Ar Bn), 4.46 (s, 2H, CH2-C = C) ), 3.40 (s, 2H, N-CH2-00), 2.93 (s, 2H, N-CH2-CH2-S), 2.47 (s, 2H, N-CH2-CH2-S); MALDI / TOF: m / z = 548.2 (MH +, 100%).

The compound 27 is deprotected with a TFA / TIPS / water mixture (95 / 2.5 / 2.5) for 2 hours at room temperature. After removal of the solvent under reduced pressure, the solid is taken up in a water / ACN mixture (4/1) and purified by semi-preparative RP-HPLC (tR = 15.7 min) to give compound 6 (7.7 mg). Analytical RP-HPLC: tR = 14.1 min (purity = 97%); 11H NMR (CDCl3, 250MHz): 51H NMR (CDCl3, 250MHz): 7.46 (s, 1H, CH-NN = N), 7.34 (m, 4H, Ph), 5.44 (s, 2H, CH2Ph), 4.42 (s, 2H, CH2-C = C), 3.84 (s, 2H, CH2-CON), 3.24 (m, 2H, CH2, N-CH, -C112-S), 2.87 (m, 2H, CH2, N) -CH2-CH2-S); 13C NMR (CDCl3, 62.5 MHz): δ 168.6 (CO amide), 137.3 (C, Triazole), 134.4 (C, Ar), 129.0 - 127.6 (CH Ar, Bn), 122.1 (CH, triazole), 59.1 (CH2) , Bn), 57.9 (N-CH2-00), 56.1 (S-CH2-CH2-N), 40.5 (CH2-CC), 34.4 (S-CH2-CH2-N); MALDI / TOF: in / z = 306.2 (MH +, 100%). II / B- Synthesis of the chelating agents of the B series The six chelating agents of the formula (II) of the B series were also separated into two categories: those of the B1 series and those of the B2 series. Bi series (chelating agents 7-9): For these compounds, the functional block is introduced by peptide coupling to Cbz-Glycine or acylation by bromoacetyl bromide. The precursor alkyne of the triazole ring is introduced via an alkylation reaction involving propargylamine or propargyl bromide (Scheme 13). ## STR2 ## ## STR2 ## ## STR1 ## ## STR2 ## Figure 13: Synthesis of chelating agents 7 to 9: (a) 2-aminophenol, DCC, DIPEA, THF, rt, 6h, 86%; (b) 1) H2, Pd / C, MeOH, 89%, 2) Propargyl bromide, rt, 48h, 24%; (c) CuAAC Procedure # 1; (d) tert-butylglycine hydrochloride, Cs 2 CO 3, DCM, 0 ° C, 30 min; (e) Propargylamine, Cs 2 CO 3, DCM, 50 ° C, 5%, 38%; (f) CuAAC, Procedure # 2, 50%; (g) TFA / TIPS / H20 (95 / 2.5 / 2.5), rt, 2h; (h) FmocGlyOH, DCC, DMF, rt, 24h; (i) 1) DMF / piperidine (4/1), rt, 3x5 min, 2) propargyl chloride, DCC, DMF, rt, 24h; (j) TFA / TIPS / H20 (95 / 2.5 / 2.5), rt, 2x1h; (k) CuAAC, Procedure # 2, 24%.

The Cbz-Glycine (4.18 g, 20.0 mmol) is dissolved in 60 mL of anhydrous THF. 2-aminophenol (2.18 g, 20.0 mmol, 1.0 equiv), and DCC (5.54 g, 22.0 mmol, 1.1 equiv) are added and the mixture is added at room temperature for 6 h. After filtration of the precipitate, the solvent is evaporated under reduced pressure. The residue obtained is precipitated in a mixture AcOEt / petroleum oil 2/1 (200 mL) to yield compound 28 in the form of a white solid (5.15 g, 17.1 mmol, 86%). 1H NMR (d6-DMSO, 250 MHz): 7.87 (s, 1H, amide), 7.35 (m, 5H, Ar Cbz), 7.22 (s, 1H, carbamate), 6.90 (m, 2H, CH Ar), 6.79 (m, 1H, CH Ar), 5.05 (s, 2H, CH 2 Cb 2), 3.83 (s, 2H, CH 2); 13C NMR (CDCl3, 62.5 MHz): 8170.1 (CO amide), 148.9 (CO carbamate), 127.3-119.9 (CH Ar, Cbz, Ar), 56.5 (CH2, Cbz), 43.6 (CH2, Gly).

Compound 28 (0.9 g, 3.0 mmol) is partially dissolved in 35 mL of methanol. 10% Pd / C (135 mg, 15% w / w) is added and the mixture is stirred vigorously under a hydrogen atmosphere (4 bar) for 1.5 h until complete dissolution of compound 28. After filtration on celite, the solvent is evaporated under reduced pressure to yield an NH Mem. pale yellow solid (447 mg, 2.68 mmol, 89%). Dissolved in 15 mL of DMF, this solid is treated with propargyl bromide (0.289 mL, 2.68 mmol, 1.0 equiv) for 2 days at room temperature. After evaporation of the solvent under reduced pressure, the compound obtained is purified by flash chromatography (eluent: hexane / AcOEt 7/3, Rf = 0.32) to give compound 29 (0.132 g, 0.65 mmol, 24%). 1H NMR (d6-DMSO, 250 MHz): 9.22 (s, 1H, NH amide), 7.0 (m, 4H, CH Ar), 3.55 (d, J = 2.5, 2H, CH 2), 3.43 (s, 2H); , CH2), 2.32 (t, J = 2.3, 1H, alkyne); 13 C NMR (CDCl 3, 62.5 MHz): 171.6 (CO), 148.3 (C-OH, Ar), 126.7 - 118.8 (CH Ar), 80.5 (CH 2 -C = C), 72.6 (CH 2 -C = C), 50.9 (N-CH2-00), 38.3 (CH2-C = C) Compound 29 (113 mg, 0.55 mmol) is dissolved in 1 mL of a DMSO / water (9/1) mixture. L-proline (12.6 mg, 0.11 mmol, 0.2 equiv), Na2CO3 (70.1 mg, 0.66 mmol, 1.2 equiv.), Benzyl bromide (65.4 .tL, 0.55 mmol, 1.0 equiv.), Ascorbate sodium (110 μl of molar aqueous solution, 0.2 equiv.), CuSO 4 · 5H 2 O (110 μl of molar aqueous solution, 0.2 equiv) and sodium azide (42.9 mg, 0.66 mmol, 1.2 equiv) are added successively according to the cycloaddition procedure No. 1 to give the compound 7 in the form of a white solid. This solid is dissolved in 5 μl of water / ACN (4/1) and purified by semi-preparative RP-HPLC (tR = 21.7 min, 3.6 mg). Analytical RP-HPLC: tR = 19.8, purity = 93%; NMR (d 6 -DMSO, 250 MHz): δ 8.11 (s, 1H, CH triazole), 7.25 (m, 5H, Ph), 7.18 (m, 4H, CH Ar), 5.53 (s, 2H, CH 2 -Pi) ), 3.78 (s, 2H, CH 2), 3.18 (s, 2H, CH 2); 13 C NMR (CDCl 3, 62.5 MHz): 5170.2 (CO amide), 147.9 (C-OH, Ar), 137.0 (C = C-CH 2), 134.2-127.8 (CH Ar), 125.6 (C = C-CH 2) 59.1 (CH 2, Bn), 49.1 (CH 2 -CO), 45.6 (C = C-CH 2); MALDI / TOF: m / z = 338.2 (MH +, 100%). Tert-butyl glycine hydrochloride (0.546 g, 5.0 mmol) is treated with DIPEA (1.39 mL, 10.0 mmol, 2.0 equiv) in 10 mL of DCM for 20 min at room temperature. The solvent is removed under reduced pressure and the residue is dissolved in dry DCM. The cesium carbonate (3.2 g, 10.0 mmol, 2.0 equiv) and bromoacetyl bromide (426 1..LL, 5.0 mmol, 1.0 equiv) are added successively and the mixture is stirred at 0 ° C. for 30 min. After filtration, the solvent is removed under reduced pressure to quantitatively conduct the compound 30 as a white solid used directly. NMR (CDCl3, 250 MHz):? 7.00 (s, 1H, NH amide), 3.93 (d, J = 5.0, 2H, CH2-N), 3.89 (s, 2H, CH2-Br), 1.45 (s, 9H, Su); 13C NMR (CDCl3, 62.5MHz): 8170.1, 168.9 (CO), 82.6 (C, tBu), 41.5 CH2-000), 30.6 (CH2Br), 28.1 (Cl-13, tBu).

Compound 30 (5.0 mmol, 1.0 equiv) is dissolved in 10 mL of DMF. Cesium carbonate (3.2 g, 10.0 mmol, 2.0 equiv) and propargylamine (386 μL, 6.0 mmol, 1.2 equiv) are added successively and the mixture is stirred for 5 days at 50 ° C. After filtration, the solvent is evaporated off under reduced pressure and the product obtained is taken up in DCM and then washed three times with a 10% citric acid solution and with a saturated NaCl solution. The organic phases are combined, dried over anhydrous sodium sulphate, filtered and the solvent is evaporated under reduced pressure. The oil obtained is purified by flash chromatography (eluent: hexane / AcOEt 3/7) to give compound 31 (434 mg, 1.92 mmol, 38%). NMR (CDCl3, 250 MHz): δ 7.49 (s, 1H, NH amide), 3.97 (d, J = 5.5, 2H, CH2CO2113u), 3.46 (d, J '= 2.5, 2H, CH2-CC), 3.33 (s, 2H, CH 2 Gly), 2.24 (t, J '= 2.5, 1H, alkyne), 1.82 (s, 1H, NH amine). 13C NMR (CDCl3, 62.5MHz):? 165.8, 164.3 (CO), 84.6 (C? Bu), 79.5 (C? CH), 78.0 (Ca-CH), 39.0 (0-12 Gly), 29.9 (CH3 Su)? ; ES / positive mode: m / z = 360.3 (MEI +, 100%).

Compound 31 (135.7 mg, 0.36 mmol, 1.2 equiv.) Is dissolved in 1.5 mL of ethanol / water (7/3). L-proline (6.9 mg, 0.06 mmol, 0.2 equiv), Na2CO3 (6.36 mg, 0.06 mmol, 0.2 equiv), benzyl bromide (35.6 μL, 0.3 mmol), sodium ascorbate (23.7 mg, 0.12 mmol, 0.2 equiv), CuSO4.5H2O (60 μl of a molar aqueous solution, 0.2 equiv) and sodium azide (28.1 mg, 0.45 mmol, 1.5 equiv) are added successively according to the cycloaddition procedure. No. 2 to give compound 32 (57 mg, 0.169 mmol, 50%). 111 NMR (CDCl3, 250 MHz): S 7.46 (s, 1H, CH triazole), 7.40 (s, 1H, NH, amide), 7.35 (m, 5H, Ar Bn), 5.53 (s, 2H, CH2 Bn) , 3.96 (d, J = 5.5, 2H, CH 2 CON), 3.92 (s, 2H, CH 2 COO), 1.48 (s, 9H, Bu); 13C NMR (CDCl3, 62.5 MHz): 129.6, 129.2, 128.9 (CH Ar), 57.4 (C1-12 Bn), 54.3 (CH2CON), 49.8 (CH2-CC), 41.5 (CH2COO), 28.5 (tBu); ES / positive mode: 360.3 (MH +, 100%). The compound 32 is deprotected with a TFA / TIPS / water mixture (95 / 2.5 / 2.5) at ambient temperature for 2 h, then the solvent is evaporated off under reduced pressure and the product obtained is dried. The resulting solid is dissolved in 5 mL of eaulACN (4/1) and purified by semi-preparative RP-HPLC (tR = 17.3 min) to afford compound 8 (7.6 mg). Analytical RP-HPLC: tR = 15.7 min, purity = 98%; NMR (CD3OD, 62.5 MHz): 8.07 (s, 1H, CH-NN = N), 7.37 (m, 5H, Ar, Ph), 4.26 (s, 2H, N-CH2-CO-O), 3.87 ( s, 2H, CH 2 -C = C), 3.74 (s, N-CH 2 -CO-N), 2.16 (s, 1H, NH amine); 13C NMR (CDCl3, 62.5 MHz):? 171.0 (CO, acid), 169.0 (CO, amide), 144.6 (CC-CH2), 137.4-127.4 (CH Ar, Bn), 122.8 (C = C-CH2), 58.7 (CH 2, Bn), 54.1 (CH 2 -CO-N), 49.2 (C = C-CH 2), 41.3 (CH 2 -COOH); (ES / positive mode: m / z = 304.2 (MH E, 100%).

The 4-methoxytrityl eysteamine resin (0.7 mmol / g, 1.0 g, 0.7 mmol) is packaged in DCM (3 x 1 min) and then DMF (3 x 1 min). A solution of Fmoc-Gly-OH (2.08 g, 7.0 mmol, 1.0 equiv) in 15 mL of DMF followed by DIPEA (1.2 mL, 7.0 mmol, 10.0 equiv) is added and the mixture is stirred for 10 min. DCC (1.45 g, 7.0 mmol, 10 equiv) is added and the mixture is stirred overnight at room temperature. The Kaiser test is then negative. The reagents are removed by filtration and the resin is washed successively with DMF (3 x 1 min), DCM (3 x 1 min), and methanol (3 x 1 min). The resin is then packaged in DCM (3 x 1 min) then DMF (3 x 1 min) and treated with a piperidine / DMF mixture (1/4) (3 x 5 min) and then washed successively with DMF (3). x 1 min), DCM (3 x 1 min) and again DMF (3 x 1 min). The Kaiser test is then positive. The resin is treated with propargyl chloride (774 μl of 70% toluene solution, 7.0 mmol, 10.0 equiv) and DIPEA (1.2 ml, 10.0 equiv) in 10 ml of DMF at room temperature for a period of one hour. night. The Kaiser test is then negative. After washing with DMF (3 x 1 min) and DCM (3 x 1 min), the compound is removed from the resin by a solution of TFA / TIPS / water (95 / 2.5 / 2.5) for 2 x 1h. The filtrates are combined and the solvent is evaporated under reduced pressure to yield compound 35.1H NMR (CD3OD, 62.5 MHz): 4.11 (m, 2H, CH2CO), 4.02 (m, 2H, CH2-CECH), 3.47 (m, 1H, SH), 3.02 (s, 2H, CH 2 -N), 2.92 (s, 2H, CH 2 -S); 13C NMR (CDCl3, 62.5 MHz): 164.4 (CO), 78.1 (C = -CH), 72.2 (CH-CH), 56.2 (CH2CO), 37.6 (CH2-CEC), 32.4 (CH2-N), 29.7. (CH2-S); MALDI / TOF: miz = 414.2 (MH +, 100%).

Compound 35 (103 mg, 0.6 mmol, 1.2 equiv) is dissolved in 2.5 mL of EtOH / water (7/3). L-proline (11.5 mg, 0.1 mmol, 0.2 equiv), Na2CO3 (39.6 mg, 0.2 mmol, 0.2 equiv), benzyl bromide (59.4 pt, 0.5 mmol, 1.0 equiv), sodium ascorbate (39.6 mg, 0.2 mmol, 0.2 equiv), CuSO4.5H2O (100 μL of a molar aqueous solution, 0.2 equiv.) And sodium azide (45.5 mg, 0.7 mmol, 1.4 equiv.) Are added successively. according to the cycloaddition procedure No. 2 to yield a brown oil (36 mg) which is purified by semi-preparative RP-HPLC (tR = 21.2 min) to yield compound 9 (5.2 mg). Analytical RP-HPLC: tR = 19.0 min, purity = 94%; 1 H NMR (CD3OD, 62.5 MHz): 7.89 (s, 1H, CH-NN = N), 7.34 (m, 5H, Ar Ph), 5.55 (s, 2H, CH2Ph), 4.49 (s, 2H, CH2); -C = C), 3.87 (s, 2H, N-CH 2 -CO), 3.42 (t, J = 6.75 Hz, 2H, N-CHI-CH 2 -S), 3.09 (t, J 6.75 Hz, 2H, N). -CH2-CH, -S); MALDI / TOF: m / z = 306.4 (M1-1 +, 100%). B2 series (chelating agents 10 -12): Compounds 10 and 11 were prepared from Cbz-Glycine. The carboxybenzyl group indeed has the advantage of being eliminated very cleanly by catalytic hydrogenation and to lead to the deprotected product without deprotection residue while providing a free unprotected amine. Thus the coupling of propiolic acid can be carried out on a reaction intermediate obtained pure. This particular approach could not be used to obtain compound 12 since the carboxybenzyl and trityl protections are not always orthogonal, the trityl being able to react during the hydrogenation. This last synthesis was therefore made from Fmoc-Glycine (Scheme 14).

Scheme 14: Synthesis of chelating agents 10 to 12: (a) 2-aminophenol, DCC, DIPEA, THF, rt, 6h, 86%; (b) 1) H2, Pd / C, MeOH, 1.5h, 2) propiolic acid, DCC, DCM, 0 ° C, 1 h, then rt, 24h, 7%; (c) CuAAC, Procedure # 2, 58%; (d) tert-butylglycine hydrochloride, DCC, DIPEA, THF, rt, 5h, 46%; (e) 1) H2, Pd / C, MeOH, 1.5h, 2) propiolic acid, DCC, DCM, 0 ° C, 1 h, then rt, 24h, 12%; (f) CuAAC, Procedure # 2, 56%; (g) TFA / TIPS / H20 (95 / 2.5 / 2.5), rt, 2h; (h) TrtOH, TFA, DCM, rt, 2h, 88%; (i) 40, DCC, THF, rt, 24h, 72%; (j) 1) DMF / piperidine (4/1), 2) propiolic acid, DCC, DCM, 0 ° C, 1 h, then rt, 24h, 28%; (k) CuAAC, Procedure # 1, 22%; (1) TFA / TIPS / H20 (9512.5 / 2.5), rt, 2h.

Compound 28 (1.50 g, 5.0 mmol) is dissolved in 50 mL of methanol and 10% Pd / C (225.0 mg, 15% w / w) is added. The mixture is stirred for 2 h under a hydrogen atmosphere (4 bar). After filtration on celite, the solvent is evaporated under reduced pressure and the compound obtained (833 mg, 5.0 mmol, quant.) Is dissolved in 20 ml of DCM. The symmetrical anhydride is previously prepared by stirring for 10 min at 0 ° C a mixture of propiolic acid (307.5 mt, 5.0 mmol, 1.0 equiv), and DCC (1.134 mg, 5.5 mmol, 1.1 equiv) in 25 mL of DCM). The symmetrical anhydride thus formed is added to the deprotected compound 36 and stirred for 1 h at 0 ° C. and then overnight at room temperature. After filtration of the DCU, the solvent is removed under reduced pressure and the compound obtained is purified by flash chromatography (eluent hexane / AcOEt 3/7) to give compound 27 (78.5 mg, 0.36 mmol, 7%). 1H, R1VIN (CDCl3, 250 MHz): 7.44 (d, J = 7.5, 1H, amide), 7.25 (s, 1H, amide), 7.07 - 6.80 (m, 4H, CH Ar), 4.19 (s, 2H). , CH2), 2.90 (s, 1H, CH alkyne). The compound 27 (78.5 mg, 0.36 mmol, 1.2 equiv.) is dissolved in 1.5 ml of water (1 HzN TAS TAS 0 CbzHN OH d HO go 41 0 -> "OH FmocHN HN cHN / TAS 43 0 NH HN TAS EtOH / water (7/3), L-proline (6.9 mg, 0.06 mmol, 0.2 equiv), Na2CO3 (6.36 mg, 0.06 mmol, 0.2 equiv), benzyl bromide (35.6 1.1.1). , 0.3 mmol, 1 equiv.), Sodium ascorbate (23.7 mg, 0.06 mmol, 0.2 equiv), CuSO4.5H2O (60 mL of molar aqueous solution, 0.2 equiv) and sodium azide (28.1 mg 0.45 mmol, 1.5 equiv.) Are added successively according to the cycloaddition procedure No. 2 to give the compound 10 (73 mg, 0.21 mmol) which is dissolved in 5 ml of a mixture of ACN / water (4/1). The solution was purified by semi-preparative RP-HPLC (tR = 22.5 min) to give compound 16 (7.6 mg) RP-analytical HPLC: tR = 18.1 min, purity = 96%) 111 NMR (CDCl 3, 250 MHz ): 8.92 (s, 1H, NH amide), 8.20 (s, 1H, NH amide), 7.99 (s, 1H, CH triazole), 7.40 - 6.60 (m, 9H, Bn, Ar), 5.49 (s, 2H, CH2 Bn ), 4.30 (s, 2H, CH 2); MALDI / TOF: m / z = 352.2 (MH +, 100%). The Cbz-Gly-OH (2.09 g, 10.0 mmol) is dissolved in 20 ml of dry THF and then tert-butyl glycine hydrochloride (1.67 g, 10.0 mmol, 1.0 equiv.) And the DCC (2.27 g, 11.0 mmol, 1.1 equiv.) Are successively added. The mixture is stirred for 5 hours at room temperature under an argon atmosphere. After filtration of the DCU, the solvent is evaporated off under reduced pressure and the colorless oil obtained is purified by flash chromatography (eluent: hexane / AcOEt 5/5, Rf = 0.32) to give compound 37 (1.48 g, 4.6 mmol, 46%). 1H NMR (CDCl3, 250 MHz): 7.44 (s, 1H, NH amide), 7.34 (m, 5H, Ph), 6.52 (s, 1H, NH carbamate), 5.12 (s, 2H, CH2-Ph), 3.92 (m, 4H, 2 CH 2 -CO), 1.47 (s, 9H, tBu); 3 C NMR (CDCl3, 62.5 MHz): 169.7, 168.6 (CO amide), 156.5 (CO carbamate), 135.9 (C Ph), 127.9 - 127.5 (CH Ar), 81.4 (C tBu), 66.3 (CH2 Bn) , 43.7 (CH2CON), 41.3 (CH2C00), 27.4 (CH3, tBu).

Compound 37 (1.135 g, 3.0 mmol) is dissolved in 20 mL of methanol and 10% Pd / C (170 mg, 15% w / w) is added. The mixture is stirred for 1 h 30 under a hydrogen atmosphere (4 bar). After filtration on celite, the solvent is evaporated off under reduced pressure and the residue is dissolved in 10 ml of DCM. The symmetrical anhydride of propiolic acid is prepared by the action of DCC (0.742 g, 3.6 mmol, 1.2 equiv) on propiolic acid (221.4 1.1L, 3.0 mmol, 1.0 equiv) in 15 mL of DCM. The symmetrical anhydride is added to the deprotected compound 38 and the mixture is stirred overnight at room temperature. After filtration of the precipitate, the solvent is removed under reduced pressure and the product obtained is purified by flash chromatography (eluent: hexane / AcOEt 3/7) to give compound 38 (84 mg, 0.35 mmol, 12%). NMR (CDCl 3, 250 MHz): δ 4.03 (s, 2H, CH 2), 3.93 (d, J - 5, 2H, CH 2), 1.45 (s, 9H, tBu); 13C NMR (CDCl3, 62.5 MHz): 168.8, 168.5 (CO, amide + ester), 152.7 (C = C-00), 82.5 (C = -CH), 74.8 (C = -CH), 42.8 (CH2- CO-N), 42.0 (CH2-00-0), 24.7 (CH3, tBu). Compound 38 (60.0 mg, 0.25 mmol) is dissolved in 1.5 mL of a DMSO / water (9/1) mixture. L-proline (5.7 mg, 0.05 mmol, 0.2 equiv), Na2CO3 (31.8 mg, 0.3 mmol, 1.2 equiv), benzyl bromide (29.7 0.25 mmol, 1.0 equiv), sodium ascorbate (50 i.t1, molar aqueous solution, 0.2 equiv.), CuSO4.5H2O (50 μl of molar aqueous solution, 0.2 equiv) and sodium azide (19.5 mg, 0.3 mmol, 1.2 equiv) are added successively according to cycloaddition procedure No. 1 to give compound 39 (52 mg, 0.14 mmol, 56%). NMR (CDCl 3, 250 MHz):? 7.95 (s, 1H, CH -NN = N), 7.32 (m, 5H, Ar Ph), 5.54 (s, 2H, CH 2 Ph), 4.33 (s, 2H, CH 2 CO-O), 3.78 (s, 2H, CH 2 -CO-N), 1.24 (s, 9H, tBu); 13 C NMR (CDCl 3, 62.5 MHz): 168.8, 168.8 (CO, amide + ester), 160.8 (C = C-CO), 142.9 (C = C-00), 133.8 (C = C-00), 129.4 - 125.8 (CH Ar, Bn), 82.6 (C, tBu), 54.7 (CH2, Bn), 43.0 (CH2-CO-N), 42.1 (CH2-00-0), 28.1 (CH3, tBu). The compound 39 is deprotected with 10 ml of a TFA / TIPS / water mixture (95 / 2.5 / 2.5) for 2 hours at room temperature. The solvent is evaporated off under reduced pressure and the product obtained is taken up in 5 ml of a water / ACN mixture (4/1) and then purified by analytical RP-HPLC (tR = 21.7 min) to give compound 11 (5.1 mg) . Analytical RP-HPLC: tR = 19.1 min, purity = 100%; 1 H NMR (CDCl 3, 62.5 MHz): 7.72 (s, 1H, CH -NN = N), 7.35 (m, 5H, Ar Ph), 5.59 (s, 2H, CH 2 Ph), 4.18 (s, 2H, CH 2) -CO-O), 3.62 (s, 2H, N-CH 2 -CO-N); 13C NMR (CDCl3, 62.5 MHz): δ 167.1, 166.0 (CO, amide + ester), 141.3 (CC-00), 128.7 (C = C-CO), 128.7 - 128.1 (CH, Bn), 54.6 (CH2, Bn), 33.7 (CH2-CO-N), 31.8 (CH2-00-0). MALDI / TOF: m / z = 318.3 (MH +, 100%). The 2-aminothiophenol (3.756 g, 30.0 mmol) is dissolved in 2.5 ml of DCM and treated with triphenylmethanol (7.8 g, 30.0 mmol, 1.0 equiv.) In 25 ml of TFA for 2 hours at room temperature. The solvent is evaporated off under reduced pressure and the oil obtained is poured into 200 ml of a saturated solution of sodium hydrogencarbonate. The product is extracted with DCM 3 times and the organic phases are combined and washed with a saturated solution of NaCl and then dried over anhydrous sodium sulphate. After evaporation of the solvent under reduced pressure, the compound 40 is obtained in the form of a white solid (9.64 g, 26.25 mmol, 88%). 1 H NMR (CDCl 3, 250 MHz): 7.25 - 7.35 (m, 15H, Trt), 7.04 (m, 2H, meta CH-CH), 6.55 (m, 1H, orthoCH Ph), 7.45 (m, 1H, para CH 3 H), 3.85 (s, 2H, NH 2 amine); 13C NMR (CDCl3, 62.5MHz):? 150.1 (CN, Ph), 144.4, 130.0, 127.8, 126.9 (Trt), 118.9 (CS, Ph), 117.2, 116.0 (CH, Ph), 71.0 (C, Trt)? . Fmoc-Gly-OH (1.485 g, 5.0 mmol, 1.0 equiv.) Is dissolved in 20 mL of anhydrous THF. Compound 40 (1.83 g, 5.0 mmol, 1.0 equiv) and then the DCC (1.135 g, 5.5 mmol, 1.1 equiv) are added successively and the mixture is stirred overnight at room temperature. After filtration of the DCU, the solvent is evaporated under reduced pressure. The oil obtained is taken up in DCM and purified by flash chromatography (eluent: hexane / AcOEt 7/3). A colorless oil is then obtained which precipitates in hexane at 0 ° C to yield compound 41 (2.334 g, 3.61 mmol, 72%) as a brown sorlide. 1 H NMR (CDCl 3, 250 MHz): 7.75 (m, 2H, Fmoc), 7.59 (m, 2H, Fmoc), 7.40 (m, 2H, Fmoc), 7.27 (m, 18H, Trt 3 CH Ar), 6.83 (m, CH Ar), 4.39 (d, J-2.5, 2H, CH 2 Fmoc), 4.10 (t, J 2.5, 1H, Fmoc), 3.62 (d, J = 5.0, 2H, CH 2); 13 C NMR (CDCl 3, 62.5 MHz): δ 143.5 (C, Fmoc), 141.3 (CN, Ph), 137.6 (C, Frnoc), 129.6 (CH meta Trt), 127.8 (CH, ortho Trt), 125.0 (CH, Ph), 123.7 (CH, Ph), 120.0 (CH, para Trt), 61.2 (CH2, Fmoc), 44.9 (CH2, G1y).

Compound 41 (1.62 mg, 2.5 mmol) is deprotected with 20 mL of piperidine / DMF (114). After evaporation of the solvent under reduced pressure, the crude product obtained is taken up in 10 mL of dry DCM. The symmetrical anhydride of propiolic acid is prepared by the reaction of propiolic acid (184.5 [. [L, 2.5 mmol, 1.0 equiv.)) On DCC (257.9 mg, 1.25 mmol, 0.5 equiv) in 10 mL. dry DCM then added to deprotected compound 61. The mixture is stirred for 10 minutes at 0 ° C. and then overnight at room temperature. After evaporation of the solvent, the crude product obtained is purified by flash chromatography (eluent: hexane / AcOEt 3/7) to give compound 42 (0.337 g, 0.71 mmol, 28%). NMR (CDCl3, 250 MHz): 8.21 (s, 1H, NH amide), 8.09 (s, 1H, NH amide), 7.25 (m, 15H, Trt), 3.68 (d, J = 5.0, 2H, CH2); ), 2.84 (s, 1H, alkyne); 13C NMR (CDCl3, 62.5 MHz):? 169.3 (CO, amide), 147.2 (HC = C-CO), 131.7-123.1 (CH, Ar), 88.1 (HC = C), 76.2 (HC = C), 62.3 (C, Trt), 47.1 (CH2-CO-N).

Compound 42 (0.238 g, 0.5 mmol, 1.0 equiv.) Is dissolved in 2 ml of a DMSO / water (9/1) mixture. L-proline (11.5 mg, 0.1 mmol, 0.2 equiv), Na2CO3 (63.6 mg, 0.6 mmol, 1.2 equiv), benzyl bromide (59.4 μL, 0.5 mmol, 1.0 equiv), sodium ascorbate (100 μl of molar aqueous solution, 0.2 equiv), CuSO 4 · 5H 2 O (100 μl of a molar aqueous solution, 0.2 equiv) and sodium azide (39.0 mg, 0.6 mmol, 1.2 equiv) are added successively according to the cycloaddition procedure No. 1 to lead to the compound 43 (69 mg, 0.11 mmol, 22%). 1H RIVIN (CDCl3, 250 MHz): 8.48 (s, 1H, NH amide), 8.32 (d, J = 8.2, 1H, NH amide), 8.10 (s, 1H, CH triazole), 7.30 (m, 22H, Trt + 2 CH Ar + Ph), 6.82 (t, J = 7.4, 2H, CH Ar), 5.55 (s, 2H, CH2-Ph), 3.91 (d, J = 8.2, 2H, CH2 Gly); 13C NMR (CDCl3, 62.5 MHz):? 164.9 (CO, amide), 152.0 (C = C-00), 143.4 (C Arom, Trt), 141.4 (C = C-CO), 137.6 (CC-00), 129.6-119.4 (CH, Ar), 59.0 (C, Trt), 53.5 (CH2, Bn), 43.3 (CH2-CO-N). The compound 43 is deprotected with a TFA / TIPS / water mixture (95 / 2.5 / 2.5) for 2 hours at room temperature. After evaporation of the solvent under reduced pressure, the crude compound obtained is taken up in 5 ml of a mixture eaulACN (4/1) and purified by RP-HPLC semipréparative (tR = 23.9 min) to yield compound 12 (4.7 mg). Analytical RP-HPLC: tR = 23.0 min, purity = 98%; 1H NMR (CDCl3, 250 MHz): 8.24 (s, 1H, NH-CO), 8.03 (d, J = 8.5Hz, 1H, NH-CO), 7.88 (s, 1H, CH-NN = N), 7.25 (m, 7H, Ar Bn + Ar), 6.78 (m, 2H, Ar), 5.50 (s, 2H, CH 2 Ph), 3.41 (s, 2H, CH 2 -CO-N); 13C NMR (CDCl3, 62.5 MHz): 164.9 (CH2-CO), 162.1 (C = C-CO), 146.7 (C-NH, Ph), 141.1 (C = C-00), 130.8, 129.2, 127.1 ( CH, Ar), 121.9 (C = C-CO), 52.3 (CH2-Ph), 43.0 (CH2-C0); MALDI / TOF: m / z --- 368.4 (Mle, 100%). III C-Synthesis of two reference chelating agents The two references 13 and 14 were synthesized by a solid phase convergent synthesis on 4-methoxytrityl cysteamine resin by a double peptide coupling (Scheme 15). 46, where n = 1.1 NH NNB. Figure 15: Synthesis of solid state reference 13 (N2S2) and 14 (N3S) chelating agents: (a) FmocGlyOH, DCC, rt, 3h; (b) 1) DMF / piperidine (4/1), 2) BocGlyOH, DCC, DIPEA, NMP, rt, 24h; (e) 1) DMF / Piperidine (4/1), 2) 15, DCC, DIPEA, NMP, rt, 24h; (d) TFA / TIPS / H2O (95 / 2.5 / 2.5), rt, 2x30 min. The methoxytrityl cysteamine resin (1.0 g, 0.7 mmol.g-1, 0.7 mmol) is packaged in DCM (3 x 1 min) and then DMF (3 x 1 min). Fmoc-Gly-OH (2.08 g, 7.0 mmol, 10.0 equiv.), DIPEA (1.2 mL, 7.0 mmol, 10.0 equiv.) And then DCC (1.45 g, 7.0 mmol, 10.0 equiv.) Are added successively to 20 ml of DMF and the whole is stirred for 3h at room temperature. The reaction is repeated a second time to ensure quantitative coupling (same amounts of reagents). The Kaiser test is then negative. The reagents are removed by filtration and the resin is washed with DMF (3 x 1 min), DCM (3 x 1 min) then DMF (3 x 1 min). The resin is then deprotected with a solution of piperidine in DMF (20%, 3 x 5 min). The Kaiser test is then positive. After successive washes with DMF (3 x 1 min), DCM (3 x 1 min), and NMP (3 x 1 min), Boc-Gly-OH (1.23 g, 7.0 mmol, 10.0 equiv.) in solution in 20 mL of NMP then DIPEA (1.2 mL, 7.0 mmol, 10.0 equiv) and DCC (1.45 g, 7.0 mmol, 10.0 equiv) are successively added. The whole is stirred overnight at room temperature. The resin is then washed with NMP (3 x 1 min) and DCM (3 x 1 min). The Kaiser test is then negative. The resin is treated twice with TFA / TIPS / water (95 / 2.5 / 2.5) for 30 minutes. The solutions are combined and the solvent is evaporated under reduced pressure. The crude product thus obtained is then taken up in 5 ml of a water / ACN mixture (4/1) and purified by semi-preparative RP-HPLC (tg = 11.5 min) to give compound 14 (9.4 mg). Analytical RP-HPLC tR = 7.1 min, purity = 97%); 1 H NMR (CDCl3, 250 MHz): 4.33 (d, J = 6.8, N-CH2-CO), 4.01 (s, 2H, NH2-CH2-C0), 3.29 (m, 2H, CH2-N), 2.92 (s, 2H, CH 2 -S) 13 C NMR (CDCl 3, 62.5 MHz): 171.7, 169.4 (CO, amide), 44.2 (N-CH 2 -CO-N), 43.4 (S-CH 2 -CO-N) , 41.2 (N-CH 2 -CH 2 -S), 26.2 (N-CH 2 -CH 2 -S). ; ES / positive mode: rn / z = 191.9 (MH +, 100%), 213.9 (MNa +, 24.5%), 229.9 (MK +, 7.1%).

The methoxytrityl cysteamine resin (1.0 g, 0.7 mmol.g-1, 0.7 mmol) is packaged in DCM (3 x 1 min) and then DMF (3 x 1 min). Fmoc-Gly-OH (2.08 g, 7.0 mmol, 10.0 equiv.), DIPEA (1.2 mL, 7.0 mmol, 10.0 equiv.) And then DCC (1.45 g, 7.0 mmol, 10.0 equiv.) Are added successively to 20 ml of DMF and the whole is stirred for 3h at room temperature. The reaction is repeated a second time to ensure quantitative coupling (same amounts of reagents). The Kaiser test is then negative. The reagents are removed by filtration and the resin is washed with DMF (3 x 1 min), DCM (3 x 1 min) then DMF (3 x 1 min). The resin is then deprotected with a solution of piperidine in DMF (20%, 3 x 5 min). The Kaiser test is then positive. After successive washes with DMF (3 x 1 min), DCM (3 x 1 min), and DMF (3 x 1 min), compound 52 (2.08 g, 7.0 mmol, 10.0 equiv) in 15 mL of DMF, DIPEA (1.2 mL, 7.0 mmol, 10.0 equiv.) and DCC (1.45 g, 7.0 mmol, 10.0 equiv) are successively added and the mixture is stirred overnight at room temperature. The reagents are removed by filtration and the resin is washed with DMF (3 x 1 min) and DCM (3 x 1 min). The Kaiser test is then negative. The resin is then treated with a TFA / TIPS / water (95 / 2.5 / 2.5) mixture, the filtrates are combined and the solvent is evaporated under reduced pressure to yield a crude product which is taken up in 5 ml of a water mixture. / ACN (4/1) and purified by semi-preparative RP-HPLC (tR = 11.5 min) to yield 13 (12.0 mg). Analytical RP-HPLC: tR = 11.5 min, purity 95%; 1H NMR (CDCl3, 250 MHz): b 4.38 (s, 2H, N-CH2-CO), 3.88 (t, J = 7.0, 2H, CH2-N), 3.80 (s, 2H, S-CH2-00) , 3.14 (t, J = 7.0, CH2-S); MALDI / TOF: m / z = 209.2 (MH +, 100%); 13C NMR (CDCl3, 62.5 MHz): 172.4, 170.1 (2 x CO, amide), 43.4 (N-CH2-CO-N), 41.8 (N-CH2-C112-S), 27.9 (S-CH2-CO) -N), 24.0 (N-CH 2 -CH 2 -S). The characteristics of the synthesized compounds are summarized in Table II below: Table II: Compounds Analytical HPLC Characteristic Function (tR in min) HPLC HPLC (MH +) observed) 1 SH 14.6 99% 319.9 2 NH2 17 , 3 99% 303.2 3 NHAc 14.4 93% 345.2 4 Phenol 19.4 93% 338.2 COOH 14.3 97% 304.1 6 HS 14.1 97% 306.2 7 Phenol 19, 8 93% 338.2 8 COOH 15.7 98% 304.2 9 SH 19 94% 306.4 Phenol 18.1 96% 352.2 11 COOH 19.1 100% 318.3 12 Thiophenol 23 98% 368, 4 13 N2 S2 (reference) 11.3 97% 191.9 14 N3S (reference) 6.9 95% 209.2 III / SYNTHESES OF THE FORMULA (III) RADIOTRACTORS The previously prepared chelating agent 1 was used as the basis for the production of technically-based tracers for medical imaging that can be used for both BFCA tracers and for integrated target tracers (Te-essentials). The technically derived tracers from reference compounds 13 and 14 have also been studied comparatively. III / A Synthesis of Technotreated Radiotracers III / A- 1. Preparation of the 99mTe-1 (TriaS-99 "Tc), 99 '" Tc-1 3 and 99InTe-1 4 Radiotracers In an Eppendorf® tube, are added in this order: 20 μl of the chelating agent at 1 mg / ml (20 μg, 62.6 nmol), 80 ml of water mQ, 35 μl of SnC12 at 1 mg / ml prepared extemporaneously (35 μg, 184.2 nmol). , 3.0 equiv.), 7011.1_, 0.1M sodium hydroxide, and 75 μL of Na99mTcO4 solution freshly eluted from the generator. After incubation for 5 minutes at room temperature, the solution is neutralized by adding 7.1 μl of 1M HCl solution and analyzed by analytical RP-HPLC (gradient: 0-100% B in 30 min, A = H2O + 0.1% TFA). , B = ACN +% TFA). III / A- 2. Preparation and characterization of the 99mTc-1 radiotracer (TriaS-99mTc) The Na99g TeO4 solution is determined by UV: E = 6220 114-1.cm'1 at 245 nm. The TriaS ligand (5 mg, 15.6 μ, mol) is dissolved in 25 mL of water. SnC12 (46.0 pmol, 3.0 equiv., 8.75 mL of a 0.1 mg / mL aqueous solution), sodium hydroxide (17.5 mL of molar aqueous solution) and then Na99gTcO4 (2.1 mL of a 7.5 mM solution) are added and the The mixture is stirred at room temperature for 5 minutes. A slight yellow color is observed. After purification by semi-preparative RP-HPLC (tR = 19.8 min), and lyophilization, the Trias-99gTc complex is obtained. 1.9 mg (4.4 pmol, 28.2%). 1H NMR (CDCl3, 250 MHz): δ 7.72 (s, 1H, CH-NN = N), 7.49 (m, 5H, Ph), 5.78 (dd, J = 26Hz, J '= 14Hz, 2H), 5.35 (d, J = 18Hz, 2H), 4.75 (m, 3H), 4.10 (dd, J = 50Hz, J = 17Hz, 1H); 13 C NMR (CDCl3, 250 MHz): 174.6 (CH2-C = C), 135.9 - 128.9 (CH3- + CH2-C = C), 62.1 (C1-12, Bn), 50.8 (N-CH2-CO) , 47.4 (CH 2 -C = C), 25.1 (8-CH 2 -0); ES / MS (positive mode): m / z = 431.9 (MH +, 100%), 453.9 (Mne, 7.2%), 469.9 (MIC, 1.8%). III / B- Rhenic Radiotracer Synthesis A solution of tin choride (63 mg, 1.05 equiv.) In carefully degassed 0.05 M HCl (1.5 mL) was added under argon to a suspension of sodium perrhenate (92 mg, 0.318). mmol) and sodium gluconate (8503 mg, 8.8 equiv.) in carefully degassed water (4.8 mL). The solution (theoretical final concentration of oxorhenium 50 mmol) is stirred for 1 hour at room temperature under argon (color change from colorless to prussian blue). The resulting rhenium gluconate solution should be free of any black precipitates for use. The ligand (50 pimol) dissolved in carefully degassed methanol (100-500 μl) is then treated with sodium gluconate solution (1 mL, 1.0 equiv) under argon for 15 min at room temperature. The pH is adjusted to 10 by adding triethylamine and the mixture is stirred for 1 hour at room temperature under argon. The green precipitate formed is then isolated by centrifugation and then purified by three successive cycles of washing with methanol and centrifugation. The product is then dried under vacuum and stored at -18 ° C.

IV / IN VITRO STUDY OF THE TECHNICATED RADIOTRACTERES OF FORMULA (III) The blood used was taken from female Balb-C mice of 20 to 25 g and used within one hour. The plasma used was obtained from blood samples of female BalbC mice from 20 to 25 g. These samples are first centrifuged for 15 minutes at 1600 rpm and the supernatant is in turn centrifuged for 15 min at 1500 rpm. The plasma thus obtained is stored at -20 ° C. for use within 3 days or -80 ° C. within a limit of 1 month.

IV / A- Kinetic study The plasma is previously placed at 37 ° C. At t = 0 min, a test solution is made by adding 50 μl of complex solution prepared according to the protocol described above (4.92 MBq in the case of TriaS-99mTc (99mTc-1) to 450 μl of plasma. The mixture is homogenized and a first sample of 50 μL is taken (t = 0 min) This sample is poured into 150 μl of 10% TFA solution The precipitation of the proteins from the plasma is observed After centrifugation for 5 minutes, the supernatant is separated from the precipitate and the activity of each of them is measured, 50 μl of supernatant are diluted in 150 μl of water and injected into radioRP-analytical HPLC (gradient: 0-100% B in 30 min , A = H20 + 0.1% TFA, B = ACN + 0.1% TFA.) The same procedure is repeated for t = 30 min, 1h, 2h, 4h and 6h and the area of the peak corresponding to the complex is evaluated. of this area with that measured at t + 0 min allows the stability curves to be obtained.This study is done in duplicate. To ensure that no dissociation of the complexes takes place, a stability study under precipitation conditions in the absence of plasma (replaced by an equivalent volume of water) was carried out. The radiochromatograms obtained with the compound TriaS99mTc are shown in FIG.

It is found that after 2 hours, the samples taken contain no degradation products, the complex is always present and intact (Figure 1). The kinetic study was then performed using murine murine plasma Balb-C fresh, obtained by centrifugation of blood samples. A freshly prepared complex solution (nanomolar) is added to the plasma (1/9 complex / plasma) and incubated at 37 ° C for 6h. At regular time intervals, a sample of the solution is taken and the proteins are separated by precipitation and centrifugation. The sample is then analyzed by radio-HPLC. Figure 2 shows the shape of the chromatograms obtained, here in the case of TriaS-mTc, taking into account the decay of technetium between the two injections, the curves reflecting the evolution as a function of the incubation time at 37 ° C. the percentage of residual complex in the samples taken is also shown in FIG. 3. The complexes studied have a stability greater than 60% after 6 hours' incubation in murine plasma at 37 ° C. For the compound TriaS-99mTc, it is observed more than 90% of residual complex after 6h of incubation Given the technical difficulties inherent to the measurement carried out at t = 0 min and the pace of palliation observed later, we can think that this sudden variation in the first half an hour of incubation is the result of an artefact related to the experiment.This analysis is all the more legitimate as the radiochromatograms obtained during the kinetic study indicate no formation of degradation product, all the activity measured in the supernatant corresponding to the compound TriaS99mTe. IV / B- Effect of the concentration of TriaS99mTc on the kinetic plateau 25 The plasma is pre-conditioned at 37 ° C. A range of plasma samples in which the complex concentration varies is prepared by mixing in Eppendorf tubes "low bind" respectively 30pL, 201.1L, 1011E, 5p1, and 2pL of complex solution prepared under the conditions described in Ille. 1 to 70 μL, 80 μL, 90 μL, 95 μL, and 98 μg of plasma.

Table III: Plasma (g) Complex solution (i.IL) Dilution factor 70 30 0.3 80 20 0.2 90 10 0.1 95 5 0.05 98 2 0.02 At t = 0 min, 50 1.11_, of mixture are taken and poured into 150 μL of TFA solution (10%). The proteins of the plasma precipitate. After 5 minutes of centrifugation, supernatant and precipitate are separated and their activities are measured. 50 μl of supernatant are then diluted in 150 μl of water and injected into analytical RP-HPLC (gradient 0-100 μl / 0B in 30 min, A = H2O + 0.1% TFA, B = ACN + 0.1% TFA). . The same procedure is repeated at t = 2h for each sample. For each sample, the residual percentage of complex after 2 hours in murine plasma at 37 ° C is evaluated by the ratio of complex peak areas at t = 0 min and t = 2h. This study is done in duplicate. Figure 4 shows the evolution of the residual percentage of TriaS-99mTe complex after 2 hours incubation in murine plasma at 37 ° C. It is found that this residual percentage does not change and remains equal to the value obtained in the case of the kinetic study (10% of complex solution in the plasma) despite the successive dilutions corresponding to an increase in the ratio [Plasma proteins ] / [Complex]. V / IN VIVO STUDY OF THE TRIA-991nTe RADIOTRACER OF FORMULA (III) The evaluation of the TriaS-99mTc complex was completed by an in vivo study in healthy mice in order to evaluate the behavior of the tracer and its biodistribution. Indeed, previously conducted studies on oxotechnetium core complexes with a pyridyl ring in place of triazole revealed high retention of the complex in the tissues, and slow elimination of blood. In addition, these complexes were essentially eliminated by the hepatobillary route. In the case of imidazoyl ligands, this tissue retention was found to be much lower and the complex was eliminated much more rapidly from the blood (Rajagopalan, R. et al., Bioconjugate Chemistry, 1997, 8 (3): 407415). Animal studies were carried out on female BalbC mice from 20 to 25 g in accordance with the Decree on Animal Experimentation (Decree 87-848, 19 October 1987). The manipulations were carried out by a person authorized for animal experimentation. Complex solutions are injected intravenously into the caudal vein of the mouse. These solutions are at physiological pH without organic solvent. For the biodistribution analyzes, the mice are anesthetized after 2 hours with 2% isoflurane and then sacrificed by exsanguination. Blood / urine biological fluids are collected and all organs are removed. For f3-imager acquisition, the mouse was anesthetized with 2% isoflurane and then sacrificed by freezing at -80 ° C. "Full body" sections are made by microtome and visualized with [3-imager (Biospace I3-imager 2000) using the minority emission j3- 99mTc (E = 2 keV) allowing a better resolution than the y imaging.

VI A-Biodistribution The biodistribution study of the TriaS-99mTc complex was carried out on a batch of 3 female Balb-C mice, a line regularly used in tumor model studies (xenografted tumor on athymic Balb-C Nude mice). Bare). In order to precisely evaluate the influence of the complexation by the TriaS ligand with respect to reduced free technetium, the same study was carried out after injection of 99mTc-reduced (99mTeO3 +) under the same conditions in the absence of ligand. Two hours after caudal intravenous injection, the animals are sacrificed by exsanguination and the various organs are removed, weighed and the associated radioactivity is measured by counting y. Figure 5 shows the biodistribution observed in each case (99mTcet 99mTcet 99mTc-reduced) two hours after injection. It is found that free technetium (reduced in the absence of TriaS ligand) accumulates mainly in the liver (60%) and the stomach (5%), suggesting a hepatic metabolism of 99mTc03- 'and its possible reoxidation products. On the other hand, in the case of Trias 99mTc, the activity measured in the liver corresponds to only about 2% of the injected activity. Most of the injected dose is recovered in the urine and kidneys (80% in total). The complex thus appears to be essentially eliminated by the renal route and not to be significantly distributed in the other organs usually fixing the technetium compounds. This result is very interesting because in many cases, a significant part of the activity is observed, a few hours after injection, in the organs of the gastrointestinal tract, thus reducing the contrast in imaging and making it even difficult or impossible to visualize a target located in the abdominal cavity. These results should also be compared to those observed for complexes involving pyridyl and imidazoyl ligands. Table IV presents a comparison between the biodistributions of TriaS-99mTe and complexes of these two types (comparison of biodistributions at 2 hours of triazoyl, pyridyl, and imidazoyl ligand complexes as a percentage of the injected dose). Table IV: HO HOOC e 0 NO ~ N / / N Tc / 0Il SS / 13 \ N Organ TriaS-99mTc A: Pyr-OH A ': Pyr-COOH B: lmi-OH Blood 1.2 17.5 20.5 0.3 Liver 2.7 25.5 10.1 5.0 Reins 4.5 7.9 8.5 0.3 Rate 0.3 0.5 NA NA Muscle 0.0 8.6 10.2 0.3 Urine 74.4 24.5 (*) 35.2 (*) 44.4 (*) Feces NA 16.9 (*) 51.5 (*) 46.3 (*) Total excretion 74.4 41.4 (*) ) 86.8 (*) 90.6 (*) The excretion values marked by (*) correspond to a measurement carried out 24 hours after injection It is found that two hours after injection, the complexes with pyridyl units A and A 'are very present in the blood, liver and muscles. On the other hand, in the case of imidazoyl B ligand complexes, no accumulation in these organs is observed: the pyridyl ligand complexes therefore have a slow elimination. These complexes are therefore less interesting because after two hours, they will lead to a less effective visualization of the target due to a lower contrast. The TriaS-99mTc complex gives comparable results to imidazole ligand complexes from the point of view of retention in the tissues and organs of the gastrointestinal tract. We can also note that pyridyl ligand complexes are eliminated much less effectively from the body than imidazole or triazole ligand complexes (TriaS99mTe): after 24 hours, only 41% of injected activity was eliminated from the body. This value rises to 87% when a carboxylic acid function is added to its structure (A '). This data confirms that it will be possible to improve the elimination of the complexes by the addition of hydrophilic groups, for example. However, TriaS99mTc differs from these analogues in that nearly 75% of injected activity was eliminated after only two hours. Finally, in the case of TriaS99mTc, the complex is essentially eliminated by the renal route. This contrasts with the results of the other three complexes presented for which 40 to 60% of the activity is detected in the feces, indicating elimination by the hepatobillary route. TriaS-99mTc therefore appears to be a very interesting complex structure in comparison to its piridyl and imidazoyl analogues as it has low tissue and blood accumulation and fast renal elimination. In order to confirm this observation, a 4th mouse that received the TriaS-99mTc complex was sacrificed and then frozen to make microtome sections. These sections were then visualized after one night of acquisition at (3-imager using the weak transmitter character 13 of 99mTc (E = 2 keV) .The I3-imager is a device making it possible to visualize an emission 13- with an extreme sensitivity and a resolution much higher than that of a y-camera.The sample to be analyzed is placed in a chamber in which a gas circulates (argon 98%, triethylamine 2%) .In the analysis chamber, two grids peiniettent The particles 5 emitted by the sample ionize the gas, producing ultraviolet light detected by a CCD camera that reconstructs an image (source: biospacelab.com) Figure 6 on the left shows the image one of the images obtained during the visualization of a sac of sacrificed mouse two hours after injection of TriaS-99mTc.It clearly distinguishes the shape of a brighter kidney that contrasts with the rest of the body.For this measurement, theselected sensitivity was very high, yet no significant residual radioactivity was observed outside the kidneys. These are therefore clearly visible. By way of comparison, Figure 6 on the right shows the case of a tracer with a strong accumulation in the organs of the gastrointestinal tract: the contrast is worse and a target located near one of these organs might not be visible. . The rapid elimination of the circulating medium complex is therefore a very positive result. This observation confirms the results of the biodistribution study: the TriaS-99mTe complex is therefore eliminated very effectively by the renal route without significant accumulation in other tissues. V / B- Stability study V / B- 1. Urine analysis Analysis of the urine collected two hours after injection: After having shown that the TriaS-99mTe complex was eliminated in the mouse by the renal route, it remained to be determined whether this complex was excreted intact or in a metabolized form. For this, the composition of the urine collected in the mouse 2h after injection of TriaS99mTe was analyzed. Urine samples were neutralized and injected into analytical HPLCLC (Figure 7). It appears that more than 60% of the dose collected in the urine corresponds to the intact Trias-99mTe complex excreted although three other less important peaks corresponding to more hydrophilic compounds are observed. The majority of the complex does not seem to undergo any metabolic degradation. The peak at about 5 min (about 6% of the collected dose) can be attributed to reduced free technetium.

Study of the stability of TriaS-99mTc and TriaS-99 (μg) Tc in healthy mouse urine: The study is carried out on two female Balb-C mice (20 to 25 g) of the same line as those used during the study. biodistribution test. TriaS-99mTe is prepared under the conditions described above then the solution is filtered on Sep-Pak Light QMA (Waters). A volume V = 100 μl is injected into each of the two mice and these are placed in metabolic cages in order to recover their excretions during the two hours of the study. Two hours after injection, the urine is removed. A sample of 200 μL of urine is neutralized by addition of HCl (1M) and then injected into analytical RP-HPLC (gradient: 0-100 ') / 0 B in 30 min, A = H20 + 0.1% TFA, B ACN + % TFA). In parallel, a solution of TriaS-99 (m + e) Tc is prepared by successively adding in an Eppendorf tube: 20 μl of TriaS at 1 μg / ml (20 μg, 62.6 nmol), 80 μl of water mQ, 35 μl of SnC12 at 1 mg / mL prepared extemporaneously (35 μg, 184.2 nmol, 3.0 equiv), 70 μl 0.1 M sodium hydroxide, 75 μl of freshly eluted Na99mTcO4 solution and 8.4 μL Na99gTcO4 (1.0 equiv.). Balb-C healthy female mouse urine (same line as previously used) is placed at 37 ° C. The test solution is prepared by adding 10 μl of complex solution to 90 μl of urine and then placed at 37 ° C. After 2 hours of incubation, the mixture is neutralized by adding a solution of 1M HCl and then diluted in 100 μl of water before being injected into analytical radio-RP-HPLC (gradient: 0 - 100% B). in 30 min, A = H20 + 0.1% TFA, B = ACN +% TFA). This study is done in duplicate. The use of a 99mTc + 99gTc mixture made it possible to clearly visualize by means of radio-HPLC the peaks corresponding to the metabolization products by means of 99mTc while making it possible to characterize them by MALDI-TOF after decay of the fractions taken. Under these conditions, there is talk of ligand labeled integrally, Trias-99mTc being in the concentration of ncolaire and TriaS-99gTc micromolar concentration. Figure 8 shows the radiochromatogram obtained under these conditions. The four peaks are always present in different proportions. The compound identified at 17.7 min was found to have a mass m / z = 432.1: this is TriaS-Te excreted intact. The masses of the two other compounds could be determined: m / z = 534.0 for the compound observed at 9 min, and two masses mlz = 713.3 and mlz = 743.3 for the compound observed at 11.8 min.

V / B- 2. Study of the stability of TriaS-99 # 7e in healthy mouse blood The Balb-C mouse blood used is freshly collected (half an hour before use). A volume of 50 μl of complex solution is added to 450 μl of blood. The mixture is homogenized and incubated at 37 ° C. After 2 hours of incubation, the mixture is centrifuged for 15 minutes at 1600 rpm and the supernatant is removed gently. A volume of 50 μL of this plasma is then added to 150 μl of 10% TFA solution in order to bring about the precipitation of the plasma proteins. After centrifugation for 5 min, the supernatant is removed. 50 μl of supernatant are diluted in 150 μl of water and then injected into analytical radio-RP-HPLC (gradient: 0-100% B in 30 min, A = H2O + 0.1% TFA, B ACN +% TFA). After precipitation of the plasma proteins, the sample was analyzed by radioHPLC and the radiochromatograms of Figure 9 were obtained.

The formation of a degradation product with a retention time of 1.4 min is observed which seems to correspond to the last visible peak in the excreted urine. According to FIG. 9, the degradation in the blood seems very important, the degradation product being very largely in the majority after 2 hours of incubation. However, in this experiment, the whole complex remains in contact with the blood during the two hours of incubation, so it is normal to observe a much higher degradation. This degradation in the blood can be exploited in the case of an extracellular protein target, the tracer unrelated to the target being degraded and eliminated by the renal route. Without having specifically identified the structure of this second degradation product, we have nevertheless been able to explain its origin, namely a degradation taking place in the blood.

According to the results of the kinetic study carried out in the plasma, it is not linked to a plasma component but probably to a metabolism by the erythrocytes. However, the exact nature of the metabolite could not be determined. In light of all these results, and in particular the analysis of the composition of the urine collected after injection in the healthy mouse, it seems that this degradation has little effect on the use of TriaS for the realization tracers in vivo. Indeed, more than 60% of the activity collected in the urine corresponds to 99mTe-TriaS intact. In addition, the 13-imager visualization of a mouse section after injection of the compound shows an excellent signal / noise ratio, the kidneys appear very clear compared to the rest of the section where very little residual activity appears. This shows that the degradation complex (s) did not accumulate in tissue or liver but were eliminated in the urine.

VII APPLICATION OF THE TRIAL OF FORMULA (II) FOR THE DEVELOPMENT OF IN VIVO RADIOTRACERS OF INTEGRIN A VII A- Generalities on integrins and their ligands Integrins are membrane receptors involved in cellular adhesion processes. They govern cell-cell and extracellular cell-matrix interactions. These integral heterodimeric glycoproteins consist of two α and β subunits. Each subunit is composed of a short cytoplasmic domain with no catalytic activity and a long extracellular domain responsible for binding to endogenous ligands (J. Xiong et al., Science 2001, 294 (5541), pp. 339-345). J. Xiong et al., Science 2002, 296 (6656), pp. 151-155, T. Xiao et al., Nature 2004, 432 (7013), pp. 59-97). In mammals, there are 18 subunits a and 8 subunits 13 leading to 24 distinct combinations. These can be classified into families according to the nature of the ligands. The most important family is that of the tripeptide-binding receptors RGD, which includes the α, β, β-, and R-3 integrins. Integrins are adhesion proteins that are involved in a large number of mechanisms. The transmembrane structure allows them to participate in the transmission of signals between the cytoplasm and the extracellular matrix (inside-out) (F. Ye et al., Journal of Thrombosis and Haemostasis, 2011. 9: p 20-25) and inversely (outside-in) (FG Giancotti et al., Science, 1999. 285 (5430): pp. 1028-1033) In contrast, the binding of the extracellular end leads to a clustering phenomenon (local assembly of integrins that form an oligomer) allowing the transmission of intracellular signals that determine, among other things, cell survival, mobility and polarity, so integrins play a key role in adhesion and polarization phenomena. and of Cellular otility Integrins also participate in angiogenic processes (J. T. Yang et al., Development, 1995, 121 (2), p. 549-560), including tumor neoangiogenesis which conditions the development of tumors in formation, and is implicated in various other pathologies (Wehrle-Haller et al., Journal of Pathology, 2003, 200, pp. 481-487). Some studies have also shown that the presence of integrins, particularly av133, may be associated with active metastasis formation (Felding-Habermann et al., Clinical and Experimental Metastasis, 2002. 19 (5): 427). -436, P. Clezardin, Cellular and Molecular Life Sciences, 1998. 54 (6): 541-548). Table V below shows the integrin expression profiles of various tumors and associated metastases (G. Mizejewski, Proceedings of the Society for Experimental Biology and Medicine, 1999. 222 (2): pp. 124-138). Table V: Cancer Main tumor focus Metastases Breast Colon Kidney Lung Melanoma Ovary Skin Brain NA if co NA a5131 a6134 a3Pi 431 NAalterna a3131 a41: 31 a'133 421131 OE2PI a5131 aubPaia av133 a61134 a3131 a3Pi 433 a2131 1 a313i 426 31 a6134 a 'X33 The integrins 433 play an essential role in tumor neoangiogenesis, in particular. As the latter is overexpressed at the level of the tumor and very little in healthy cells, it is therefore a preferred target for the early detection of primary tumors, tumor recurrence and metastases (WL Rust et al., Journal of Biomedicine and Biotechnology, 2002. 2 (3): pp. 124-130, H. Jin et al., Br J Cancer, 2004. 90 (3): 561-565, R. Haibner, European Journal of Nuclear Medicine and Molecular Imaging, 2006. 33 (0): 54-63, A. Malter, Drug Discovery Today, 2001. 6 (19): 1005-1024). Integrin 003 is one of eight integrins recognizing the structured ArgGly-Asp (or RGD) tripeptide motif (Scheme 16) present in many extracellular matrix proteins such as vitronectin, fibronectin, or fibrinogen (E. Ruoslahti, Matrix Biology, 2003. 22 (6): 459-465) .20 Scheme 16: RGD Tripeptide "Arg-Gly-Asp" The integrin ligands ct, f33 currently being developed are of different types: Monoclonal antibodies such as as Vitaxin (Phase I and II) which are highly selective and can be labeled with various radioelements for use in imaging. Peptide or pseudopeptide ligands having the linear or cyclic RGD sequence are used in vivo. Non-peptide ligands mimicking the RGD motif. These compounds are often obtained by screening chemical libraries. Disintegrins such as Leberagin-C or Acurhagin-C are toxins also currently being studied (I. Limam et al., Matrix Biology, 2010. 29 (2): 117-126; WJ Wang, British Journal of Pharmacology, 2010. 160 (6): 1338-1351). In order to demonstrate the potential of the TriaS platform of formula (II) for the preparation of in vivo radiotracers, two types of technetium radiotracers targeting integrin 433, a marker commonly used for molecular imaging of cancer, have been developed.

Two distinct approaches have been studied: - a first approach which makes use of the concept of Tc-essential tracers, and which consists of the realization of integrated tracer mimics of RGD constructed from the structure TriaS of formula (II) by introduction of a guanidium pattern and a mime aspartate via chemistry-click, and - a second approach which addresses the design of modular bifunctional compounds, and which consists in developing bifunctional tracers constructed from cyclopentapeptide c (RGDfK). VI / B- Development of Integrin Integral Tracer 433 Several integrated complexes ("Tc-essential") mimicking the tripeptide RGD in which the chelation of the metal brings its rigidity to the structure have been synthesized. The arginine residue is conserved while an aspartate mime is introduced at the triazole ring G 63 R NI-12 + H2N N H HN by chemistry-click. Three complexes were thus prepared among which 99mTc-51a (Scheme 17). The functionalized 99mTc-51a complex was also evaluated in murine plasma, which showed a high degree of stability. greater than 50% after 6h of incubation at 37 ° C. In addition, no degradation product was observed, although the stability of the functionalized TriaS complexes seems lower than that of TriaS, this result suggests that the incorporation of Guanidinium and carboxylate functions do not interfere with the chelation process of technetium and cause little destabilization of the complex obtained VI / B-L Synthesis strategy Compound 49, an acetylenic precursor, was prepared in two stages from Fmoc-Arg (Pb0- 0H by successive coupling of propargylamine and tritylated mercaptoacetic acid (Scheme 18) .beta. 12N NH Scheme 18: Preparation of the acetylenic tracer precursor integrated a) Propargylamine, DCC, DIPEA, DCM, rt, 24h, 82%; b) DMF / piperidine (4/1), rt, 2h; c) 15, DCC, DIPEA, rt, 24h, 88% This compound was then involved in the synthesis of the series of alkylcarboxylate ligands 51a-c and para-substituted benzoic ligand 53 (Scheme 19). NH2 -> H2N NH NH2b NH2N (NH NH2 NH NH STrt OR 50a-cn R Rt 1 d3u 50a 49% 2 il3u 50b 34% 3 H 50c - 51 ac n 1 51a 2 51b 3 51c Tc "S / 8 N 99mTc- 51a-cn 1 "Tc-51a 2 99r" Tc-51b NHPbf NH 0 NE1 HN STrt 49 Figure 19: Attachment of aspartate miming by combinatorial chemistry via chemistry-click: a) Cycloaddition of Huisgen (procedure n ° 2) ): Tert-butyl bromoacetate (resp. Tert-butyl bromopropionate and 4-bromobutyric acid), NaN 3, Cu (II), EtOH / H 2 O (9/1), MW, 80 ° C, 30 min; b) Cycloaddition Huisgen (procedure 2): tert-butyl bromoacetate (resp. tert-butyl bromopropionate and 4-bromobutyric acid), NaN 3, Cu (II), EtOH / H 2 O (9/1), MW, 80 ° C. 30 min, c) TFA / TIPS / H2O (95 / 2.5 / 2.5), rt, 1h, d) NaTCO4, SnCl2, NaOH, rt, 5 min.

Finally, the 99mTc-51a complex as well as the two complexes 99gTc-51b and 99gTe-53 were prepared under the same conditions as for TriaS-Te (Scheme 19). VI / B- 2. Synthesis Methods Synthesis of the acetylenic precursor 49: The FmocArg (Pbf) OH (8.11 g, 12.5 mmol, 1.0 equiv.) Is dissolved in 50 ml of dry DCM. Propargylamine (0.8 mL, 12.5 mmol, 1.0 equiv) and HOBt (2.025 g, 15.0 mmol, 1.2 equiv) are added and the pH is adjusted to 8 by addition of DIPEA. After addition of the DIPEA (8.7 mL, 15.0 mmol, 1.2 equiv.), The DCC (3.1 g, 15.0 mmol, 1.2 equiv.) Is introduced and the mixture is stirred under an argon atmosphere at room temperature for 24 h. The formation of a white precipitate of DCU is observed. The DCU is removed by filtration and then the DCM is evaporated and the oil obtained is taken up in AcOEt and then washed with a saturated solution of sodium chloride, and with a 10% citric acid solution. The organic fractions are combined and dried with anhydrous sodium sulphate and then evaporated. The compound (oil) obtained is taken up in DCM and purified by chromatography on a silica column (eluent hexane / AcOEt 20/80, UV revelation, Rf = 0.3). The product is dried overnight under reduced pressure to yield 48 as a white solid. 7.04 g, 10.3 mmol, yield = 82%. 1 H NMR (CDCl 3): δ 7.72 (d, 2H, J = 6.8 Hz, CH Ar, Fmoc), 7.54 (d, 2H, J = 6.8 Hz, CH Ar, Fmoc), 7.352 (t, 2H, J = 6.5 Hz, CH Ar, Fmoc), 7.25 (d, 2H, J = 7.8 Hz, CH Ar, Fmoc), 4.27 (m, 3H, CH 2 Fmoc + Glycyl), 3.97 (s, 2H, CH 2 -C, = CH), 3.26 (m, 2H, CH 2 Arg (e)), 2.89 (s, 2H, CH 2 Pbf), 2.57 (s, 3H, CH 3 Pbf (a)), 2.50 (s, 3H, CH 3 Pbf (c) )), 2.12 (s, 1H, CH2-C = CH); 2.05 (s, 3H, CH 3 Pbf (b)), 1.7-1.5 (m, 4H, CH 2 Arg (f, g)), 1.41 (s, 3H, CH 3 Pbf (d)); 13 C NMR (CDCl3): δ 158.8 (CO amide), 156.5 (CO carbamate), 143.6-117.6 (C Arom, Pbf + Fmoc), 86.4 (C, Pbf), 79.5 (-C CH), 71.3 (-C = --- CH), 67.0 (CH2 Fmoc), 49.9 (CH2 Are)), 46.9 (C, Fmoc), 43.0 (CH2, Pbf), 28.7 (CH2, Arg (g)), 28.5 (CH2 Pbf (d) ), 24.6 (CH2, Arg (f)), 19.3 (CH3, Pbf (a)), 18.0 (CH3, Pbf (b)), 12.4 (CH3, Pbf (c)); (MALDI / TOF: nilz = 419.3 [MLI I.

Compound 48 (4.19 g, 10.0 mmol, 1.0 equiv) is dissolved in 20 mL of DMF / piperidine (4/1) and stirred for 2 h at room temperature. This deprotection is monitored by TLC (eluent: hexane / AcOEt 20/80, Rf = 0.3). The DMF is evaporated under reduced pressure. The oil obtained (10.0 mmol, 1.0 equiv.) Is taken up in 25 ml of dry DCM and 15 (3.34 g, 10.0 mmol, 1.0 equiv) and then HOBt (1.62 g, 12.0 mmol, 1.2 equiv) are added. The pH is adjusted to 8 by addition of DIPEA then the DIPEA (5.8 mL, 10.0 mmol, 1.0 equiv) is added and finally the DCC (2.48 g, 12.0 mmol, 1.2 equiv). The mixture is stirred for 24 h at room temperature under an argon atmosphere. The formation of a white precipitate of DCU is observed. The DCU is removed by filtration and the DCM is evaporated under reduced pressure. The oil obtained is taken up in AeOEt and washed with a saturated solution of sodium chloride and then with a 10% citric acid solution. The organic fractions are combined, dried and evaporated. The product obtained is taken up in DCM and purified by chromatography on a silica column (eluent: AcOEt / hexane 80/20, UV revelation). After evaporation and drying, the compound 49 is obtained in the form of a white solid. 4.48 g, 8.75 mmol, yield = 88%. III NMR (CDCl3): δ 7.89 (t, 1H, J = 2.5 Hz, NH amide (i)), 7.4-7.1 (m, 15H, CH Ar, Trt), 7.07 (d, 1H, J = 7.5 Hz, NH amide (h), 4.33 (d, 1H, J = 5Hz, CH, Glycyl), 3.90 (s, 1H, CH 2 -CHECH), 3.10 (m, 2H, CH 2, Arg-e)), 3.03 (s). , 2H, CH 2 S), 2.92 (s, 2H, CH 2, Pbf), 2.54, 2.47 (s, 3H, CH 3 Pbf x 2), 2.07 (s, 4H, CH 3 Pbf (b) + CH 2 CHCH), 1.44 (s, 6H). , 2 CH3 Pbf (d)). 13 C NMR (CDCl3):? 171.3 (CO amide (i)), 168.9 (CO amide (h)), 158.8 (C Pbf), 143.9 (C Arom, Trt), 132.2 (C Ar Pbf), 129.5-126.8 ( CH Ar, Trt), 124.7 (C Ar, Pbf), 117.6 (C Ar Pbf), 86.4 (C, Pbf), 79.5 (CECH), 71.3 (CECH), 67.7 (C, Trt), 53.5 (CH2, Pbf) ), 36.17 (CH2, Arg (e)), 30.4 (CH2, Arg (g)), 28.6 (CH3, 2 x Pbf (d)), 25.3 (CH2, Arg (f)), 19.39 (CH3, Pbf ( a)), 18.0 (CH3, Pbf (b)), 12.4-CH3, Pbf (c)); MALDI / TOF: m / z = 513.2 [MH1. Synthesis of Chelating Agents 51a, 51b and 53: Compound 49 (93.6 mg, 0.12 mmol, 1.2 equiv) is dissolved in ethanol (750 μL). Huisgen dipolar cycloaddition procedure 2 is applied with the respective halogenated compounds (0.1 mmol, 1.0 equiv) to yield the protected ligand 50a (resp 50b, and 52) and then the deprotected chelating agents 51a, 51b and 53. The The halogenated compound used is tert-butyl bromoacetate (5.4 μL, 0.1 mmol, 1.0 equiv). 50a is obtained in the form of a brown oil (46 mg, 48.9 punol, yield = 49%). After stirring for 1 h in a TFA / TIPS / water (95 / 2.5 / 2.5) mixture, the solvent is evaporated. The solid is taken up in a water / ACN mixture (4/1) and purified by semi-preparative RP-HPLC. The product is lyophilized to yield 51a as a white powder (10.4 mg). RP-analytical HPLC: tR = 8.5 min; 1 H NMR (MeOD): δ 7.99 (s, 1H, NH amide), 7.81 (s, 1H, CH triazole), 5.34 (s, 2H, CH 2 - 000), 4.58 (m, 1H, CH 2 -C), 4.05. -m, 1H, CH Arg), 3.31 (s, 2H, CH 2 S), 1.95-1.75 (m, 6H, 3 x CH 2 Arg); 13C NMR (MeOd):? 173.8, 171.8 (CO amides), 158.6 (CN, Arg), 146.1 (CH2-CC), 125.8 (CH2-CC), 54.5 (CH2-000), 52.0 (CH, Arg), 41.9 (CH2-CC), 35.3 (CH2, Arg), 30.2 (CH2S), 26.3, 26.1 (2 x CH2, Arg) MALDI / TOF: m / z = 387.1 [ML1 +]. The halogenated compound used is tert-butyl bromopropionate (12.8 μL, 0.1 mmol, 1.0 equiv). 50b is obtained in the form of a brown oil (32 mg, 34.0 μmol, yield 34%). After stirring in TFA / TIPS / water (95 / 2.5 / 2.5), the solvent is evaporated. The solid is taken up in a water / ACN mixture (4/1) and purified by RP-HPLC semipréparative. The product is lyophilized to yield 51b as a white powder (3.1 mg). Analytical RP-HPLC: tR = 9.8 min; MALDI / TOF: m / z - 401.1 [MH +].

The halogenated compound used is para-bromomethylbenzoic acid (21.4 mg, 0.1 mmol, 1.0 equiv). 52 is obtained in the form of a brown solid (22.1 mg, 23.0 μmol, yield 23%). After stirring in TFA / TIPS / water (95 / 2.5 / 2.5), the solvent is evaporated. The solid is taken up in a water / ACN mixture (4/1) and purified by RP-HPLC semipréparative. The product is lyophilized to yield 53 as a white powder (1.3 mg). Analytical RP-HPLC: tR = 16.3 min; MALDI / TOF: 462.1 [MH1. Synthesis of the 99gTc-51a, 99gTc-51b, 99gTe-53 and 99mTe-51a radiotracers: Compound 51a (20 lig, 52 nmol, 20 μl of 1 mg / ml solution) is dissolved in 60 μl of distilled water. . After adding 27 μL of SnC12 solution to. 1 mg / ml, and 54 μl of 0.1 M NaOH solution, a solution of Na99gTcO4 is added (1.0 equiv.) And the solution is incubated for 5 minutes at 37 ° C. After adding 5.4 liters of 1M HCl solution, the complex is analyzed by RP-HPLC. Analytical RP-HPLC: tR = 11.4 min; MALDI / TOF: m / z = 499.0 [MFFI.

Compound 51b (20 μg, 50 nmol, 201 μl of 1 mg / ml solution) is dissolved in 64 μl of distilled water. After adding 28 μg of 1 mg / ml SnC12 solution and 56 ml of 0.1 M NaOH solution, a solution of Na99gTcO4 is added (1.0 equiv.) And the solution is incubated for 5 minutes at 37 ° C. After adding 5.6 μl of 1M HCl solution, the complex is analyzed by RP-HPLC. Analytical RP-HPLC: tR = 11 6 min; MALDI / TOF: mh = 513.0 [MI-11.

Compound 53 (20 μg, 43.2 mmol, 201 μl of 1 mg / ml solution) is dissolved in 64 μl of distilled water. After addition of 24 μl of 1 mg / ml SnC12 solution and 48 μl of 0.1 M NaOH solution, a solution of Na99gTcO4 is added (1.0 equiv.) And the solution is placed for 5 minutes at 37 ° incubation. C. After adding 4.8 μl of 1M HCl solution, the complex is analyzed by RP-HPLC. Analytical RP-HPLC: tR - 17.0 min; MALDI / TOF: mlz = 575.0 [M11 +]. Compound 51a (20 μg, 52 nmol, 201 μl of 1 mg / ml solution) is dissolved in 60 g of distilled water. After addition of 27 μl of SnC12 solution at 1 mg / ml, and 54 μl of 0.1 M NaOH solution, 75 μl of Na99mTeO4 solution is added and the solution is incubated for 5 minutes at 37 ° C. . After addition of 5.4 μl of 1M HCl solution, the complex is analyzed by RP-HPLC. Analytical RP-HPLC: tR = 11.2 min and tR = 11.6 min. VI / B- 3. Results The 99mTe-51a, 99gTe-51b and 99gTe-53 complexes were studied by analytical RP-HPLC. The chromatograms obtained are shown in FIG. 10. The three complexes were characterized by mass (MALDI-TOF). It is found that in the case of the complexation of the two ligands 51a and 51b, no signal is present at 4-5 min, and this same signal is very weak in the case of the complexation of 53. There is therefore no more residual reduced technetium: the labeling is quantitative. The addition of functional groups to the structure of TriaS, likely to interfere in the chelation of the metal, therefore has no negative influence on it.

VII C- Development of bifunctional tracers of the integrin avj33 VI / C- 1. Synthesis strategy Numerous ligands of the integrin 433 were identified having good affinities and an interesting selectivity for this integrin with respect to the integrin. . The choice of the targeting molecule is very wide, and it is the cyclopentapeptide c (RGDfV) that it has been chosen to exemplify.

VI / C- 2. Synthesis methods Support synthesis of cyclopentapeptides c (RGDfK) and c (RGDf (N-Me) K): The cyclopentapeptides used were prepared on solid support in Fmoc strategy according to the synthesis scheme shown in Scheme 20 below: ## STR1 ## wherein: X = H 55 X = Me 55b X = H 56 FmocHN- (D) -Phe-Lys (Mmt) -Arg (Pbf) -Gly-Asp-OAll X = Me 56b Xg X = H 57 FrnocHN- (D) -Phe-Lys (Mmt) -Arg (Pbf) -Gly-Asp-COOH X = Me 57b X b, h NHH HN + H2N N NH2 X FI 56 X = Me 58b NHMmt-OMe NHMmt Scheme 20: Supported synthesis of c (RGDfK) and c (RGDf (N-Me) K) peptides: a) FmocAsp (0A11) 0H, DIC, DMAP, DCM / DMF (1/2), rt, 24h; b) DMF / piperidine (4/1), rt, 5 min, 5x; c) FmocGlyOH, DIC, DIPEA, NMP, rt, 24h; d) FmocArg (Pbf) OH, DIC, DIPEA, NMP, rt, 24h; e) FmocLys (Mmt) OH, DIC, DIPEA, NMP, rt, 24h; f) Fmoc- (D) -PheOH, DIC, DIPEA, NMP, rt, 24h; g) tetrakis-triphenylphosphine palladium, AcOH, NMM, CHCl3, rt, 24h; h) HIGH, DIPEA, NMP, rt, 24h; i) o -NBS-Cl, collidine, NMP, rt, 15 min, 3x; j) 1) DBU, NMP - 2) (CH3) 2SO4, NMP x2; k) mercaptoethanol, DBU, NMP, rt, 5 min, 2x The Wang resin (1.14 g, 0.5 mmol) is packaged in DCM (1 x 15 min, 2 x 1 min), then washed with DMF (3 x 1 min). The DMAP (6.1 mg, 0.05 mmol, 0.1 equiv.) Is added in solution in 10 ml of DMF and the resin is stirred for 20 min. FmocAsp (0A11) 0H (1.98 g, 5.0 mmol, 10 equiv) is dissolved in 10 ml of DCM and 4 to 5 drops of DMF. The mixture is placed at 0 ° C for 5 min. DIC (390e, 2.5mmol, 5.0 equiv) is added under argon atmosphere. The mixture is stirred at room temperature for 20 min and then poured onto the resin. The resin is stirred for 24 hours at room temperature and then washed with DMF (3 x 1 min) and DCM (3 x 1 min). Substitution of the resin is evaluated by UV assay at 290 nm. S = 0.412 mmol.g-1, yield 94%.

The resin is packaged in DCM (3 x 1 min) then DMF (3 xl min). Benzyl bromide (297 μL, 2.5 mmol, 5.0 equiv) and then DIPEA (870 μL, 5.0 mmol, 10 equiv) are added and the mixture is stirred at room temperature for 1 h. After washing with DMF (3 x 1 min), DCM (3x1 min) the resin is packaged in DMF (3 x 1 min) and deprotected with a DMF / Piperidine (4/1) mixture (5 x 5 min). After washing with DMF (3 x 1 min), DCM (3 x 1 min), a Kaiser test is performed and gives a blue color (positive). FmocGlyOH (1.486 g, 5.0 mmol, 10.0 equiv) is added in solution in NMP, then DIPEA (870 5.0 mmol, 10 equiv), C1HOBt (848 mg, 5.0 mmol, 10 equiv) and DIC (775e). 5.0 mmol, 10.0 equiv.) Are added successively. After 24h stirring, the resin is washed with NMP (3 x 1 min) then DCM (3 x 1 min). The Kaiser test is then negative. This deprotection / coupling operation is repeated successively with the following amino acids: FmocArg (Pbf) OH (3.24 g, 5.0 mmol, 10.0 equiv) and FmocLys (Mmt) OH (1.60 g, 2.5 mmol, 5.0 equiv.) To lead to Resin 53. A resin aliquot is cleaved with TFA / TIPS / water (95 / 2.5 / 2.5) for 1h at room temperature. After evaporation of the solvent under reduced pressure, the compound is taken up in an ACN / water mixture and analyzed by mass. MALDI / TOF: m / z = 737.3 [M11 +]. The resin (0.25 mmol) is packaged in DCM (1 x 30 min, 2 x 1 min) then DMF (3 x 1 min). The deprotection is carried out with a DMF / Piperidine mixture (4/1) (5 x 5 min) and then the resin is washed with DMF (3 x 1 min), DCM (3 x 1 min) and NMP (3 x 1 min) . Kaiser test positive. 0-NBSC1 (222 mg, 1.0 mmol, 4.0 equiv) and collidine (162.5 mmol, 2.5 mmol, 10.0 equiv) are dissolved in NMP (5 mL) and added to the resin. After stirring for 2 x 15 min at room temperature, the solvent is removed by filtration. Kaiser negative test.

The resin is then washed with NMP (3 x 1 min) and DBU (115 μL, 0.75 mmol, 3 equiv) is added in 5 mL of NMP. After stirring for 3 minutes, Me2SO4 (240 μL, 2.5 mmol, 10.0 equiv) is added and the resin is stirred for 2 x 2 min. Finally, a solution of DBU (190 μL, 1.25 mmol, 5.0 equiv) and mercaptoethanol (175 μL, 2.5 mmol, 10.0 equiv) is added to the NMP and the resin is stirred for 2 x 5 min. The resulting resin 55b is washed with NMP (3 x 1 min), DCM (3 x 1 min). An aliquot of resin is cleaved with a TFA / TIPS / water mixture (95 / 2.5 / 2.5) for 1 h at room temperature. After evaporation of the solvent under reduced pressure, the compound is taken up in an ACN / water mixture and analyzed by mass. ESI: m / z = 265.2 [M + 211-1 and 529.3 [M + H +].

Resin 55 (or 55b) (0.25 mmol) is packaged in DCM (1 x 30 min, 2 x 1 min) followed by NMP (3 x 1 min). Fmoc- (D) -PheOH (0.49 g, 2.5 mmol, 10.0 equiv) is added in solution in NMP, then DIPEA (218 IL, 2.5 mmol, 10 equiv.), C1HOBt (212 mg, 2.5). mmol, 10 equiv.) and DIC (194 2.5 mmol, 10.0 equiv.) are added successively. After 24h stirring, the resin is washed with NMP (3 x 1 min) then DCM (3 x 1 min). An aliquot of resin is cleaved with a TFA / TIPS / water mixture (95 / 2.5 / 2.5) for 1 h at room temperature. After evaporation of the solvent under reduced pressure, the compound is taken up in an ACN / water mixture and analyzed by mass. 56 X = H: ESI: m / z = 884.5 [M + 56b X = Me: ESI: m / z = 449.9 [M + 2F11, 898.5 [M + 11 ±] Resin 56 (respectively 56b) is packaged in DCM (1 x 30 min, 2 x I min) then CHC13 (3 x 1 min). Pd (PPh3) 4 (174 mg, 0.15 mmol, 3.0 equiv) is dissolved in 8 mL of CHC13 / NMM / AcOH (92.5% / 2.5% / 5.0%) and added to the resin. The resin is stirred for 24 hours at room temperature and protected from light. After successive washes with a solution of 0.5% DIPEA in DMF (3 x 1 min), a solution of 0.5% sodium diethyldithiocarbamate in DMF (3 x 1 min), DMF (3 x 1 min), a 8% DIPEA solution in DMF (3 x 1 min), DMF (3 x 1 min), and DCM (3 x 1 min), an aliquot is cleaved with a TFA / TIPS / water mixture (95 / 2.5 / 2.5) during lh at room temperature. After evaporation of the solvent under reduced pressure, the compound is taken up in an ACN / water mixture and analyzed by mass. - 57 X ---- H: EST: m / z = 844.5 [M + - 57b X = Me: ESI m / z = 429.7 [M + 2I]], 858.4 [M + H +] Resin 57 (resp. packaged in DCM (1 x 30 min, 2 x 1 min) then DMF (3 x 1 min). The deprotection is carried out with a DMF / piperidine (4/1) mixture (5 x 5 min) and the resin is then washed with DMF (3 x 1 min), DCM (3 x 1 min) and NMP (3 x 1 min). ). DIPEA (35 mm, 0.2 mmol, 4 equiv) and then HATU (38 mg, 0.1 mmol, 2 equiv) are added in solution in NMP. After 24h stirring, the resin is washed with NMP (3 x 1 min) then DCM (3 x 1 min). An aliquot of resin is cleaved with a TFA / TIPS / water mixture (95 / 2.5 / 2.5) for 1 h at room temperature. After evaporation of the solvent under reduced pressure, the compound is taken up in an ACN / water mixture and analyzed by mass. X = H: ESI: m / z = 604.2 [M + - 58b X = Me: ESI: mlz = 309.2 [M + 2H +], 618.3 [M + H] The two cyclopentapeptides 58 and 58b could thus be obtained and characterized in Mass (MALDI-TOF): m / z = 604.2 [MI ri and 618.3 [MEI +] respectively (Scheme 21). 0 - NH3 + NH3 + 58 - m / z = 604.2 [MF1 +] 58b - 618.3 [MH4] Scheme 21: Cyclopentapeptide c (RGDfK) (58) and its N-methylated form (58b) Synthesis of the bifunctional tracer c (RGDfK) - Lys-99mTcTriaS-PEG: A bifunctional tracer from unmethylated cyclopeptide 58 was then synthesized. In this example, the tracer will have a polyethylene glycol pattern to guide its biodistribution. We have chosen 0- (2-aminoethyl) -0'-42-azidoethyl) -pentaethylene glycol or azido-PEG-NH 2 (n = 6) which is a polyethylene glycol having already the azide function and can therefore be introduced by chemistry-click . He was subsequently designated PEG-N3 (Figure 22). H2N 6 Scheme 22: Structure of PEG-N3 In the synthesized complex, the TriaS structure has a glutamic acid motif in place of lysine. The free carboxylic acid function thus added makes it possible to connect the structure to the cyclopentapeptide by peptide coupling. Compound 60 which will be coupled to the resin is prepared beforehand in solution by coupling propargylamine to glutamic acid (Scheme 23). FrnocHN 60 FiN FelocHN 59 H NI OtBu Scheme 23: Synthon 60 Preparation a) Propargylamine, DCC, CI-HOBt, DIPEA, DCM, rt, 24h; b) TFA / DCM, rt, 30 min The synthesis of the c (RGDfK) -Lys-99mTcTriaS-PEG complex is described in Scheme 24.

HcNyNH 66 "mTc-66 Scheme 24: Synthesis of c (RGDff () - Lys-99mTcTriaS-PEG: a) CI-HOBt (0.6 M), DCM / TFE, rt, 2x 30 min; b) BocLysOH, DIC, HOBt NMP, DIPEA, rt, 24h, c) DMF / piperidine (4/1), rt, 5x5 min, d) 60, DIC, DIPEA, NMP, rt, 24h, e) 15, HATU, DIPEA, NMP, rt, 24h, f) Cycloaddition of Huisgen (Procedure # 2): PEG-N3 (Fig. IV.37), Cu (II), MW, NMP, 80 ° C, 30 min, g) TFA / TIPS / H20 (95 / 2.5 / 2.5) h) Na99mTcO4, SnCl2, NaOH, H2O, rt, 5 min At first, resin 58 was deprotected under mild conditions (CJHOBt (0.6M), AcOH, NMM, rt 2 x 30 min) so as to remove the protective group Mmt without cleaving the resin or partially removing the Pbf protection from arginine, the chain is then extended by coupling the Boc-Lys (Fmoc) -OH. The carboxylic acid function makes it possible to graft 60 onto the resin leading to compound 63. The TriaS structure is then constituted by peptide coupling of tritylated mercaptoacetic acid 15. The reaction of Hu isgen with PEG-N3 to lead to compound 65. After deprotection and cleavage by acidolysis, the ligand 66 had to be engaged in the complexation of the heart oxotechnetium to drive 10 to c (RGDfl () - Lys-99mTe-TriaS-PEG (99mTe-66). a, 6, c, 0 PleHN O 65 64 11211-H PC-IN 9 76 0 0 NHBoc H HN '^ / ° J \ _' He ° ° NH STM1 O NH 56 PbIHN NH sTrt 0 NHHHH NHEoc NH H HN ## STR2 ## ## STR2 ## ## STR2 ## Resin 58 (0.25 mmol) is packaged in DCM (1 x 30 min, 2 x 1 min), followed by TFE / DCM 1/1 mixture (3 x 1 min) 25 mL of 0.6M HOBt solution in TFE / DCM (1/1) are added and the resin is stirred for 30 minutes at room temperature. The resin is rinsed with DCM / TFE 1/1 (3 x 1 min), DCM (3 x 1 min), and NMP (3 x 1 min) Boc-Lys (Fmoc OH (1.17 g, 2.5 mmol, 10 equiv) is dissolved in 20 mL of NMP, followed by Cl-HOBt (0.43 g, 2.5 mmol, 10 equiv), DIPEA (435 mmol, 10 equiv), and DIC (390 μ, 2.5 mmol, 10 equiv) and this mixture is added to the resin After stirring at room temperature for 24 hours, the resin is washed By NMP (3 x 1 min), DCM (3 x 1 min) and DMF (3 x 1 min) and then deprotected by 10 DMF / Piperidine 4/1 (5 x 5 min). Compound 60 (1.20 g, 2.5 mmol, 10 equiv) is dissolved in 20 mL of NMP with DIC (390 mmol, 10 equiv) and DIPEA (435 L, 2.5 mmol, 10 equiv). then added to the resin. After 24h stirring at room temperature, the resin is washed with NMP (3 x 1 min) then DCM (3 x 1 min). An aliquot of resin is cleaved with TFA / TIPS / water (95 / 2.5 / 2.5) for 1h at room temperature. After evaporation of the solvent under reduced pressure, the compound is taken up in an ACN / water mixture and analyzed by mass. MALDI / TOF: 1120.5 [M + H +]. Resin 63 (0.25 mmol) is packaged in DCM (1 x 30 min, 2 x 1 min), then DMF (3 x 1 min), and then deprotected with a 4/1 DMF / Piperidine mixture (5 x 5 min) and washed with DMF (3 x 1 min), DCM (3 x 1 min) and NMP (3 x 1 min). Compound 15 (835 mg, 2.5 mmol, 10.0 equiv) is dissolved in 10 mL of NMP, followed by HATU (952 mg, 2.5 mmol, 10.0 equiv), and DIPEA (435 μL, 2.5 mmol, 10.0). equiv.) are added. The mixture is added to the resin. After 24h stirring at room temperature, the resin is washed with NMP (3 x 1 min) then DCM (3 x 1 min). A resin aliquot is cleaved with TFA / TIPS / water (95 / 2.5 / 2.5) for 1h at room temperature. After evaporation of the solvent under reduced pressure, the compound is taken up in an ACN / water mixture and analyzed by mass. MALDI / TOF: 972.0 [M + H +]. Resin 64 (0.125 mmol) is packaged in DCM (1 x 30 min, 2 x 1 min) followed by NMP (3 x 1 min). The resin is dissolved in 2.3 ml of NMP and then L-proline (25 μl of 1M solution, 0.025 mmol, 0.2 equiv), Na 2 CO 3 (25 μl of 1M solution, 0.025 mmol, 0.2 equiv). sodium ascorbate (50 μl of 1M solution, 0.05 mmol, 0.4 equiv), CuSO4.5H2O (25 μl of 1M solution, 0.025 mmol, 0.2 equiv.), O- (2-aminoethyl) -O'- (2-azidoethyl) pentaethylene glycol (45.8 mg, 0.125 mmol, 1.0 equiv.) And 130 μL of water are added. The resin is then placed in the microwave (80 ° C, 300W, 30 min) then washed with NMP (3 x 1 min), and DCM (3 x 1 min). An aliquot of resin is cleaved with a TFA / TIPS / water mixture (95 / 2.5 / 2.5) for 1 h at room temperature. After evaporation of the solvent under reduced pressure, the compound is taken up in an ACN / water mixture and analyzed by mass. MALDI / TOF: 1322.6 [M + Hl. VI / D- Evaluation Tests V / D-L Integrin Binding Assay The in vitro tests were performed according to a suitable protocol as described below. Et133 integrin (Chemicon, Temecula, CA) is diluted to 1000 ng / mL in buffer 1 (20 mM Tris HCl pH 7.4, 150 mM NaCl, 2 mM CaCl2, 1 mM MgCl2, 1 mM MnCl2). An aliquot of 100 μL / well is added to a 96-well plate (Millipore, Multiscreen-IP HTS) and the whole is incubated overnight at 4 ° C. The plate is washed with buffer 2 (50 mM Tris HCl pH 7.4, 100 mM NaCl, 2 mM CaCl2, 1 mM MgCl2, 1 mM MnCl2 and 1% bovine serum albumin and incubated for 2 h at room temperature. The plate is then incubated for 3 h in the presence of different amounts of ligands (from 0.1 nM to 10 μM) and with 0.06 nM [125I] iodoechistatin.When incubated, the wells are washed twice with buffer 2 and counted in the presence of scintillation fluid (Top count NXT apparatus, PerkinElmer) V / D- 1. In vivo test on xenografted mouse having developed a U87MG type tumor Cell culture: The U87MG cell line was supplied by the European Collection of Cell Culture (SIGMA) and was stored in liquid nitrogen before being cultured The culture medium contains the following elements (for 500 ml): EMEM (Eagle's minimum essential medium) ): 500 mL; 2 mM L-glutamine: 5 mL of a 200 mM solution; 1% amino acids non-essential: 5 ml of commercial solution; 1 mM sodium pyruvate: 5 mL of a 100 mM solution; - 10% FCS (Fetal Calf Serum): 50 mL; penicillin (100 U / mL) and streptomycin (100 μg / mL): 5 mL of a 10,000 penicillin U / mL solution and 10 mg / mL streptomycin in 0.9% NaCl. The medium is filtered and can be stored for 15 days at + 4 ° C. The cells are adherent, and are therefore cultured in flasks. They are maintained at 37 ° C. in a humidified atmosphere at 5% CO 2. Culturing: The cell bulb was removed from the liquid nitrogen and placed immediately in ice. It is thawed under water, and its contents are transferred to a 15 mL vial and the ampoule is rinsed with a little culture medium. The volume is supplemented to 10 mL with culture medium. The mixture is centrifuged (5 min at 1500 rpm) to remove the DMSO that was present for freezing. The supernatant is removed and the cells are resuspended. 5 ml of culture medium are added and the mixture is homogenized before being transferred to a 50 ml flask. It is placed in an oven and its cap unscrewed. The first pass must be made after 24 hours. 20 Passages: for a 275 mL (75 cm3) bottle. Trypsin, medium and Hank 's saline should be used at room temperature. (1) The vial is taken out of the oven under sterile conditions and the cells are observed under a microscope to verify that they have reached confluence. (2) The vial is emptied into a beaker of bleach and carefully rinsed with mL of Hank's saline solution. (3) 5 ml of trypsin are added and the flask is placed for 5 minutes in an oven to promote cell detachment. The still adherent cells are then peeled off by tapping the box on the bench. (4) 5 mL of medium is added and the mixture is homogenized trying to break up the maximum of cell clusters (Vw1 = 10 mL). (5) For a 1/10 passage, 1 mL of the above mixture is introduced into a new 275 mL vial containing 19 mL of medium. After homogenization, the flask is placed in an oven. Depending on the needs, the passage can be done in different proportions from Vtot = 10 mL: passage 1/2: 5 mL cells + 15 mL passage medium 1/3: 3 mL cells + 17 mL passage medium 1/5 2 mL cells + 18 mL of 1/10 passage medium: 1 mL cells + 19 mL of medium When culturing, the first pass is from a 50 mL vial. Rinsing is then carried out with 3 ml of Hank's saline solution, the cells are peeled off with 2 ml of trypsin and then 2 ml of medium are added (Vtot = 4 ml). In the new 275 mL vial, the previous 4 mL is added to 16 mL of media. Different counts were carried out for boxes passed at 1/10 once a week. There are 10,106 to 12,106 cells per box (Malassez counting cell). Preparation of cells for xenografts Tumors are obtained by subcutaneous injection of approximately 5 × 10 6 U87MG cells suspended in 150 μl of EMEM. The number of boxes needed is determined according to the number of tumors to be formed. In general, two supernumerary tumors are predicted for safety. The appropriate number of boxes is treated as described above until step (4). The cell suspensions are then pooled in 50 mL falcons (to be adapted according to the total volume). After centrifugation (5 min at 1500 rpm), the supernatant is removed and the pellets are combined by suspending in culture medium, with a total volume of 50 ml. The number of cells is evaluated by counting on a Malassez cell. The volume corresponding to the number of cells required for the injections is taken. The suspension is centrifuged and the supernatant removed. The cells are resuspended in a volume of EMEM to 150 μl per injection. Implantation of tumors and in vivo studies: The animal studies were carried out in accordance with the Decree on Animal Experimentation (Decree 87-848, 19 October 1987). Tumors were developed on athymic female mice (BaIbC nu / nu) obtained from Charles River Laboratories. The mice are delivered aged 6 weeks (20 g). They are used 1 week after their arrival. For in vivo studies, a subcutaneous injection of approximately 5.106 U87MG cells suspended in 150 μL of EMEM is performed on the right front shoulder of the mice. When tumors are to be collected for in vitro studies, 2 to 3 tumors can be implanted on each animal: one on each shoulder and one in the middle of the back. In all cases, the animals are used 15 days after the injection of the cells. The tumors formed have a diameter ranging from 2 to 4 mm, the largest being the most vascularized. Biodistribution study: The ligands are labeled with 99mTc according to the protocol described in Part III / A-2 above. For each tracer, an injection of 100 FtL is made in the vein of the tail of a vigilant mouse that has developed a U87MG tumor. After 1.5 h, the 4 mice were anesthetized with isoflurane (2%). The urine and then the blood (400 to 800 μL) are taken first, followed by the pancreas, spleen, kidneys, heart, lungs, bile and liver.

The organs are counted then frozen and stored at -20 ° C. They were weighed after radioactive decay. The tumor is also removed and counted. It is then introduced into a potter containing 150 μl of PBS buffer and 1.5 μl of a cocktail of protease inhibitors. It is milled, then 600 μl of MeOH are added (MeOH / PBS 8/2). After further grinding, the homogeneous tumor is transferred into an ependorf tube, counted and then centrifuged. The supernatant is taken, counted, as well as the pellet. The supernatant is then analyzed by radio-HPLC (Varian HPLC) with a 0-100% B gradient in 30 min. The tracers are analyzed under the same conditions.

Claims (19)

REVENDICATIONS1. Compound corresponding to the following formula (I): ## STR2 ## in which: unit A is chosen from the groups of formula: R 3 .54 OR O lz R 5 - 1114 or R 6 R 6 R 6 R 6 (DI R 7 - unit B is chosen from the groups of formula: Or R 6 or OH - n is 0 or 1, - R 1, R 2, R 3, R 4, R 5, R 6 and R 7, which may be identical or different, are chosen from H, an alkyl, alkoxy, aryl or aralkyl radical; heteroalkyl, heteroaryl, heteroaralkyl, a saturated or unsaturated mono- or polycyclic hydrocarbon or heterocarbon group, a mono- or a polysaccharide, or an amine derivative of mono- or polyether, a polyamide, said radicals and / or groups substituted by one or more several hydroxyl, acidic, amino acid, thiol, thioalkyl, urethane, urea, halogen, polysaccharide groups, one in which L is a spacer arm (or linker) and V is a vecte optionally and co It is intended that: amines, aminoalkyls, or an L-V ur group, V is unit A represents the following acetylenic group: V or unit B represents one of the following acetylenic groups: R4 3 or O tex, CH 2. Compound according to claim 1 corresponding to the following formula (IA): (IA) in which the unit A is chosen from the groups of formula: Omo` OR R6 OR OR OR OR R6 Ri ~ SH 0 OH R6 3. A compound obtainable from a compound of formula (I) according to claim 1 or claim 2, corresponding to the following formula (II): ## STR2 ## wherein R1, R2, R3, R4, R5, R6 and R7 are as defined in claim 1, and: the unit A 'is chosen from the groups of formula: NN Y 0, ........ .zz) zzi, o -., - 1-zz,., o -111.4 OR or RY '' '...' "SH Ri '' '' '' 'NH2 Ri' '' 'NFI R6 R6 Re OR OR OR R6 OR R6 0 .- '' 'OH O' unit B 'is selected from the groups of formula R3 \) 111.1 Kr'. N \\ N --- NY OR OR OR OR - Y is selected from an alkyl, alkoxy, aryl, aralkyl, heteroalkyl, heteroaryl, heteroaralkyl radical, a saturated or unsaturated mono- or polycyclic hydrocarbon or heterocarbon group, a mono- or polysaccharide, or an amine derivative of mono- or polysaccharides, a polyether, a polyamine, a polythioether, a polyester, said radicals and / or groups being optionally substituted with one or more hydroxyl groups, acids, amines, aminoalkyls, amino acids, thiols, thioalkyls, urethanes, ureas, halogens, or an LV group in which L is a spacer arm (or linker) and V is a vector, and provided that: (or unit A 'represents the following triazole group: R3 N) The / i, 4 N N ---- NY, 7 or unit B' represents one of the following triazole groups: R3 OR N7 NN Y 4. Compound according to claim 3, corresponding to the following formula (IA): (HA) in which the unit A 'is chosen from the groups of formula: Rs or 0,14 Rr' NFI2R OR OR R5 <: eizza R (<"" SH OR OR R6 0 OH 5. A compound according to claim 3 or claim 4 having the following formula (IIB): R 2 R 1, R 3 R 6, NH NH-HR 4 R 6 sH Y 6. Process for the preparation of a compound of formula (II) according to one of claims 3 to 5 by reaction of a compound of formula (I) according to claim 1 or claim 2 with a Y-type organic azide. N3 wherein Y is as defined in claim 3, said reaction being carried out in the presence of copper. 7. Compound obtainable from a compound of formula (II) according to one of claims 3 to 5, corresponding to formula (III) below: (III) wherein n, RI, R2, R3 , R4, R5, R6 and Y are as defined in claims 1 and 3, and: - M is a metal radioelement, - n 'and n ", identical or different, are equal to 0 or 1. The compound of claim 7 wherein Y is an LV group wherein: the spacer arm L is selected from a substituted or unsubstituted aliphatic or aromatic polycarbonyl chain, a polyether, a polyamine, a polylysine, a dendrimer, a polypeptide, a linear or cyclic peptide platform of ARFT type, a polysaccharide, a phospholipid, a nucleic acid or a peptide nucleic acid, and the vector V is a biologically active molecule chosen from a peptide or a peptide derivative, a protein, a nucleic acid, a liposome, a modified or unmodified DNA or RNA oligonucleotide, a nucleotide, a nucleoside, a aptamer, or a modified or unmodified peptide nucleic acid, a vitamin, a steroid, a phospholipid, a central nervous system receptor , a polyamine, a polyester, a polythioether, a substituted or unsubstituted aliphatic, aromatic or heteroaromatic polymer. 9. Compound according to claim 8 wherein the spacer arm L is chosen from a peptide or a peptide derivative comprising 1 to 12 amino acid residues, polyethyleneglycol oxide (PEG) or polypropylene glycol (PPG) comprising 1 to 40 EG or PG units, a polyamine comprising 1 to 20 monomeric units, a mono- or polysaccharide comprising 1 to 20 saccharide units. 10. Compound according to one of claims 7 to 9 wherein M is selected from 99cr, 99rn--. 185-186-187 1 C, 1C, 1c, xe, Re and 188Re, and n and n 'are equal to 1. 11. The compound of claim 7, wherein Y is an L-V group in which L is a spacer arm and V is a vector selected from biologically active molecules. 12. Kit consisting of: - a container comprising a compound of formula (II) as defined in claims 3 to 5 and a reducing agent, and - a portable generator comprising a metal radioelement solution, preferably selected from 94mTc, 99gTc , 99mTc, 185Re, 86Re, 187Re, and 188Re, said metal radioelement being in oxide form, and - a container comprising a base in a solvent or a buffer. 13. Compound of formula (III) according to one of claims 7 to 11 for its use in vivo as a diagnostic radiotracer. 14. Compound of formula (III) for its use according to claim 13, as a contrast agent for diagnosis, as a potential therapeutic agent, or as a radiotherapeutic agent for targeted radiotherapy of pathologies. Compound of formula (III) for its use according to claim 14, as a contrast agent for the diagnosis by MonoPhotonic Emission Tomography (TEMP) or Positron Emission Tomography (PET), and preferably as a flow radiotracer. circulatory and metabolic, or as a tissue marker. 16. Compound of formula (III) according to one of claims 7 to 11 for use as a medicament. 17. Compound of formula (III) for its use according to claim 16, as integrated targeting radiotherapeutic agent for the treatment of cancers, neurodegenerative diseases, diseases of the central nervous system, atherosclerosis and thrombosis, cardiovascular diseases. , liver, kidney or heart disease, hypoxia or inflammation. 18. Compound of formula (III) for its use according to claim 16, as a bifunctional radiotherapeutic agent for targeted radiotherapeutic treatments chosen from metabolic radiotherapy, local radiotherapy, vector radiotherapy, radioimmunotherapy and radio. -immunology. 19. Compound of formula (III) for its use according to claim 18, for the treatment of cancers, neurodegenerative diseases, pathologies of the central nervous system, atherosclerosis and thrombosis, hypoxia, inflammation, diseases cardiovascular, hepatic, renal or cardiac pathologies.