Macrocyclic ligands with picolinic ester groups, complexes thereof and medical use

Abstract

The present invention relates to new macrocyclic ligands substituted by at least one picolinic ester group, to radioactive complexes thereof and to their use in medical imaging and / or therapy, in particular in interventional radiology. The present invention also relates to new processes for the preparation of the ligands according to the invention, and also to intermediates in the preparation thereof.

Description

Technical Field

[0001] This invention relates to novel macrocyclic ligands and their complexes, particularly radioactive complexes, and their use in medical imaging and / or in therapy, particularly in interventional radiology.

[0002] The present invention also relates to a novel method for preparing ligands as described in the present invention, and intermediates thereof. Background Technology

[0003] The need for targeted and personalized therapy in oncology has spurred the development of new treatment strategies based on early detection tools and combined with more specific and efficient delivery-based therapies.

[0004] Interventional radiology is a very promising area of ​​personalized medicine. It enables the precise diagnosis and / or immediate treatment of lesions or tumors within a single, identical series of events, guided and controlled by imaging. Described as minimally invasive surgery, it can therefore be performed on an outpatient basis, resulting in significant savings from costly hospital stays and achieving effectiveness often comparable to conventional surgery. Therefore, interventional radiology can serve as an alternative to or extension of conventional surgical treatment.

[0005] Interventional radiology makes it possible to access lesions or tumors located within the body to perform diagnostic procedures (such as sampling) or therapeutic actions. Imaging using fluorescence microscopy, echography, scanners, or MRI enables precise localization, guidance, and optimal control of medical procedures.

[0006] Therefore, there is a need for novel molecules that can be used in medical imaging and / or therapy, particularly in interventional radiology. More specifically, there is a need for ligands that can achieve chemical element, particularly metal, complexation to obtain complexes that can be used in medical imaging and / or therapy, particularly in interventional radiology.

[0007] Such ligands must be stable in human serum and must be strong enough to chelate metals so that the latter can reach their target without spreading to other sensitive organs or tissues such as bones, lungs and kidneys. Summary of the Invention

[0008] The purpose of this invention is to provide novel ligands capable of complexing chemical elements, particularly radioactive elements.

[0009] Another object of the present invention is to provide novel complexes, particularly radioactive complexes.

[0010] The object of this invention is to provide ligands and / or complexes that are particularly useful in medical imaging and / or therapy, especially in cancer treatment.

[0011] Another object of the present invention is to provide a pharmaceutical composition comprising a complex capable of enabling medical imaging, targeting, and / or treatment of cancer.

[0012] The object of this invention is to provide a novel method for preparing these ligands.

[0013] Starting with the research described in WO 2017 / 109217 and Le Fur et al. (Inorganic Chemistry, Vol. 57, No. 4, pp. 2051-2063, 2018), the inventors have developed novel ligands with high affinity for certain metals, particularly rare earth metals, whose complexes are highly stable and exhibit high kinetic inertness. Furthermore, these complexes can be readily radiolabeled and then exhibit satisfactory radiochemical yields and purity. These complexes can also be stably and reproducibly incorporated into iodized oils, thus exhibiting biodistribution characteristics that enable their use in cancer therapy.

[0014] This invention relates to a compound having the following general formula (I):

[0015]

[0016] Where R is a group having the following formula (II):

[0017] –C≡C-Ph-L1-(CH2) n -L2(II)

[0018] in

[0019] -L1 represents Ph or –C≡C- or CH2.

[0020] -L2 represents H, Ph, or alkylphenyl.

[0021] -n is between 4 and 12.

[0022] Or one of its pharmaceutically acceptable salts.

[0023] According to a preferred embodiment, the present invention relates to a compound having the general formula (I), wherein the group R is selected from:

[0024] -The group R, where L1 = CH2, n = 7, and L2 = H, corresponds to the following structure:

[0025]

[0026] -The group R, where L1 = Ph, n = 8, and L2 = H, corresponds to the following structure:

[0027]

[0028] -The group R, where L1 = –C≡C-, n = 8, and L2 = Ph, corresponds to the following structure:

[0029]

[0030] It is one of the pharmaceutically acceptable salts.

[0031] The inventors have developed novel ligand-metal complexes (also known as chelate complexes) starting with the pyclen macrocycle (3,6,9,15-tetraazabicyclo[9.3.1]pentadecano-1(15),11,13-triene), which are differently substituted with acetate and / or pyridinecarboxylate (6-methylene-2-pyridinecarboxylic acid) groups. The pyclen macrocycle has the following formula:

[0032]

[0033] Similar to the complexes described in WO 2017 / 109217, the complexes according to the present invention exhibit good thermodynamic stability and good kinetic inertness. These complexes are also soluble in iodized oils, such as... This is an iodized oil manufactured and sold by Guerbet, composed of ethyl esters of iodized fatty acids from poppy oil. Therefore, it dissolves in iodized oils such as... The complexes according to the invention can be specifically targeted to the liver and can enable the visualization and / or treatment of cancers (e.g., liver cancer).

[0034] These complexes are found in iodized oils such as... They also exhibit good extraction rates in iodized oils such as... It exhibits particularly good radioactive incorporation (radiochemical yield) and in in vitro experiments The radioactive solution exhibits good stability.

[0035] In particular, The combination of the carrier properties of these products, the therapeutic efficacy of radioactive elements, and their good tolerability makes it possible to provide safe and easy-to-implement therapeutic cancer treatments.

[0036] The complex according to the invention is obtained by means of iodized oil, such as The carrier formulation enables the following: in particular, to avoid undesirable delivery of the complex, thus reducing the risk of adverse effects in healthy organs, especially the healthy liver or extrahepatic organs, and to achieve an effective dose of radiation in tumors.

[0037] More specifically, this carrier-based approach facilitates the work of interventional radiologists when injecting the complex according to the invention. For example, during intra-arterial injection monitored using fluorescence microscopy, the radiologist's movements will be more precise and safer, allowing for adjustment of the complex delivery rate as the complex according to the invention is absorbed by the tumor.

[0038] definition

[0039] The term "ligand" is understood to mean a compound capable of complexing chemical elements such as metals, preferably radioactive elements. According to one embodiment, the ligand within the scope of this invention is in anionic form and can complex radioactive elements in cationic form, such as metal cations in oxidized state (III). According to the invention, a compound having formula (I) is a ligand.

[0040] The term "radioactive element" is understood to mean any known radioactive isotope of a chemical element, whether naturally occurring or artificially produced. According to one embodiment, the radioactive element is selected from the radioactive isotopes of yttrium, actinium, copper, gallium, indium, scandium, and the lanthanides. The term "lanthanides" refers to atoms selected from the group consisting of: La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu.

[0041] The term "alkylphenyl" is understood to mean a straight-chain or branched alkyl group bonded to a phenyl group, preferably containing 1 to 20 carbon atoms, more preferably 1 to 8 carbon atoms. Preferably, the alkylphenyl is octylphenyl.

[0042] The term "complex" is understood to mean the combination of a ligand and a chemical element, preferably a radioactive element, as defined above. The terms "complex" and "chelate" are synonymous.

[0043] The term "thermodynamic stability" refers to the affinity of a ligand for a given element, particularly a given metal. It relates to the equilibrium constant of the following reactions:

[0044]

[0045] Its mathematical expression is as follows:

[0046] dissociation constant

[0047]

[0048] Association constant

[0049]

[0050] The values ​​are generally expressed in the form of decimal logarithm logKa or Kd in the form of -log. According to one embodiment, the complex according to the invention has high affinity. According to one embodiment, the complex according to the invention has a thermodynamic equilibrium constant of at least 16 (LogKa is at least equal to 16).

[0051] The complexes formed by the equilibrium reaction described above can dissociate under various influences (pH, the presence of metals, or competing ligands). In the context of the use of complexes in human medicine, this dissociation can have serious consequences, as it can lead to the release of metals into the body. To limit this risk, it is necessary to seek complexes with slow dissociation, i.e., complexes with good kinetic inertness. Kinetic inertness can be determined by dissociation experiments in acidic media. These experiments can determine the half-life (T0) of each complex under defined conditions. 1 / 2 ).

[0052] In the context of this invention, the terms "to treat," "treatment," or "therapeutic treatment" mean reversing, alleviating, or suppressing the progression of a condition or discomfort to which the term applies, or one or more symptoms of such condition.

[0053] The term "medical imaging" refers to the means of acquiring and reproducing images of a human or animal body through various physical phenomena, such as the absorption or emission of photons (visible light, infrared radiation, X-rays, gamma rays), nuclear magnetic resonance, ultrasound reflection, or radioactivity. According to one embodiment, the term "medical imaging" refers to X-ray imaging, MRI (magnetic resonance imaging), single-photon emission computed tomography (SPECT), positron emission tomography (PET), and luminescence. Preferably, the medical imaging method is X-ray imaging. If the complex according to the invention contains a gamma emitter, SPECT is performed; if the complex according to the invention contains a β+ emitter, PET is performed.

[0054] the term This refers to iodized oil, and more specifically to oil used in pharmaceuticals. It is an injectable solution manufactured and sold by Gaber Company and consists of ethyl esters of iodized fatty acids from poppy oil. It is a product specifically designed for visualization, localization, and / or transarterial chemoembolization in the treatment of intermediate-stage hepatocellular carcinoma in adults, and for the diagnosis of malignant or non-malignant liver lesions via selective hepatic artery route through hepatic spread.

[0055] The term "organic acid" (or "organic acid functional group") is understood to refer to substances that exhibit acidic properties, that is, the ability to release H+ in an aqueous medium. + or H3O +A cationic organic compound (or organic functional group). Among organic acids, carboxylic acids, sulfonic acids, phosphates, and phosphonates may be mentioned. Preferably, the organic acid functional group according to the invention is a carboxyl group. Such acid functional groups are salt-forming and may exist in their basic form. In particular, these acid functional groups exist in the form of pharmaceutically acceptable salts as defined below; for example, in the form of sodium or meglumine (1-deoxy-1-(methylamino)-D-glucitol or N-methyl-D-reduced glucosamine) salts.

[0056] Iodized oil

[0057] The term "fatty acid" is understood to refer to a saturated or unsaturated aliphatic carboxylic acid exhibiting a carbon chain of at least four carbon atoms. Natural fatty acids have carbon chains of 4 to 28 carbon atoms (usually an even number). The term "long-chain fatty acid" is used for lengths of 14 to 22 carbon atoms, and "very long-chain fatty acid" is used when there are more than 22 carbon atoms. Conversely, the term "short-chain fatty acid" is used for lengths of 4 to 10 carbon atoms, particularly 6 to 10 carbon atoms, and especially 8 or 10 carbon atoms. Those skilled in the art are familiar with the relevant nomenclature and its particular use:

[0058] -C i -C p C represents i To C p The range of fatty acids,

[0059] -C i +C p C represents i Fatty acids and C p The sum of fatty acids.

[0060] For example:

[0061] - Fatty acids with 14 to 18 carbon atoms are written as "C". 14 -C 18 fatty acid",

[0062] -C 16 Fatty acids and C 18 The sum of fatty acids is written as C 16 +C 18 ,

[0063] - For saturated fatty acids, those skilled in the art will use the designation Ci:0, where i is the number of carbon atoms in the fatty acid. For example, palmitic acid will be represented by the designation (C16:0).

[0064] - For unsaturated fatty acids, those skilled in the art will use the following designation Ci:x nN, where N is the position of the double bond in the unsaturated fatty acid starting from the carbon opposite the acid group, i is the number of carbon atoms in the fatty acid, and x is the number of double bonds (degree of unsaturation) in the fatty acid. For example, oleic acid will be represented by the designation (C18:1n-9).

[0065] Advantageously, the iodized oil according to the invention comprises or consists of: iodized fatty acid derivatives, preferably ethyl esters of iodized fatty acids, more preferably ethyl esters of iodized fatty acids from poppy oil, olive oil, rapeseed oil, peanut oil, soybean oil, or walnut oil, and still more preferably ethyl esters of iodized fatty acids from poppy oil or olive oil. More preferably, the iodized oil according to the invention comprises or consists of: ethyl esters of iodized fatty acids from poppy (also known as black poppy or poppy variety sunflower (Papaver somniferum var. nigrum)) oil. Poppy oil, also known as poppy seed oil, preferably contains more than 80% unsaturated fatty acids (particularly linoleic acid (C18:2n-6) and oleic acid (C18:1n-9)), including at least 70% linoleic acid and at least 10% oleic acid. Iodized oil is obtained from oils such as poppy oil by total iodination (Wolff et al. 2001, Medicine 80, 20-36) under conditions that allow one iodine atom to bond to each double bond of unsaturated fatty acids, followed by transesterification.

[0066] The iodized oil according to the invention preferably contains 29% to 53% (w / w), more preferably 37% to 39% (w / w) of iodine.

[0067] As an example of iodized oil, one could mention (Derived from rapeseed (Brassica compestis) oil) (Derived from peanut oil) (Derived from poppy oil, but in the form of fatty acid triglycerides) or (Derived from olive oil)

[0068] Iodized oil is preferred. It is an iodized oil used as a contrast agent and in certain interventional radiology procedures. This oil is a mixture of ethyl esters of iodized and non-iodized fatty acids from poppy seed oil. It is primarily (specifically, over 84%) composed of iodized long-chain fatty acids (specifically C44%) derived from poppy seed oil. 18 It consists of a mixture of ethyl esters of fatty acids, preferably a mixture of ethyl monoiodide and ethyl diiodide. Iodized oil can also be an oil based on ethyl monoiodide stearate (C18:0) derived from olive oil. This type of product is called... It was sold several years ago.

[0069] The main features are as follows:

[0070] compound Proportion in fatty acid mixture Ethyl palmitate (ethyl C16:0) 4.6% to 6.7% (w / w), preferably 4.8% (w / w) Ethyl stearate (ethyl C18:0) 0.8% to 1.9% (w / w), preferably 1.2% (w / w) Ethyl monoiodostearate 11.3% to 15.3% (w / w), preferably 13.4% (w / w) Ethyl diiodostearate 73.5% to 82.8% (w / w), preferably 78.5% (w / w)

[0071]

[0072] Compounds having general formula (I)

[0073] According to one embodiment, the compound having general formula (I) is in the form of a salt, preferably in the form of a pharmaceutically acceptable salt.

[0074] The term "pharmaceutically acceptable salt" specifically refers to a salt that retains the bioavailability and properties of the compounds according to the invention. Examples of pharmaceutically acceptable salts can be found in Berge et al. ((1977), J. Pharm. Sd. [Journal of Pharmaceutical Sciences], Vol. 66, 1). For example, compounds having general formula (I) are in the form of sodium or meglumine (1-deoxy-1-(methylamino)-D-glucitol or N-methyl-D-reduced glucosamine) salts.

[0075] The present invention also relates to solvates of compounds having formula (I), such as hydrates.

[0076] According to one embodiment, compounds having formula (I) are selected from the group consisting of one of the following compounds and their pharmaceutically acceptable salts:

[0077]

[0078] (This compound is the compound of Example 11a and has the name 6,6'-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane-3,6-diyl)bis(methylene))bis(4-((4-octylphenyl)ethynyl)pyridinecarboxylic acid))

[0079]

[0080] (This compound is the compound of Example 11b and has the name 6,6′-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane-3,6-diyl)bis(methylene))bis(4-((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)pyridinecarboxylic acid))

[0081]

[0082] (This compound is the compound of Example 11c and has the name 6,6′-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane-3,6-diyl)bis(methylene))bis(4-((4′-octyl-[1,1′-biphenyl]-4-yl)ethynyl)pyridinecarboxylic acid)).

[0083] According to a specific embodiment, the compound having formula (I) is the following compound:

[0084]

[0085] Or one of its pharmaceutically acceptable salts.

[0086] Complex

[0087] The present invention also relates to complexes of compounds having formula (I) as defined above or pharmaceutically acceptable salts thereof with chemical element M, preferably a metal.

[0088] According to one embodiment, the compound having general formula (I) is in the form of a neutral complex with a cation in oxidation state III.

[0089] According to one embodiment, chemical element M is a metal cation selected from the group consisting of: copper (II), gallium (III), indium (III), scandium (III), yttrium (III), samarium (III), terbium (III), holmium (III), lutetium (III), actinium (III), and manganese, preferably yttrium, lutetium, terbium, indium, gallium, copper, and actinium. More preferably, chemical element M is a metal cation selected from the group consisting of: yttrium (III), lutetium (III), copper (II), and actinium (III).

[0090] Preferably, M is a radioactive element selected from radioactive isotopes of yttrium, lutetium, terbium, indium, gallium, copper, actinium, and manganese.

[0091] According to a specific embodiment, chemical element M is a radioactive element selected from the group consisting of the following: 44 Sc(III), 47 Sc(III), 111 In(III) 152 Tb(III), 155 Tb(III), 149 Tb(III), 161 Tb(III), 64 Cu(III), 61 Cu(III), 67 Cu(II), 68 Ga(III), 90 Y(III), 153Sm(III), 166 Ho(III) 177 Lu(III), 52 Mn and 225 Ac(III), preferably 90 Y(III), 177 Lu(III), 67 Cu(II), 225 Ac(III), 111 In(III) 152 Tb(III), 155 Tb(III), 149 Tb(III), 161 Tb(III) and 68 Ga(III).

[0092] According to one embodiment, the complex has the following general formula (III):

[0093]

[0094] The groups R and M are as defined above.

[0095] Examples 12 and 13 illustrate the synthesis of such complexes.

[0096] According to a specific embodiment, the complex having formula (III) is selected from the group consisting of the following complexes:

[0097]

[0098] (The complex having formula (III) is formed using the compound of Example 11a)

[0099]

[0100] (The complex having formula (III) is formed using the compound of Example 11c)

[0101] as well as

[0102]

[0103] (The complex having formula (III) is formed using the compound of Example 11b).

[0104] Pharmaceutical Composition

[0105] This invention also relates to a pharmaceutical composition comprising a compound of formula (I) as defined above or a complex of formula (III) as defined above, and optionally one or more pharmaceutically acceptable excipients. The pharmaceutical composition may be contained in a pharmaceutically acceptable medium as a compound of formula (I) as defined above or a complex of formula (III) as defined above. For example, radiation protectants or antioxidants may be mentioned as excipients. The term "radiodegradation" is understood to mean a chemical reaction caused by ionizing radiation that readily initiates or accelerates the degradation mechanism of a radiopharmaceutical. Radiation protectants have properties that prevent or limit these radiochemical degradation phenomena.

[0106] The pharmaceutical composition may comprise an oil phase, particularly iodized oil. According to specific embodiments, the pharmaceutical composition further comprises ethyl esters of iodized fatty acids from poppy oil.

[0107] According to one embodiment, the pharmaceutical composition according to the invention comprises at least one pharmaceutically acceptable excipient. According to another embodiment, the pharmaceutical composition according to the invention does not comprise an excipient.

[0108] According to one embodiment, the pharmaceutical composition according to the invention comprises iodized oil and a compound or complex according to the invention. Typically, the pharmaceutical composition according to the invention consists of... It consists of compounds or complexes according to the present invention. It consists of ethyl esters of iodinated fatty acids from poppy oil. Preferably, the pharmaceutical composition according to the invention comprises... Composed of, or composed of, the compounds of Example 11b. It consists of the complex of Example 13a (i.e., the yttrium-90 complex of the compound of Example 11b) or the complex of 13c (i.e., the lutetium-177 complex of the compound of Example 11b).

[0109] Preferably, the pharmaceutical composition according to the invention is radiopaque and therefore visible by X-ray radiography.

[0110] According to a specific embodiment, the pharmaceutical composition is an injectable composition. According to one embodiment, the pharmaceutical composition according to the invention is administered via intrahepatic artery injection.

[0111] This invention relates to complexes or pharmaceutical compositions as defined above for use in the treatment of cancer, particularly liver cancer.

[0112] The present invention also relates to complexes or pharmaceutical compositions as defined above for use in medical imaging.

[0113] This invention relates to the use of complexes as defined above in the preparation of medicaments for treating cancer.

[0114] The present invention also relates to the use of complexes or pharmaceutical compositions as defined above in medical imaging.

[0115] This invention relates to a method of therapeutic treatment for a patient suffering from cancer, the method comprising administering to the patient a complex or pharmaceutical composition as defined above. In particular, the treatment method does not include a surgical treatment phase.

[0116] The present invention also relates to a method for medical imaging of tumors, the method comprising:

[0117] - The stage of administering the complex or pharmaceutical composition according to the invention to a patient suffering from cancer; and

[0118] - Detecting the stage of a tumor using medical imaging methods.

[0119] The term "cancer" is understood to refer to the abnormal proliferation of cells (also known as a tumor) within the body's normal tissues. These cancer cells all originate from the same clone, the cell that caused the cancer, which has acquired certain characteristics that allow it to divide indefinitely. During tumor development, some cancer cells can migrate from their site of origin and form metastases.

[0120] In the context of cancer, liver cancer, particularly primary liver cancer, is particularly mentioned, and hepatocarcinoma is preferred. According to specific embodiments, in the context of cancer, liver cancer, epithelioid angioendothelioma, cholangiocarcinoma, neuroendocrine tumors, and metastases of other cancers (such as metastases of colorectal cancer) may be mentioned.

[0121] According to a specific embodiment, the cancer is intermediate-stage hepatocellular carcinoma in an adult.

[0122] Preparation method and radiolabeling of compounds having general formula (I)

[0123] The present invention also relates to a method for preparing a compound having general formula (I) according to the present invention.

[0124] In this preparation method, the deprotection stage is known to those skilled in the art and corresponds to a conventional reaction of amide hydrolysis. The functionalization stage is also known to those skilled in the art and corresponds to a standard alkylation reaction (see Loic Bellouard, J. Chem. Soc., Perkin 1, (23), 1999, pp. 3499-3505).

[0125] This preparation method is advantageously based on the reaction of oxalate diester with pyclen, which makes it possible to block two nitrogen atoms (N-6 and N-9) of pyclen so as to selectively act on the third atom (N-3) that remains free. Following the functionalization of the nitrogen at the 3-position, deprotection of the oxalamide group according to scheme 1 yields pyclen with controlled substitution at the 3-position:

[0126]

[0127] Option 1

[0128] According to one embodiment, the protection phase is carried out in the presence of methanol.

[0129] This invention relates to a method for preparing compounds having general formula (I), the method comprising a functionalization stage of compounds having the following general formula (IX):

[0130]

[0131] To form compounds having the following general formula (X):

[0132]

[0133] E2 is a C1-C4 alkyl protecting group, which can be selected from, for example, the group consisting of methyl, ethyl, isopropyl and tert-butyl.

[0134] The preparation method further includes:

[0135] - A stage for deprotecting compounds having the general formula (X) to obtain compounds having the following general formula (XI):

[0136]

[0137] as well as

[0138] - The functionalization stage of compounds having general formula (XI) according to scheme 2, to obtain compounds having general formula (I) as defined above:

[0139]

[0140] Option 2

[0141] E1, E2, and E3 are C1-C4 alkyl protecting groups, which can be selected independently, for example, from the group consisting of methyl, ethyl, isopropyl, and tert-butyl.

[0142] This patent application also describes compounds having the following general formula (X):

[0143]

[0144] E2 is a C1-C4 alkyl protecting group, which can be selected from, for example, the group consisting of methyl, ethyl, isopropyl and tert-butyl.

[0145] According to a specific embodiment of the method for preparing a compound having formula (I), the preparation of the substituted pyridine carboxylate intermediate is carried out according to scheme 3 via a brominated derivative at the 4-position, which enables the placement of the selected residue by a palladium-catalyzed coupling reaction with an alkyne (“sauerkraut” reaction, Comprehensive Chirality, Vol. 4, pp. 18-32, 2012).

[0146]

[0147] Option 3

[0148] Where R' represents a value with the following equation: -L1-(CH2) n -L2 groups:

[0149] in

[0150] -L1 represents Ph or –C≡C- or CH2.

[0151] -L2 represents H or Ph or alkylphenyl, and

[0152] -n is between 4 and 12.

[0153] Preferably, R' is one of the following groups:

[0154]

[0155] The present invention also relates to a method for radiolabeling compounds having the general formula (I). The radiolabeling method is preferably carried out at a pH of 5 to 9, preferably 5 to 7, preferably 5.2, to enable complexation. According to a particular embodiment, the radiolabeling is carried out in the presence of an acetate buffer to adjust the pH and thus allow complexation to occur. According to one embodiment, the radiolabeling is carried out in the presence of water or an alcohol (e.g., ethanol) or a mixture thereof.

[0156] Radioactive labeling is carried out at a temperature of 60°C to 100°C, preferably 80°C to 100°C, and more preferably 80°C.

[0157] The results of the radiolabeling are shown in Table 1 below. The radiochemical purity of the complex according to the present invention after complexation with yttrium-90 is expressed as the percentage of the total radioactivity involved. The radiolabeled complex was extracted to... The percentage represents the fraction of total radioactivity extracted into the oil phase.

[0158]

[0159] Ligand 1.10 -3 M

[0160] RCP: Radiochemical Purity

[0161] Table 1

[0162] These data demonstrate the effectiveness of radiolabeling of the ligands according to the invention and the high affinity of the radiolabeled complexes according to the invention for the oil phase.

[0163] At the end of the radiolabeling process, the radiolabeled complex incorporated into the oil phase was subjected to stability testing in human serum. For this purpose, the oily solution was incubated in the presence of human serum at 37°C with moderate stirring.

[0164] The distribution of radioactivity in the oil phase and serum is measured periodically to determine the fraction of radioactivity diffusing into the serum as a function of time. Extraction curves are then plotted, allowing for the evaluation and comparison of the behavior of different products. These tests are described in Example 16. Attached Figure Description

[0165] Figure 1 The release of yttrium-90 or indium-111 from the compounds of Examples 13a and 13b into the aqueous phase (physiological saline), respectively.

[0166] Figure 2 Release of yttrium-90 from compounds of Examples 13a, 14 and 15 into human serum (aqueous phase).

[0167] Figure 3 Compare the release of yttrium-90 from compound 2 into human serum (aqueous phase).

[0168] Figure 4 Release of yttrium-90 from the compounds according to the invention and comparative compounds 3 to 5 in human serum (aqueous phase) in Examples 13a, 14 and 15.

[0169] Figure 5 For the compound of Example 13a, assessment of the tumor capture dose ratio relative to healthy liver.

[0170] Figure 6 Biodistribution results of the compound in Example 13a compared to the compound in Example 13b, percentage of the injected dose per organ.

[0171] Figure 7 Example 13c: Release of lutetium-177 from the compound according to the invention into human serum and saline.

[0172] The following examples are described by way of illustration of the present invention. Example

[0173] Equipment, materials and methods

[0174] Radioactive labeling of ligands, thermal synthesis of complexes:

[0175] Yttrium chloride-90 was purchased from PerkinElmer Life Sciences, and indium-111 from Curium. Lutetium-177nca (without carrier) was supplied by ITM. In these examples, the radioactivity at play ranged from 28 μCi to 8.51 mCi (1.04–314.87 MBq for yttrium), 4.71 mCi (174 MBq for indium), and 673 MBq (for lutetium).

[0176] The product (HPLC solvent, buffer, etc.) was used as is without further purification. Unless otherwise specified, the ligand was dissolved in ethanol.

[0177] Experiments were conducted in crimped borosilicate glass vials. These vials were heated in a Bioblock heating module, which could hold up to six vials. A Lab Dancer S40 (VWR) vortex mixer was used when stirring was required. Centrifugation was performed using an MF 20-R (Awel) centrifuge.

[0178] Radioactivity was measured in a CRC-127R activity meter (Capintec), which was calibrated every morning.

[0179] Quality control was performed by thin-layer chromatography (TLC) on Whatman No. 1 filter paper with a 0.1% NEt3 / MeOH mixture as eluent. Radiochemical purity was determined using a Cyclone phosphorescence imager (PerkinElmer) and Optiquant software.

[0180] The high-performance liquid chromatography (HPLC) analysis described in Method 10 was performed on a Dionex Ultimate 3000 HPLC product line equipped with a diode array detector and an fLumo radiochromatographic detector (Berthold Group), managed by Chromeleon software.

[0181] In the synthetic methods described below, the commercial products and solvents are primarily derived from... Merck and The company operates at an ambient temperature between 20°C and 25°C. Solvent evaporation is carried out using a Buchi R-210 evaporator at approximately 40°C under reduced pressure.

[0182] Rapid chromatographic purification was performed using irregular silica gel or neutral alumina columns (40g, 80g, 120g, 220g or 440g) from the Buqi Company brand via the following apparatus:

[0183] -Teledyne The CombiFlash NextGen 300+ is equipped with a 200 to 400 nm UV detector or a 200 to 800 nm UV-visible detector.

[0184] - The Reveleris X2 from Buchi Corporation is equipped with a UV or UV-visible detector (200 to 850 nm) and an evaporative light scattering detector (ELSD).

[0185] According to method 11, in a system equipped with a 200 to 600 nm UV detector and ELSD... Purification was performed using a preparative HPLC column on a PuriFlash F4250.

[0186] Analysis and reaction monitoring were performed by TLC in a vessel filled with elution solvent vapor. The support used was a particle size containing the fluorescent indicator F254. The silicone on the glass plate, or the alkaline alumina on the glass plate, or containing [materials from...] The particle size of the fluorescent indicator F254 is Neutral alumina on an aluminum plate. The specific displacement (Rf) of the compound is defined by the following calculation:

[0187]

[0188] Analysis and reaction monitoring were also performed by high-performance liquid chromatography on an Agilent 1200 series product line equipped with a G1315D DAD SL UV or UV / visible detector, and using Software processing, or processing can be performed on the Shimadzu LCMS-2020 product line equipped with an SPD-M30A UV or UV / Vis detector and a quadrupole mass spectrometer, followed by processing with Labsolution software. Samples introduced from the liquid chromatograph are then sprayed and ionized at atmospheric pressure via electrospray (ESI) in either a positively charged (ES+) or negatively charged (ES-) form. Infusion is also... The analysis was performed on an Ultimate 3000RS HPLC system at an injection rate of 5 μl / min, and the sample was collected via... Mass was measured using the amazon X ion trap. Results are expressed as mass-to-charge ratio (m / z).

[0189] Analytical and reaction monitoring methods

[0190] Different analytical and reaction monitoring methods were used for each compound. These methods are described below and will be illustrated for each synthesis.

[0191] Method 1 HPLC (High Performance Liquid Chromatography)

[0192] Instrument: Agilent HP1200; Column: Waters Corporation: Xbride amide 3.5μm; 4.6 x 150mm; Elution buffer A: acetonitrile, Elution buffer B: formate buffer 10mM pH=3.3; Flow rate: 1.0ml / min; Temperature: 25℃; Injection: 10μl; Wavelength: 254nm; Gradient:

[0193]

[0194] Method 2 LCMS (High Performance Liquid Chromatography / Mass Spectrometry)

[0195] Instruments: Shimadzu LC / MS; Column: Waters Kinextex C8 100 x 2.1 mm 1.7 μm; Eluent A: 0.05% trifluoroacetic acid (TFA) / water, Eluent B: acetonitrile; Flow rate: 0.5 ml / min; Temperature: 30 °C; Injection volume: 1 μl; Wavelength: 210 nm; Gradient:

[0196] Time (minutes) ％A ％B 0.01 50 50 5.00 5 95 10.00 5 95 10.01 50 50 15.00 50 50

[0197] Method 3 LCMS

[0198] Instruments: Shimadzu LC / MS; Column: Thermo Fisher Scientific Hypersil Gold 50 x 2.1 mm 1.9 μm; Eluent A: 0.1% formic acid / water (v / v), Eluent B: acetonitrile; Flow rate: 0.5 ml / min; Temperature: 60 °C; Injection volume: 1 μl; Wavelength: 260 nm; Gradient:

[0199] Time (min) Solution A% Solution B% Flow rate (ml / min) 0 75 25 0.5 1 75 25 0.5 11 0 100 0.5 13 0 100 0.5 14 75 25 0.5 20 75 25 0.5

[0200] Method 4: LCMS

[0201] Instrument: Shimadzu LC / MS; Column: Thermo Fisher Scientific: Symmetry C18 150x 4.6mm 5μm; Eluent A: 0.05% trifluoroacetic acid / water (v / v), Eluent B: acetonitrile; Flow rate: 1ml / min; Temperature: 25℃; Injection: 1μl; Wavelength: 260nm; Gradient:

[0202] Time (min) Solution A% Solution B% Flow rate (ml / min) 0 98 2 1 12 0 100 1 20 0 100 1 25 98 2 1 30 98 2 1

[0203] Method 5: LCMS

[0204] Instruments: Shimadzu LC / MS; Column: Waters Kinextex C8 100 x 2.1 mm 1.7 μm; Elution buffer A: 0.3% formic acid / water (v / v), Elution buffer B: acetonitrile; Flow rate: 0.5 ml / min; Temperature: 30 °C; Injection volume: 1 μl; Wavelength: 274 nm; Gradient:

[0205]

[0206]

[0207] Method 6: LCMS

[0208] Instrument: Shimadzu LC / MS; Column: Kinextex C8 100 x 2.1 mm 1.7 μm; Elution buffer A: 0.3% formic acid / water (v / v), Elution buffer B: acetonitrile; Flow rate: 0.5 ml / min; Temperature: 30 °C; Injection volume: 1 μl; Wavelength: 274 nm; Gradient:

[0209] Time (minutes) ％A ％B 0.01 40 60 0.5 40 60 8.0 25 75 10.0 10 90 10.5 10 90 11.000 40 60 13.00 40 60

[0210] Method 7: LCMS

[0211] Instrument: Shimadzu LC / MS; Column: Accucore C30 150 x 2.1 mm 2.6 μm; Elution buffer A: 0.3% formic acid / water (v / v), Elution buffer B: acetonitrile; Flow rate: 0.6 ml / min; Temperature: 40 °C; Injection volume: 1 μl; Wavelength: 320 nm; Gradient:

[0212] Time (minutes) ％A ％B 0.01 50 50 5.00 5 95 10.00 5 95 10.01 50 50 15.00 50 50

[0213] Method 8: LCMS

[0214] Instrument: Shimadzu LC / MS; Column: Thermo Scientific Hypersil GOLD 150 x 3 mm 3 μm; Elution Buffer A: 0.1% formic acid / water (v / v); Elution Buffer B: 0.1% formic acid / acetonitrile (v / v); Flow rate: 1 ml / min; Temperature: 60 °C; Injection volume: 1 μl; Wavelength: 320 nm; Gradient:

[0215] Time (minutes) ％A ％B 0.01 50 50 11.00 0 100 13.00 0 100 16.00 50 50 20.00 50 50

[0216] Method 9: LCMS

[0217] Instrument: Ultimate 3000RS / amaZon X LC / MS; Column: Waters Corporation, Symmetry C18 50*2.1mm 3.5μm; Elution buffer A: 0.05% trifluoroacetic acid / water (v / v); Elution buffer B: acetonitrile; Flow rate: 0.208 ml / min; Temperature: 60℃; Injection: 1 μl; Gradient:

[0218] Time (minutes) ％A ％B 0.01 98 2 4.00 0 100 6.70 0 100 14.00 98 2 20.70 98 2

[0219] Method 10 HPLC

[0220] Instrument: Dionex Ultimate 3000HPLC; Column: Thermo Fisher Scientific, Accucore C18 100x3mm, 2.6μm; Eluent A: Water; Eluent B: Acetonitrile; Flow rate: 0.4ml / min; Temperature: 25℃; Gradient:

[0221]

[0222]

[0223] Method 11 Preparative HPLC (purification on a preparative column)

[0224] Instrument: PuriFlash F4250; Column: Waters Corporation, Symmetry C18 150*30mm 5μm; Elution Buffer A: 0.05% trifluoroacetic acid / water (v / v); Elution Buffer B: acetonitrile; Flow rate: 40ml / min; Temperature: Ambient temperature; Injection: 2ml

[0225] Example 1: Synthesis of monoalkylated macrocyclic methyl 2-(3,6,9-triaza-1(2,6)-pyridinecyclodecane-3-yl)acetate

[0226] Example 1a: Synthesis of 5-aza-1(1,4)-piperazine-3(2,6)-pyridinecycloheptane-12,13-dione

[0227]

[0228] Pyclen base (Inorganic Chemistry, Vol. 36, No. 14, pp. 2992-3000; 10 g, 0.047 mol) was dissolved in 400 mL of methanol. Then, under an inert atmosphere, a solution of diethyl oxalate (Sigma Aldrich, 1.01 equivalents) dissolved in 200 mL of methanol was added over 20 min with stirring. The mixture was stirred at ambient temperature for 3 hours. The solvent was then evaporated under vacuum.

[0229] A white solid was obtained, w = 12.7 g.

[0230] Yield = Quantity

[0231] Carrier: Alkaline alumina

[0232] Eluent: Dichloromethane / Methanol (9:1)

[0233] Rf = 0.66

[0234] HPLC method: 1

[0235] RT (retention time) = 9.0 min

[0236] Example 1b: 2-(1 2 ,1 3 Synthesis of methyl 5-dioxo-5-aza-1(1,4)-piperazine-3(2,6)-pyridinecycloheptane-5-yl)acetate

[0237]

[0238] The intermediate obtained in Example 1a (10.3 g, 0.040 mol) was suspended in 260 mL of acetonitrile, and 1.55 equivalents of K₂CO₃ were added to the suspension. The resulting mixture was stirred for 15 minutes under an inert atmosphere. 1.01 equivalents of methyl bromoacetate (Aldrich; reference number: 147910-100G) dissolved in 260 mL of acetonitrile was added dropwise over 30 minutes under an inert atmosphere, and the mixture was stirred for 3 hours. The solvent was then evaporated under vacuum to obtain an oily substance.

[0239] The crude oily substance was dissolved in 970 ml of ethyl acetate, and the salt was extracted with 35 ml of water. The organic phase was dried over Na2SO4 and filtered, and then the solvent was evaporated.

[0240] A white solid was obtained, w = 13.5 g.

[0241] Yield = Quantity

[0242] Carrier: Alkaline alumina

[0243] Eluent: Dichloromethane / Methanol (9:1)

[0244] Rf = 0.85

[0245] HPLC methods: Method 1

[0246] RT = 2.7 min

[0247] Example 1b': 2-(1 2 ,1 3 Synthesis of tert-butyl dioxo-5-aza-1(1,4)-piperazine-3(2,6)-pyridinecycloheptane-5-yl)acetate

[0248]

[0249] The synthesis was carried out according to the procedure described in Example 1b, wherein tert-butyl bromoacetate (124230-10G, Aldrich) was used instead of methyl bromoacetate in the process described in Example 1b.

[0250] This yields a yellow, oily substance.

[0251] w = 710mg.

[0252] Yield = 99%.

[0253] Example 1c: Synthesis of methyl 2-(3,6,9-triaza-1(2,6)-pyridinecyclodecane-3-yl)acetate

[0254]

[0255] A solution of 13.3 g of the intermediate described in Example 1b and 11 ml of 98% sulfuric acid diluted in 265 ml of methanol was heated under reflux for 18 h. The solution was then cooled to ambient temperature, and then 138 ml of [unspecified substance] was added. A21 resin (Aldrich, reference number 216410-1KG), then stir for 30 minutes. Filter the solution and wash the resin with methanol.

[0256] Wash the oily substance three times with 50 ml of ether to remove dimethyl oxalate.

[0257] The oily substance was dissolved in dichloromethane, the solution was dried over MgSO4, filtered, and the solvent was evaporated.

[0258] The crude product was purified by rapid chromatography using a 440 g neutral alumina column with a dichloromethane / methanol gradient.

[0259] A white solid was obtained, w = 4.81 g.

[0260] Yield = 43%

[0261] Carrier: Neutral alumina

[0262] Eluent: Dichloromethane / Methanol (9:1)

[0263] Rf = 0.46

[0264] HPLC method: 1

[0265] RT = 6.6 min.

[0266] Examples 2, 3, and 4 below illustrate the synthesis of alkynes.

[0267] Example 2: Synthesis of 1-ethynyl-4-(10-phenyldec-1-yn-1-yl)benzene

[0268] Example 2a: Synthesis of dec-9-yn-1-ylbenzene

[0269]

[0270] Lithium acetylene-ethylenediamine complex (Aldrich, reference number 186155, 1444 mg, 2 equivalents) was diluted in 66 mL of pentane / DMSO (7:3) mixture. The solution was stirred and degassed twice with nitrogen, then cooled to 0 °C. 1-Bromo-8-phenyloctane (Interchim, 95% purity; reference number OR8184; 2000 mg; 7.06 mmol) dissolved in 7 mL of DMSO / Et₂O (1:1) mixture was added, and the reaction medium was vigorously stirred at ambient temperature for 22 hours. The solution was cooled to 0 °C, and then 160 mL of saturated NH₄Cl solution was carefully added. The product was extracted with 2 × 160 mL of diethyl ether, dried over sodium sulfate (Na₂SO₄), filtered, and concentrated to dryness. The crude yellow oil was purified by rapid chromatography using a silica column (40 g, Buqi, reference number 14000024) with a heptane / dichloromethane gradient.

[0271] Obtain colorless liquid

[0272] Yield = 90%

[0273] Carrier: Silica

[0274] Eluent: Heptane

[0275] Rf = 0.34

[0276] LCMS Method: 2

[0277] RT = 3.9 min

[0278] 1¹H NMR (300MHz, CDCl₃): δ 7.29 (m, 2H, phenyl), 7.19 (m, 3H, phenyl), 2.62 (t, J = 7.5Hz, 2H, R-CH₂-phenyl), 2.20 (td, J = 6.9Hz and J = 2.6Hz, 2H, R-CH₂-yne), 1.95 (t, J = 2.7Hz, 1H, -C≡CH), 1.67–1.35 (m, 12H, lipophilic chain).

[0279] Example 2b: Synthesis of trimethyl((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)silane

[0280]

[0281] ((4-bromophenyl)ethynyl)trimethylsilane (2000 mg, 7.90 mmol; Aldrich, reference number 494011) was diluted in 19 mL of diisopropylamine, and then 1,1′-bis(diphenylphosphine)ferrocene (0.02 equivalents; Aldrich, reference number 697230), copper iodide (0.06 equivalents; Aldrich, reference number 03140), and triphenylphosphine (0.04 equivalents; Aldrich, reference number T84409) were added. The solution was degassed under an inert atmosphere and then heated to 90 °C. The alkyne obtained in Example 2a (1.1 equivalents) was added through a diaphragm, and the reaction medium was stirred under heat for 19 hours. The solution was cooled to ambient temperature and filtered through cellophane, and the residue was washed with diethyl ether. The filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether, washed with saturated NaCl solution, dried over MgSO4, filtered, and concentrated to dryness. The black liquid was adsorbed onto silica gel 60A (Merck; reference number: 1.09385.2500) and purified on a silica column (40g; Buqi, reference number 14000024), eluted with a mixture of heptane and dichloromethane.

[0282] A colorless liquid was obtained, with a weight w = 1418 mg.

[0283] Yield = 93%

[0284] Carrier: Silica

[0285] Eluent: Heptane / Dichloromethane (80:20)

[0286] Rf = 0.27

[0287] LCMS Method: 2

[0288] RT = 5.9 min

[0289] 1¹H NMR (60 MHz, CDCl₃): δ 7.31 and 7.18 (m, 9H, phenyl), 2.62 and 2.26 (m, 4H, R-CH₂-phenyl and R-CH₂-yyn), 1.33 (m, 12H, 6 CH₂ alkyl chain), 0.22 (s, 9H, 3 x CH₃ for TMS).

[0290] Example 2c: 1-ethynyl-4-(10-phenyldec-1-yn-1-yl)benzene

[0291]

[0292] The intermediate obtained in Example 2b (1418 mg, 3.67 mmol) was diluted with 2.2 mL of anhydrous tetrahydrofuran. The solution was cooled in a water / ice bath, and then 4.4 mL (1.2 equivalents) of 1 M tetrabutylammonium fluoride (Aldrich, reference number 216143) was added dropwise to THF via a syringe and needle through a diaphragm. The reaction medium was stirred at ambient temperature for 2 hours. Then 12 mL of water was added, followed by three extractions with 20 mL of diethyl ether to extract the product. The organic phases were combined, dried over Na2SO4, filtered, and concentrated to dryness. The resulting yellow liquid was purified on a silica column (40 g, Buqi, reference number 14000024) with heptane as elution.

[0293] A colorless liquid was obtained, with a weight w = 773 mg.

[0294] Yield = 67%

[0295] Carrier: Silica

[0296] Eluent: Heptane / Dichloromethane (80:20)

[0297] Rf = 0.43

[0298] LCMS Method: 2

[0299] RT = 4.9 min

[0300] 1 ¹H NMR (60MHz, CDCl₃): δ 7.47–7.18 (m, 9H, phenyl), 3.08 (s, 1H, CHyne), 2.70–2.27 (m, 4H, R-CH₂-phenyl and R-CH₂-yne), 1.33 (m, 12H, 6×CH₂alkyl chain).

[0301] Example 3: Synthesis of 1-ethynyl-4-octylbenzene

[0302] Example 3a: Synthesis of trimethyl((4-octylphenyl)ethynyl)silane

[0303]

[0304] 1-Bromo-4-(n-octyl)benzene (3000 mg, 11.14 mmol, 1 equivalent; Alfa Aesar, reference A14676.06) was diluted in 27 mL of diisopropylamine, followed by the addition of 0.02 equivalents of 1,1′-bis(diphenylphosphine)ferrocene (Aldrich, reference 697230), 0.06 equivalents of copper iodide (Aldrich, reference 03140), and 0.04 equivalents of triphenylphosphine (Aldrich, reference T84409). The solution was degassed under an inert atmosphere and then heated to 85 °C. Trimethylsilylacetylene (1.1 equivalents; Aldrich, reference 218170) was then added through a diaphragm. The reaction medium was heated for 19 hours, then cooled to ambient temperature and filtered through cellophane. The salt was washed with diethyl ether. The filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether and then washed with a saturated NaCl solution. The organic phase was then dried over MgSO4 and filtered, followed by solvent evaporation. A black liquid was obtained, which was adsorbed onto silica gel 60 (Merck, reference number 1.09385.2500) and purified on an 80 g silica column using a gradient elution of heptane / dichloromethane.

[0305] A yellow liquid was obtained, w = 2371 mg

[0306] Yield = 74%

[0307] Carrier: Silica

[0308] Eluent: Heptane

[0309] Rf = 0.43

[0310] LCMS Method: Method 3

[0311] RT = 9.9 min

[0312] IR:

[0313] key key type Specific type of key <![CDATA[Absorption peak cm -1 > Appearance νC-C C≡C Disubstituted alkyne <![CDATA[2157cm -1 ]]> weak peak

[0314] Example 3b: Synthesis of 1-ethynyl-4-octylbenzene

[0315]

[0316] The intermediate obtained in Example 3a (2254 mg, 7.87 mmol) was diluted in 11.8 mL of anhydrous THF, and the medium was conditioned with nitrogen. The solution was cooled in a water / ice bath, and then 9.4 mL (1.2 equivalents) of 1 M tetrabutylammonium fluoride (Aldrich, reference number 216143) was added dropwise to THF through a diaphragm. The reaction medium was stirred at ambient temperature for 2 hours. At the end of the reaction, 40 mL of water was added. The product was extracted with 80 mL of diethyl ether. The organic phase was dried over Na2SO4 and filtered, and the solvent was evaporated. A crude yellow liquid was obtained, which was purified by using a silica column (80 g, Buqi, reference number 140000025) with heptane as eluent.

[0317] A colorless liquid was obtained, w = 1162 mg

[0318] Yield = 68%

[0319] Carrier: Silica

[0320] Eluent: Heptane

[0321] Rf = 0.42

[0322] LCMS method: 3

[0323] RT = 8.2 min

[0324] Infrared:

[0325] key key type Specific type of key <![CDATA[Absorption peak cm -1 > Appearance νC-H C≡C True acetylene <![CDATA[3297cm -1 ]]> medium peak

[0326] Example 4: Synthesis of 4-ethynyl-4'-octyl-1,1'-biphenyl

[0327]

[0328] 1-Bromo-4-(n-octyl)benzene (592 mg, 2.2 mmol; Alfa Esa, reference number A14676.06), 4-((trimethylsilyl)ethynyl)phenylboronic acid pinacol ester (1321 mg, 2 equivalents; Interchim, H51697), and Cs₂CO₃ (3.48 equivalents; Alfa Esa, reference number 10924) were diluted in 10 mL of tetrahydrofuran and 4 mL of water, and the solution was purged with nitrogen. Palladium(II) acetate (0.04 equivalents, Aldrich, reference number 520764) and triphenylphosphine (0.02 equivalents) were added, and the reaction medium was heated at 70 °C in the dark for 20 hours. The solution was cooled to ambient temperature and extracted with diethyl ether. The organic phase was then dried over Na₂SO₄ and filtered, and the solvent was evaporated. A black oily substance was purified by rapid chromatography on a silica column (40 g, Buqi Company; reference number 140000024) with heptane / AcOEt as the eluent. Evaporation yielded a white / yellow solid. The obtained purified intermediate (980 mg, 2.70 mmol) was diluted in 2.70 mL of anhydrous THF, and the medium was conditioned with nitrogen. The solution was cooled in a water / ice bath, and then 4.59 mL (1.7 equivalents) of 1 M TBAF was added dropwise to THF through a diaphragm. The reaction medium was stirred at ambient temperature for 2 hours. At the end of the reaction, 10 mL of water was added. The product was extracted with 40 mL of diethyl ether. The organic phase was dried over Na₂SO₄ and filtered, and the solvent was evaporated. A solid was obtained, which was purified by silica column (40 g, Buqi Company) with heptane / ethyl acetate as the eluent.

[0329] A white / yellow solid was obtained, w = 784 mg

[0330] Yield = 55%

[0331] key key type Specific type of key <![CDATA[Absorption peak cm -1 > Appearance νC-H C≡C True acetylene <![CDATA[3306cm -1 ]]> medium peak

[0332] Examples 5, 6, 7 and 8b below illustrate the scallion reaction and the synthesis of lipophilic pyridine carboxylate esters.

[0333] Example 5: Methyl 6-(hydroxymethyl)-4-((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)pyridinecarboxylate

[0334]

[0335] Methyl 4-bromo-6-(hydroxymethyl)pyridinecarboxylate (890 mg, 3.621 mmol; 1 equivalent; Interchim, reference number 20210326; synthesis described in patent WO 2017 / 109217, page 44) was diluted in 22 mL of dimethylformamide. The solution was adjusted under an inert atmosphere, and then 7 mL of triethylamine, Pd(PPh3)2Cl2 (0.05 equivalent), PPh3 (0.1 equivalent), and CuI (0.1 equivalent) were added. After stirring for a few minutes, the acetylene (1-ethynyl-4-(10-phenyldecyl-1-yn-1-yl)benzene) (1.2 equivalent) obtained in Example 2c was added to the reaction medium, and the solution was heated to 110 °C. The solution was cooled to ambient temperature, and then 100 mL of diethyl ether was added. The organic phase was washed with 50 ml of saturated NH4Cl solution, then with 50 ml of saturated NaCl solution, dried over Na2SO4, filtered, and concentrated to dryness. A black oily substance was obtained, which was adsorbed onto silica gel 60A and purified by rapid chromatography using an 80 g silica column and a heptane / AcOEt mixture.

[0336] A beige solid was obtained, w = 923 mg

[0337] Yield = 53%

[0338] TLC: Silica

[0339] Eluent: Heptane / AcOEt (4:6)

[0340] Rf = 0.3

[0341] HPLC: Method 4

[0342] RT=16.4min m / z(ES+)=480.31

[0343] NMR: 1 ¹H NMR (60 MHz, CDCl₃): δ 8.19 and 7.72 (m, 2H, pyridine), 7.67–7.31 (m, 9H, phenyl), 4.97 (s, 2H, CH₂OH), 4.10 (s, 3H, CH₃ ester), 3.47 (m, 1H, OH primary alcohol), 2.82–2.43 (m, 4H, R-CH₂-phenyl and R-CH₂-yne), 1.47 (m, 12H, 6CH₂ alkyl chain).

[0344] Example 6: Synthesis of methyl 6-(hydroxymethyl)-4-((4-octylphenyl)ethynyl)pyridinecarboxylate

[0345]

[0346] Methyl 4-bromo-6-(hydroxymethyl)pyridinecarboxylate (1500 mg, 6.10 mmol; 1 equivalent; Interchim, reference number 20210326; synthesis described in patent application WO 2017 / 109217, page 44) was diluted in 37 mL of anhydrous tetrahydrofuran. Nitrogen degassing was then performed twice consecutively, followed by the addition of 12 mL of triethylamine, Pd(PPh3)2Cl2 (0.05 equivalent), PPh3 (0.1 equivalent), and CuI (0.1 equivalent). After stirring for several minutes, the alkyne (1-ethynyl-4-octylbenzene) (1.2 equivalent) obtained in Example 3b was added to the reaction medium, and the solution was heated to 40 °C. The solution was cooled to ambient temperature and filtered through Whatman cellophane, and the residue was washed with 100 mL of Et2O. The filtrate was washed with 100 ml of saturated NH4Cl solution and 40 ml of saturated NaCl solution. The organic phase was then dried over Na2SO4, filtered, and concentrated to dryness. A black oily substance was obtained, which was adsorbed onto silica gel 60A and purified by rapid chromatography using a silica column (Buqi Company; 80 g) and a heptane / AcOEt mixture. A white solid was obtained, w = 1852 mg.

[0347] Yield = 80%

[0348] TLC: Silica eluent: Heptane / AcOEt (8:2)

[0349] Rf = 0.45

[0350] HPLC: Method 4

[0351] RT = 15.3 min

[0352] m / z(ES+)=380.28

[0353] Example 7: Synthesis of methyl 6-(hydroxymethyl)-4-((4′-octyl-[1,1′-biphenyl]-4-yl)ethynyl)pyridinecarboxylate

[0354]

[0355] Methyl 4-bromo-6-(hydroxymethyl)pyridinecarboxylate (4.88 mmol; 1 equivalent; Interchim, reference number 20210326; synthesis described in patent application WO 2017 / 109217, page 44), anhydrous THF (6.1 ml / mmol), and alkyne (4-ethynyl-4'-octyl-1,1'-biphenyl) (1.1 equivalent), Et3N (2 ml / mmol), Pd(PPh3)2Cl2 (0.1 equivalent), and CuI (0.1 equivalent) obtained in Example 4 after two nitrogen degassing operations were mixed. The solution turned black and the reaction medium was stirred at 40 °C in an inert environment. The solution was cooled to ambient temperature and filtered through Whatman paper, and the residue was washed with 100 ml of Et2O. The organic phase was washed twice with 100 ml of saturated NH4Cl solution and 1 × 100 ml of saturated NaCl solution. It was then dried over Na2SO4, filtered, and concentrated to dryness. A black oily substance was obtained, which was adsorbed onto silica and purified by rapid chromatography using a silica column and a heptane / AcOEt mixture.

[0356] A beige solid was obtained, w = 1668 mg

[0357] Yield = 75%

[0358] m / z(ES+)=456

[0359] Example 8 below illustrates the synthesis of the compound (methyl 6-(hydroxymethyl)-4-((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)pyridinecarboxylate) obtained in Example 5 via a reaction involving the acetylation of a protecting alcohol.

[0360] Example 8:

[0361] Example 8a: Synthesis of methyl 6-(acetoxymethyl)-4-bromopyridinecarboxylate

[0362]

[0363] The intermediate methyl 6-(hydroxymethyl)-4-bromopyridinecarboxylate (25.409 g; 103.26 mmol) was diluted in 516 mL of dichloromethane, and the medium was then conditioned under a nitrogen atmosphere. 26 mL of triethylamine was added in a single addition, followed by dropwise addition of acetic anhydride (7.6 equivalents; Aldrich, 242845) through a dropping funnel. The reaction medium was then stirred at ambient temperature for 2 hours. The organic phase was washed with 50 mL of deionized water, dried over Na₂SO₄, filtered, and concentrated to dryness.

[0364] A white solid was obtained, w = 33.65 g.

[0365] Yield = Quantity

[0366] Carrier: Silicone

[0367] Eluent: Heptane / AcOEt (4:6)

[0368] Rf = 0.6

[0369] HPLC method: 5RT = 3.56 min

[0370] m / z(ES+)=288

[0371] NMR: 1 ¹H NMR (60MHz, CDCl₃): δ 8.19 and 7.72 (m, 2H, pyridine), 5.35 (s, 2H, CH₂Ac), 4.07 (s, 3H, CH₃ ester), 2.25 (s, 3H, CH₃ acetate)

[0372] Example 8b: Synthesis of methyl 6-(acetoxymethyl)-4-((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)pyridinecarboxylate

[0373]

[0374] The compound obtained in Example 8a (20.53 g, 71.36 mmol) was diluted in 800 mL of tetrahydrofuran, and the solution was adjusted under an inert atmosphere. Triphenylphosphine (0.1 equivalent), Pd(PPh3)2Cl2 (0.05 equivalent), CuI (0.1 equivalent), and 143 mL of Et3N were added to the solution. A solution of the compound obtained in Example 2c in 200 mL of tetrahydrofuran was added to the reaction medium in one go, and the solution was heated at 60 °C for 50 min. The reaction medium was cooled to ambient temperature, filtered, and washed with 250 mL of tetrahydrofuran. The solvent was evaporated under vacuum. The crude product was then redissolved in 910 mL of diethyl ether and filtered. The organic phase was then washed with 500 mL of saturated NH4Cl solution, 500 mL of saturated Na2CO3 solution, and 250 mL of saturated NaCl solution. The organic phase was dried over Na2SO4, filtered, and then concentrated under vacuum. A brown solid was obtained, which was then recrystallized from a heptane / AcOEt mixture by hot filtration.

[0375] The solid was then rinsed with 100 ml of cold AcOEt to obtain a white solid, w = 35.58 g.

[0376] Yield = 96%

[0377] Carrier: Silicone

[0378] Eluent: Heptane / AcOEt (4:6)

[0379] Rf = 0.65

[0380] HPLC method: RT = 8.15 min

[0381] m / z(ES+)=522

[0382] NMR: 1 ¹H NMR (60 MHz, CDCl₃): δ 8.11 and 7.57 (m, 2H, pyridine), 7.42–7.19 (m, 9H, phenyl), 5.30 (s, 2H, CH₂Ac), 3.99 (s, 3H, CH₃ ester), 2.59–2.30 (m, 4H, R-CH₂-phenyl and R-CH₂-yne), 2.17 (s, 3H, CH₃ acetate), 1.35 (m, 12H, 6CH₂ alkyl chain).

[0383] Example 8c: Synthesis of an intermediate obtained from Example 8b based on the compound of Example 5 (methyl 6-(hydroxymethyl)-4-((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)pyridinecarboxylate).

[0384]

[0385] The intermediate obtained in Example 8b (33.36 g, 63.95 mmol) was diluted in 255 mL of methanol. 27 mL of triethylamine (3 equivalents) was added, and the reaction medium was then heated under reflux for 23 hours. The reaction medium was filtered, and the filtrate was cooled in an acetone / dry ice bath. After filtration, a white solid was obtained with a weight w = 22.91 g.

[0386] Yield = 75%

[0387] Example 9 below illustrates the activation reaction of alcohols in the form of methanesulfonates.

[0388] Example 9: Synthesis of substituted methyl 4,6-(((methanesulfonyl)oxy)methyl)pyridinecarboxylate

[0389]

[0390]

[0391] The intermediate obtained in Examples 5, 6, or 7 (1.64 mmol, 1 equivalent) was diluted in 18 mL of DCM (11 mL / mmol). The solution was conditioned under an inert atmosphere and then cooled in a water / ice bath. Triethylamine (3 equivalents) and methanesulfonyl chloride (1.5 equivalents) were added dropwise. The reaction medium was stirred for 10 min, and then 18 mL of saturated NaHCO3 solution was added to bring the reaction to a complete stop. The organic phase was recovered, dried over Na2SO4, and concentrated to dryness. A yellow oil was obtained, which was purified by rapid chromatography on a silica column using a diheptane / AcOEt mixture.

[0392] The results are shown in the table below:

[0393] Example 9a Example 9b Example 9c molar mass 457.59 557.71 533.68 Yield 97％ 97％ 63％ LCMS method Method 8 Method 4 Method 9 RT 8.1min 9.7min ND m / z(ES+) 458 558.31 534

[0394] a:NMR: 1 ¹H NMR (60 MHz, CDCl₃): δ 8.20 and 7.76 (m, 2H, pyridine), 7.48–7.24 (m, 9H, phenyl), 5.45 (s, 2H, CH₂OH), 4.04 (s, 3H, CH₃ ester), 3.19 (s, 3H, CH₃ methanesulfonyl), 2.75–2.36 (m, 4H, R-CH₂-phenyl and R-CH₂-yne), 1.40 (m, 12H, 6CH₂ alkyl chain).

[0395] Example 10 below illustrates the alkylation reaction of the compound obtained in Example 1c with the methanesulfonation reactant described in Example 9.

[0396] Example 10: Alkylation of the intermediate (methyl 2-(3,6,9-triaza-1(2,6)-pyridinylcyclodecane-3-yl)acetate) obtained in Example 1c

[0397]

[0398]

[0399]

[0400] The compound obtained in Example 1c (methyl 2-(3,6,9-triaza-1(2,6)-pyridinium cyclodecane-3-yl)acetate) (462 mg, 1.66 mmol, 1 equivalent) was diluted in 30 mL of anhydrous acetonitrile, and then calcined calcium carbonate (2.5 equivalents) and the intermediate obtained in Example 9 (9a, 9b, or 9c) (2.1 equivalents) were added. The reaction medium was heated at 60 °C with stirring. The solution was then cooled to ambient temperature and filtered. The salt was washed with acetonitrile, and the filtrate was concentrated to dryness. An orange oil was obtained, which was purified by rapid chromatography on a silica column using a DCM / MeOH mixture.

[0401]

[0402] Example 11 below illustrates the generation of lipophilic ligands.

[0403] Example 11: The intermediate obtained in Example 10 was saponified to obtain a compound having formula (I).

[0404]

[0405] Group R is selected from:

[0406]

[0407]

[0408] The intermediate (1.00 mmol, 1 equivalent) obtained in Example 10 (10a, 10b, or 10c) was diluted in 10 mL of a solution of 2M potassium hydroxide in ethanol. The reaction medium was stirred at ambient temperature for 15 min. 15 mL of DCM was added, and the solution was then cooled in a water / ice bath. Metal-free 30% hydrochloric acid was then added until the pH reached 6-7 and a precipitate was obtained. The salt was filtered off and washed with DCM, and the filtrate was concentrated to dryness. A crude yellow solid was obtained, which was purified on a preparative column, except for compound 11c, which remained crude.

[0409] Fractions rich in important products were combined, concentrated under vacuum, and then freeze-dried.

[0410] Example 11a Example 11b Example 11c molar mass 959.25 1159.49 1111.44 Yield 41% (purified) 26% (purified) 42%(crude product) LCMS method Method 4 Method 4 Method 9 RT 13.3min 13.93min 9.0min m / z(ES+) 959.6 1159.7 1111.6

[0411] Examples 12, 13, 14 and 15 illustrate complexation reactions with different important metals.

[0412] Example 12: Synthesis of the complex having formula (III) according to the present invention

[0413] Example 12a: Synthesis of a 6,6′-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane-3,6-diyl)bis(methylene))bis(4-((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)pyridinecarboxylic acid)metal(III) complex

[0414]

[0415]

[0416] 50 mg of the ligand obtained in Example 11b was dissolved in 13.3 mL of methanol, and a metal hydrochloride hexahydrate (1.5 equivalents) was added to the medium. The pH of the solution was adjusted to 6 using sodium methoxide solution (0.12 M), and the reaction medium was stirred at ambient temperature for 30 min. The solution was concentrated to dryness, and the crude solid was treated with 4 mL of dichloromethane. The solvent was then evaporated under reduced pressure to obtain a yellow solid.

[0417] Example 12a Example 12b Example 12c molar mass 1245.37 1331.43 1315.39 Yield Quantitative Quantitative Quantitative HPLC method Method 7 Infusion Infusion RT 7.05min NA NA m / z(ES+) 1246.6 1331.6 1315.5

[0418] Example 13: Synthesis of Radiolabeled Complexes

[0419] Example 13a: Synthesis of the yttrium-90 complex of the ligand (6,6′-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane-3,6-diyl)bis(methylene))bis(4-((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)pyridinecarboxylic acid)) prepared in stage 11b

[0420] 500 μl of a solution of the compound obtained in Example 11b (C = 10) -3 mol / L) was removed and deposited in an SF8 glass vial, and 500 μL of buffered sodium acetate solution (3M, pH 5.2) was added to a batch of approximately 629 MBq (17 mCi) of chloride. 90 Y]([ 90 Y]Cl (PerkinElmer). The radioactive solution (approximately 500 μl) was then recovered and stored in a vial containing 500 μl of ligand solution. The mixture was gently stirred and then incubated at 80 °C for 20 min. At the end of the reaction, the sample was drawn using an insulin syringe and deposited onto a thin-layer chromatography plate (chromatographic paper 1CHR, GE Group). The amount of radioactivity in the vial was measured using an ionization chamber (VDC-405 activity meter, model VIK202, with software v3.29; Comecer Netherlands, Netherlands), which was pre-calibrated for measuring radioactivity in vials sealed in glass vials and resuspended in water / ethanol medium. 90 The radioactivity emitted by the decomposition of Y].

[0421] Subsequently extracted middle.

[0422] Add 1 ml of physiological saline (Mini-Plasco NaCl 0.9%, B. Braun Group), then 2 ml Ultra Fluid (Gabor) was sequentially added to the reaction medium generated by the radiolabeling contained in the vial, and the mixture was vigorously stirred manually with tongs to emulsify it. The emulsion was then disrupted by centrifugation (2600g, 20min) (Sigma 2-6, Fisher Bioblock Scientific) to obtain the product derived from... The composition consists of an oily lower phase containing radiolabeled complexes (referred to as the "Lipiodolic phase") and an upper phase containing a water / ethanol mixture. Pre-calibrated measurements were performed using... middle[ 90 The same ionization chamber as [Y] was used to measure the amount of radioactivity contained in the vial. Most of the upper phase was aspirated with a syringe. The Lipiodolic phase was then recovered in a pre-weighed SF8 glass vial using a 23G0, 60x 25mm needle (Sterican, B. Braun Group) attached to a 1.0ml syringe (1ml syringe Luer BDPlastipak, BD).

[0423] The amount of radioactivity contained in vials containing ethanol / ligand phase and Lipiodolic phase, respectively, was measured using an ionization chamber pre-calibrated for each measurement condition. The vials containing the Lipiodolic phase were weighed using a precision balance (model TE64-0CE, Sartorius) to calculate the volumetric activity of the radiotracer.

[0424] Calculate the synthetic yield, radiochemical purity, and volumetric activity of the radioactive tracer. :

[0425] Synthesis yield

[0426] The synthesis yield of the target radioactive tracer was determined to be greater than or equal to 50%. This was calculated using the following formula:

[0427]

[0428] Determination of Radiochemical Purity (RCP) by Thin-Layer Chromatography

[0429] The plates (chromatographic paper 1CHR, GE Group) were eluted with a solution of 0.1% (by volume) triethylamine (Et3N) in methanol (MeOH) until the migration front reached the top of the plate. Radioactivity present on the dried plates was then detected using an FLA-7000 phosphorescence imager, operated in conjunction with the acquisition software of the same name (version 1.1, Fujifilm). The RCP of the labeled radioligands was calculated using the Multi Gauge v3.1 program (Fujifilm), based on the quantification of radioactivity detected on the plates migrating in the reaction medium. In practice, this quantification was based on the creation of significant regions plotted on each region associated with the detected radioactivity. The RCP calculations are as follows:

[0430]

[0431] Calculation of volume activity

[0432] Volume activity was determined by weighing vials containing the radioactive tracer in a lipodolic phase and measuring the volume using an ionization chamber. 90 Y] activity (measured activity against cosmic background noise and [ 90 The physical decay of Y] (“background noise”) has been corrected. Calculations are performed as follows, taking into account... Its density is 1.28 g / ml.

[0433] Volumetric activity (MBq / m³) = Specific activity (MBq / g) x Density (Lipiodol) (g / ml)

[0434] Where specific activity (MBq / g) = activity (lipiodolic phase) (MBq) / Lipiodol weight (g)

[0435] and Weight (g) = Weight (full bottle) - Weight (empty bottle, pre-weighed).

[0436] Example 13b: The indium-111 complex of the ligand (6,6′-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane-3,6-diyl)bis(methylene))bis(4-((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)pyridinecarboxylic acid)) obtained in Example 11b

[0437] Using the same scheme described in Example 13a, an indium-111 complex was formed using an indium-111 solution (Curium Corporation, 4.71 mCi, 174 MBq).

[0438] Example 13c: The lutetium-177 complex of the ligand (6,6′-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane-3,6-diyl)bis(methylene))bis(4-((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)pyridinecarboxylic acid)) obtained in Example 11b

[0439] Using the same scheme described in Example 13a, a lutetium-177 complex was formed using a lutetium-177 solution (673 MBq).

[0440] The result of the tagging

[0441] Example 13a Example 13b Example 13c Radiochemical purity (%) 99.2 95.5 94.1 Yield (%) 99 94.5 87.4

[0442] Example 14: The yttrium-90 complex of the compound (6,6′-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane-3,6-diyl)bis(methylene))bis(4-((4′-octyl-[1,1′-biphenyl]-4-yl)ethynyl)pyridinecarboxylic acid)) obtained in Example 11c

[0443]

[0444] Add 0.5 ml of yttrium chloride-90 acetate buffer solution at pH 5.2 to 0.5 ml of the solution obtained in Example 11c at a concentration of 10... -3 The ligand was dissolved in DMSO at a concentration of mol / L. The solution was heated at 80°C for 15 min. 1 ml of physiological saline was added + 2 ml of... The mixture was then vigorously stirred. The phases were then separated by centrifugation (4500 rpm, 20 min), and the oil phase was collected to obtain the desired radioactive tracer.

[0445] RCP (%) 92.7 Yield (%) 89.5

[0446] Example 15: The yttrium-90 complex of the compound (6,6′-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridinecyclodecane-3,6-diyl)bis(methylene))bis(4-((4-octylphenyl)ethynyl)pyridinecarboxylic acid)) obtained in Example 11a

[0447]

[0448] Add 0.5 ml of yttrium chloride-90 acetate buffer solution at pH 5.2 to 0.5 ml of the solution obtained in Example 11a at a concentration of 10... -3 The ligand is dissolved in ethanol at a concentration of mol / L. The solution is heated at 80°C for 15 min. Then, 1 ml of physiological saline and 2 ml of... The mixture was then vigorously stirred. The phases were then separated by centrifugation (3500 rpm, 15 min), and the oil phase was collected to obtain the desired radioactive tracer.

[0449] RCP (%) 99.7 Yield (%) 92.9

[0450] Example 16: Stability Study

[0451] 1 / Research on compounds according to the present invention:

[0452] Radiolabel prototype (brand) Stability testing was then conducted, consisting of an incubation period at 37°C in the presence of physiological saline or human serum, and kinetic monitoring of radioactivity transfer from the oil phase to the aqueous phase. These results are presented as release curves, with the horizontal axis representing incubation time (hours) and the vertical axis representing the release rate (% of radioactivity transferred to the aqueous phase).

[0453] Take 1 ml of freshly prepared radioactive tracer (Examples 13a, 13b, 13c, 14, 15) and deposit it into a 12 ml flat-bottomed glass flask. Measure the radioactivity using an activity meter and record the time. Add 10 ml of physiological saline or human serum and stir the mixture. Then place the flask in an incubator at 37°C equipped with a stirrer set to 30 rpm.

[0454] Keep stirring for several days. Remove the aqueous phase at different times to determine the release of yttrium-90 (radiolabeled complexes of Examples 13a, 14 and 15), indium-111 (radiolabeled complex of Example 13b), or lutetium-177 (radiolabeled complex of Example 13c).

[0455] The release results of yttrium-90 or indium-111 of the compounds in Examples 13a and 13b into the aqueous phase (physiological saline) are presented as follows: Figure 1 middle.

[0456] The release results of yttrium-90 from compounds 13a, 14, and 15 into human serum (aqueous phase) are presented in the following figures. Figure 2 middle.

[0457] The release results of lutetium-177 from compound 13c in saline and human serum are presented in the following figures. Figure 7 These results indicate that the lutetium-177 complex of Example 13c exhibits stability in saline / serum comparable to that observed in the compounds of Examples 13a and 13b (yttrium-90 complex and indium-111 complex).

[0458] Figure 1 , Figure 2 and Figure 7 This indicates that the compounds of the subject matter of this invention are stable in saline and human serum, that is, radioactivity is retained in the lipiodol phase and does not escape into the aqueous phase (the release of compounds in Examples 14 and 15 is less than 30%, and the release of compounds in Examples 13a, 13b and 13c is less than about 10% over a period of at least 350 hours), which makes their use in radiotherapy for liver tumors conceivable.

[0459] 2 / Comparative compound studies:

[0460] The following comparative compounds were studied under the same conditions in order to compare their properties with those of the compounds of the present invention.

[0461] a) Structure of the comparative compound pyridine carboxylate:

[0462]

[0463] Comparative object 1 Comparative object 2 R H <![CDATA[C≡CH-(CH2)9CH3]]>

[0464]

[0465] Comparative product 1 contains no lipophilic residues on its pyridine carboxylate unit and was not extracted. middle.

[0466] The results obtained by comparing product 2 show that radioactive labeling and extraction... This substance is irreproducible.

[0467] These results contrast with those described in Example 17 with radiolabeling, and are fully reproducible for the compounds described in Example 11b.

[0468] In addition, the stability of Comparative Compound 2 in human serum under the above experimental conditions is as follows: Figure 3 As shown; it is significantly more pronounced than that observed in the product according to the invention. Figure 2 )Difference.

[0469] This is because, in Figure 3 In the study, it was found that more than 50% of the radioactivity had escaped into the aqueous phase by T0+200 hours.

[0470]

[0471] This indicates that the structure of the lipophilic residue R placed on the pyridine carboxylate unit is crucial for obtaining the same properties (radiolabeling, reproducibility, and stability) as the compounds of the present invention.

[0472] During the optimization of the lipophilic residues, prototypes of the relevant structures were prepared and tested. Clearly, to obtain compounds stable during testing in physiological saline, the structure of group R must be tuned very precisely.

[0473] b) Compare the structures of compounds 3, 4, and 5:

[0474]

[0475]

[0476] Extraction of different compounds prepared The data is shown in the table below:

[0477]

[0478] Stability data is presented in Figure 4 middle.

[0479] Compared to the three comparative compounds, the stability curves of the compounds of this invention show a slower and lower magnitude of radioactive transfer to serum. This is because the three comparative compounds are unstable in serum, meaning they exhibit rapid and significant radioactive escape to the aqueous phase.

[0480] This indicates that the structures of these compounds cannot obtain a stable radiolabeled oil phase.

[0481] Example 17: Biodistribution study of the compounds obtained in Example 13a

[0482] Radioactive labeling is performed according to the procedure described in Example 13a.

[0483] Yttrium-90 90 YCl in HCl was supplied by PerkinElmer. Radiochemical purity greater than 95%.

[0484]

[0485] The quality of the radiolabeled material obtained in each test demonstrates that the protocol is reproducible. This robustness of the radiolabeling enables the production of batches of radiopharmaceuticals for in vivo studies.

[0486] Fifty-six female rats (Sprague-Dawley, 8 to 10 weeks old, weighing 220 to 225 g, Janvier, France) were acclimatized for 5 days (23°C, 22% humidity) with free access to food and water.

[0487] Hepatocellular carcinoma was induced in rats using Novikoff N1S1 cells (ATCC, UK).

[0488] Tumor induction involved injecting N1S1 cells into rats according to the protocol described in the literature (Garin E., Denizot B., Roux J. et al., Description and technical pitfalls of a hepatoma model and of intra-arterial injection of radiolabeled Lipiodol in the rat, Lab Animals, 2005, 39, 314-320).

[0489] The radiolabeled complex of Example 13a was injected via a cannula (26G) pre-inserted into the hepatic artery of a rat. The injection dose was approximately 3.5 MBq.

[0490] Animals were euthanized at 1 hour, 24 hours, 3 days, and 6 days, and their blood and organs were removed and weighed after dissection.

[0491] The tubes containing organs were counted using a gamma counter calibrated for yttrium-90 (PerkinElmer, USA).

[0492] The results are shown in the table below. Figure 5 As shown.

[0493]

[0494] Distribution of radioactivity in the liver

[0495] Biodistribution studies have shown that the product according to the invention is indeed captured by tumors, with a tumor / healthy liver ratio of at least 3 (see [reference]). Figure 5 Furthermore, the dose captured by a healthy liver is low, as it is approximately 5% of the injected dose. This selectivity in the distribution of radioactive compounds within tumors makes it possible to envision their use in radiotherapy for liver tumors.

[0496] The same experiment was performed using the compound (indium-111) of Example 13b. Results showed that the tumor / healthy liver injection dose ratio was greater than 5 at both the 1-hour and 6-day timeframes, consistent with results observed with the compound of Example 13a. This selectivity in the distribution of the radioactive compound of Example 13b within the tumor allows for the envisioning of its use in radiotherapy for liver tumors.

[0497] The percentage of the compounds in Examples 13a and 13b injected into the femur and bone marrow at 1 hour and 6 days post-injection are shown in the figure. Figure 6These results indicate that the residual dose of radioactivity in these organs is extremely low (less than 0.05%). These low-dose results captured in these sensitive organs allow for the envisioning use of this compound in radiotherapy for liver tumors.

Claims

1. A compound having the following general formula (I): (I) Where R is a group having the following formula (II): –C≡C-Ph-L1-(CH2) n -L2 (II) in -L1 represents Ph or –C≡C- or CH2. -L2 represents H or Ph. -n is between 4 and 12. Or one of its pharmaceutically acceptable salts.

2. The compound having formula (I) as claimed in claim 1, wherein the compound is selected from the group consisting of the following compounds: 。 3. A complex of a compound having formula (I) according to any one of claims 1 and 2, or a pharmaceutically acceptable salt thereof, with a chemical element M; wherein M is a radioactive element selected from the group consisting of: 44 Sc(III), 47 Sc(III), 111 In(III), 152 Tb(III), 155 Tb(III), 149 Tb(III), 161 Tb(III), 64 Cu(III), 61 Cu(III), 67 Cu(II), 68 Ga(III), 90 Y(III), 153 Sm(III), 166 Ho(III), 177 Lu(III), 52 Mn and 225 Ac(III).

4. The complex of claim 3, wherein the complex is selected from the group consisting of the following compounds: Where M is selected from 177 Lu(III), 90 Y(III) and 111 In(III), Where M is 90 Y(III), as well as Where M is 90 Y(III).

5. A pharmaceutical composition comprising the compound as described in any one of claims 1 and 2, and optionally one or more pharmaceutically acceptable excipients.

6. A pharmaceutical composition comprising the complex as described in claim 3 and optionally one or more pharmaceutically acceptable excipients.

7. The pharmaceutical composition of claim 5, further comprising: iodized oil.

8. A pharmaceutical composition comprising the following compounds: Or it may contain the following complexes: 。 9. Use of the complex as described in claim 3 in the preparation of medical imaging reagents.

10. Use of the pharmaceutical composition of claim 5 in the preparation of medical imaging reagents.

11. A method for preparing compounds having the following general formula (I): (I) As defined in any one of claims 1 to 2, the method includes a step of functionalizing a compound having the following general formula (IX): (IX), To form compounds having the following general formula (X): (X)， E2 is a C1-C4 alkyl group; The compound having general formula (X) undergoes a deprotection stage to obtain a compound having the following general formula (XI): (XI) as well as The functionalization stage of the compound having general formula (XI) yields a compound having general formula (I): E2 and E3 are C1-C4 alkyl groups, and X is a methanesulfonate group.

12. The method of claim 11, wherein, The C1-C4 alkyl group is selected from the group consisting of methyl, ethyl, isopropyl and tert-butyl.

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