Compound for positron emission tomography

Abstract

To describe compounds, compositions, and methods for diagnosing and / or monitoring pathogenic disease using positron emission tomography.SOLUTION: Also described are conjugates of the formula B-L-P, wherein B is a radical of a targeting agent selected from vitamin receptor binding ligands (such as folate), PSMA binding ligands, or PSMA inhibitors; L is a divalent linker comprising aspartic acid, lysine, or arginine, and P is a radical of an imaging agent or radiotherapy agent, such as a radionuclide or radionuclide containing group, or a radical of a compound capable of binding a radionuclide, such as a metal chelating group.SELECTED DRAWING: Figure 1A

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a joint venture of U.S. Provisional Patent Application No. 61 / 904,387, filed November 14, 2013. No. 61 / 904,400 filed on November 14, 2013, and Regarding the specification of No. 61 / 909,822 filed on November 27, 35 U.S.C. § 119(e) The disclosures of each of which are incorporated herein by reference in their entireties. To be incorporated.

[0002] The invention described herein relates to the use of radionuclides to diagnose and / or treat diseases and conditions. The present invention relates to compounds, compositions, and methods for monitoring the The invention uses radionuclides for positron emission tomography (PET) to detect diseases and conditions. The present invention relates to compounds, compositions and methods for diagnosing and / or monitoring. [Background technology]

[0003] PET uses a set of gamma rays emitted indirectly by a radionuclide that produces positrons. It is a nuclear imaging technique that detects the two emitted gamma rays traveling in exactly opposite directions. Therefore, it is necessary to determine their original location and thereby the origin of the emitted gamma rays. From the computer analysis, a three-dimensional image of all the positron emitters can be reconstructed. According to the study, compared with other radiological imaging modalities such as SPECT, PET has the advantages of higher detection sensitivity (about two orders of magnitude), better spatial resolution (about 5 mm), and better imaging. Larger signal to noise ratio and greater suitability for preclinical and clinical applications demonstrate excellent tracer quantification in both. In addition to this, in contrast to the approximately 90 minutes required for a body scan in standard SPECT image diagnosis, the acquisition of PET images can always be performed in approximately 20 minutes. Furthermore, in vivo PET imaging generally requires a radioactive tracer at a concentration below nanomolar (10 ~10 -10 ~10 -12 ), which has been reported to minimize possible damage to other biological systems. Finally, PET enables quantitative dynamic imaging, which can facilitate a kinetic study of target engagement through receptor occupancy. In this specification, it has been discovered that a PET agent can be directed to a predetermined tissue using a vitamin receptor and / or prostate specific membrane antigen (PSMA). For example, vitamin receptors are overexpressed in certain pathogenic cells including many cancer cell types, activated macrophages, and activated monocytes. In particular, the folate receptor is overexpressed in many cancers.

[0004] The folate receptor, which binds folic acid, a vitamin, with high affinity (<1 nM), i.e., a protein anchored to 38KD GPI, is overexpressed in many malignant tissues including ovarian, breast, bronchial, and brain cancers. It is estimated that 95% of all ovarian carcinomas overexpress the folate receptor. In contrast, normal tissues other than the kidney, choroid plexus, and placenta express low or undetectable levels of the folate receptor. Moreover, most cells acquire the necessary folic acid using unrelated reduced folate carriers.

[0005] ​​​​Folate receptors are also overexpressed in activated macrophages and activated monocytes. Furthermore, folate receptor β, i.e., the non-epithelial isoform of the folate receptor, has also been reported to be expressed in activated but quiescent synovial macrophages. Activated macrophages non-specifically engulf and kill foreign pathogens within the macrophage, and also present degraded peptides derived from foreign proteins on the macrophage cell surface, whereby (wherein they can be recognized by other immune cells), and also secrete cytokines and other factors that regulate the functions of T and B lymphocytes, thereby further stimulating the immune response and can be involved in the immune response. However, activated macrophages can also sometimes be the cause of the pathophysiology of diseases. For example, activated macrophages can contribute to atherosclerosis, rheumatoid arthritis, the pathophysiology of autoimmune diseases, among several other conditions, and graft-versus-host disease.

[0006] After receptor binding of vitamins to their vitamin receptors, such as the receptor binding of folic acid and folic acid analogs and derivatives to the folate receptor, rapid endocytosis delivers the vitamin into the cell, where it is unloaded in the endosomal compartment at a lower pH. Importantly, covalent bonding of small molecules, proteins, and even liposomes to vitamins and other vitamin receptor-binding ligands does not inhibit the binding ability of the ligand to its receptor, and thus such ligand conjugates are readily delivered to cells and can enter the cell by receptor-mediated endocytosis. Therefore, diagnostic agents, imaging agents, and therapeutic agents can be delivered to cells by conjugating them to folic acid and other vitamin receptor-binding ligands. Directed towards vitamin receptors including acid receptors and delivered into vitamin receptor-expressing cells This can be achieved.

[0007] The prostate is a male reproductive organ that functions to produce and store semen and provides nutrients and fluid for the survival of sperm introduced into the vagina during reproduction. Like other tissues, the prostate can develop malignant (cancerous) or benign (non-cancerous) tumors. According to reports, prostate cancer is one of the most common cancers in Western societies and is the second leading form of malignancy among American men. It provides nutrients and fluid for the survival of sperm introduced into the vagina during reproduction. Like other tissues, the prostate can develop malignant (cancerous) or benign (non-cancerous) tumors. According to reports, prostate cancer is one of the most common cancers in Western societies and is the second leading form of malignancy among American men. It can develop malignant (cancerous) or benign (non-cancerous) tumors. According to reports, prostate cancer is one of the most common cancers in Western societies and is the second leading form of malignancy among American men. According to reports, prostate cancer is one of the most common cancers in Western societies and is the second leading form of malignancy among American men. It is the second leading form of malignancy among American men.

[0008] Prostate-specific membrane antigen (PSMA) is a biomarker that is overexpressed in prostate cancer. PSMA is overexpressed in malignant prostate tissue compared to other organs of the human body such as the kidney, proximal small intestine, and salivary gland. PSMA is also expressed in the neovasculature within many non-prostate solid tumors including lung, colon, breast, kidney, liver, and pancreatic carcinomas, but not in normal vasculature. However, PSMA is expressed only slightly in the brain. PSMA is a type II cell surface membrane-bound glycoprotein with a molecular weight of up to about 110 kDa, including an intracellular portion (amino acids 1 - 18), a transmembrane domain (amino acids 19 - 43), and an extensive extracellular domain (amino acids 44 - 750). So far, the roles of this intracellular portion and transmembrane domain have been reported to be unimportant, but the extracellular domain is involved in several distinct activities. For example, PSMA plays a role in the central nervous system in metabolizing N-acetylaspartylglutamate (NAAG) to glutamate and N-acetylaspartic acid. PSMA also plays a role in the proximal small intestine. It is overexpressed in malignant prostate tissue compared to other organs of the human body such as the kidney, proximal small intestine, and salivary gland. PSMA is overexpressed in malignant prostate tissue compared to other organs of the human body such as the kidney, proximal small intestine, and salivary gland. PSMA is also expressed in the neovasculature within many non-prostate solid tumors including lung, colon, breast, kidney, liver, and pancreatic carcinomas, but not in normal vasculature. However, PSMA is expressed only slightly in the brain. PSMA is also expressed in the neovasculature within many non-prostate solid tumors including lung, colon, breast, kidney, liver, and pancreatic carcinomas, but not in normal vasculature. However, PSMA is expressed only slightly in the brain. PSMA is also expressed in the neovasculature within many non-prostate solid tumors including lung, colon, breast, kidney, liver, and pancreatic carcinomas, but not in normal vasculature. However, PSMA is expressed only slightly in the brain. However, PSMA is expressed only slightly in the brain. PSMA is a type II cell surface membrane-bound glycoprotein with a molecular weight of up to about 110 kDa, including an intracellular portion (amino acids 1 - 18), a transmembrane domain (amino acids 19 - 43), and an extensive extracellular domain (amino acids 44 - 750). PSMA is a type II cell surface membrane-bound glycoprotein with a molecular weight of up to about 110 kDa, including an intracellular portion (amino acids 1 - 18), a transmembrane domain (amino acids 19 - 43), and an extensive extracellular domain (amino acids 44 - 750). PSMA is a type II cell surface membrane-bound glycoprotein with a molecular weight of up to about 110 kDa, including an intracellular portion (amino acids 1 - 18), a transmembrane domain (amino acids 19 - 43), and an extensive extracellular domain (amino acids 44 - 750). So far, the roles of this intracellular portion and transmembrane domain have been reported to be unimportant, but the extracellular domain is involved in several distinct activities. So far, the roles of this intracellular portion and transmembrane domain have been reported to be unimportant, but the extracellular domain is involved in several distinct activities. So far, the roles of this intracellular portion and transmembrane domain have been reported to be unimportant, but the extracellular domain is involved in several distinct activities. For example, PSMA plays a role in the central nervous system in metabolizing N-acetylaspartylglutamate (NAAG) to glutamate and N-acetylaspartic acid. For example, PSMA plays a role in the central nervous system in metabolizing N-acetylaspartylglutamate (NAAG) to glutamate and N-acetylaspartic acid. PSMA also plays a role in the proximal small intestine. Remove the γ-linked glutamic acid from poly-γ-glutamic acid type folic acid, and also remove the α-linked glutamic acid from peptides and small molecules, playing a role in removing them.

Summary of the Invention

Problems to be Solved by the Invention

[0009] Although the detailed role of PSMA in prostate cancer cells remains unresolved, PSMA, like vitamin receptors, is known to undergo rapid internalization into cells similar to cell surface binding receptors. PSMA is taken up through clathrin-coated pits and can then be recycled back to the cell surface or go to lysosomes. Therefore, diagnostic agents, imaging agents, and therapeutic agents can be directed to PSMA and delivered into PSMA expressing cells such as prostate cancer cells.

Means for Solving the Problems

[0010] It has been discovered herein that the compounds and compositions described herein are useful for targeting and delivering radionuclides for diagnosing and / or monitoring various diseases and conditions caused by pathogenic cell populations. In addition, the compounds and compositions described herein are also useful for targeting and delivering radionuclides for treating various diseases and conditions caused by pathogenic cell populations with radiation therapy. In one exemplary and non-limiting embodiment of the invention described herein, the compounds and compositions described herein are used for various diseases and conditions caused by pathogenic cell populations.

[0011] In one exemplary and non-limiting embodiment of the invention described herein, the compounds and compositions described herein are used for various diseases and conditions caused by pathogenic cell populations. ​​​​It is used for diagnosing and / or monitoring a condition or for treatment. Another example In an exemplary embodiment, the compounds and compositions described herein are administered for diagnosing and / or monitoring various diseases and conditions caused by pathogenic cell populations or for treatment. In another embodiment, the use of compounds and compositions for manufacturing agents for diagnosing and / or monitoring various diseases and conditions caused by pathogenic cell populations or for treatment is described herein In another embodiment, kits for preparing and / or using the compounds and compositions described herein for diagnosing and / or monitoring various diseases and conditions caused by pathogenic cell populations or for treatment are described herein for diagnosing and / or monitoring various diseases and conditions caused by pathogenic cell populations or for treatment for diagnosing and / or monitoring various diseases and conditions caused by pathogenic cell populations or for treatment for diagnosing and / or monitoring various diseases and conditions caused by pathogenic cell populations or for treatment In another embodiment, the compounds and compositions described herein are administered for diagnosing and / or monitoring various diseases and conditions caused by pathogenic cell populations or for treatment

Brief Description of the Drawings

[0012]

Figure 1A

Figure 1B

Figure 1C

Figure 2A

Figure 2B

Mode for Carrying Out the Invention

[0013] In each of the foregoing embodiments, and in each of the following embodiments, the chemical formula is , including all pharmaceutically acceptable salts of those compounds, and represents not only, but also the any and all hydrates and / or solvates of any of the chemical formulas, and it should be understood that it represents. Some functional groups, such as hydroxy, amino, and similar groups, are water and / or complexes and / or coordination compounds of various physical forms of those compounds, together with various solvents are found to form. Therefore, it should be understood that the chemical formulas described herein include these various hydrates and / or solvates and represent them. Also, not only the hydrates and / or solvates of the chemical formulas of the compounds, but also the anhydrous and / or unsolvated forms of the chemical formulas of the compounds are understood to be described by such chemical formulas. / or unsolvates

[0014] As used herein, the term "composition" generally refers to any product containing a specified amount of a specified component and any product directly or indirectly resulting from a combination of a specified amount of a specified component. The compositions described herein can be prepared from the isolated compounds described herein or from salts, solutions, hydrates, solvates, and other forms of the compounds described herein. It is understood that several functional groups, such as hydroxy, amino, and similar groups, form complexes and / or coordination compounds of various physical forms of those compounds together with water and / or various solvents. Also, these compositions can be prepared from various amorphous forms, non-amorphous forms, partially crystalline forms, crystalline forms, and / or morphological shapes of the compounds described herein. It is also understood that these compositions can be prepared from various hydrates and / or solvates of the compounds described herein. Therefore, such pharmaceutical compositions of the compounds described herein include each of the various morphological shapes and / or forms of hydrates or solvates of the compounds described herein, or any combination thereof. Thus, such pharmaceutical compositions of the compounds described herein include each of the various morphological shapes and / or forms of hydrates or solvates of the compounds described herein, or any It is to be understood to include combinations. In addition to this, it is to be understood that these compositions can be prepared from various co-crystals of the compounds described herein. It is to be understood to include combinations. In addition to this, it is to be understood that these compositions can be prepared from various co-crystals of the compounds described herein.

[0015] As specific examples, these compounds can include one or more carriers, extenders, and / or pharmaceutical additives. The compounds described herein or the compositions containing them can be formulated in any conventional dosage form suitable for the methods described herein in a therapeutically effective amount. The compounds described herein or the compositions containing them, including such formulations, can be administered by a wide range of conventional routes for the methods described herein and in a wide range of dosage forms using known procedures (generally, refer to Remington: The Science and Practice of Pharmacy (21st Edition, 2005)). The compounds described herein or the compositions containing them, including such formulations, can be administered by a wide range of conventional routes for the methods described herein and in a wide range of dosage forms using known procedures (generally, refer to Remington: The Science and Practice of Pharmacy (21st Edition, 2005)). The compounds described herein or the compositions containing them, including such formulations, can be administered by a wide range of conventional routes for the methods described herein and in a wide range of dosage forms using known procedures (generally, refer to Remington: The Science and Practice of Pharmacy (21st Edition, 2005)). ngton: The Science and Practice of Pharma cy (21st Edition, 2005)).

[0016] In each of the foregoing embodiments and in each of the following embodiments, these chemical formulas are also to be understood to include, individually and as any and all possible mixtures, each possible isomer, such as stereoisomers and geometric isomers, of the respective compounds. In each of the foregoing embodiments and in each of the following embodiments, these chemical formulas are also to be understood to include, individually and as any and all possible mixtures, each possible isomer, such as stereoisomers and geometric isomers, of the respective compounds. In each of the foregoing embodiments and in each of the following embodiments, these chemical formulas are also to be understood to include, individually and as any and all possible mixtures, each possible isomer, such as stereoisomers and geometric isomers, of the respective compounds. In each of the foregoing embodiments and in each of the following embodiments, these chemical formulas are also to be understood to include, individually and as any and all possible mixtures, each possible isomer, such as stereoisomers and geometric isomers, of the respective compounds. In each of the foregoing embodiments and in each of the following embodiments, these chemical formulas are also to be understood to include, individually and as any and all possible mixtures, each possible crystal form, partial crystal form, and non-crystalline and / or or amorphous form of those compounds.

[0017] Exemplary embodiments of the present invention are described by the following clauses. Formula, B-L-P A conjugate of or a pharmaceutically acceptable salt thereof. In the formula, B is a vitamin receptor-binding ligand, A radical of a target drug selected from a PSMA binding ligand and a PSMA inhibitor, L is a divalent linker, and P is a radical of an imaging agent or a radiotherapy drug, such as a radioactive nuclide or a radical of a radionuclide-containing group, or a precursor thereof, or a compound capable of binding to a radionuclide or a radionuclide-containing group, such as a metal chelate group. is.

[0018] The conjugate described in the preceding clause, wherein the target drug is a radical of a folic acid receptor binding ligand. conjugate. The conjugate described in any one of the preceding clauses, wherein the target drug is a radical of folic acid. . A conjugate described in any one of the preceding clauses, comprising folic acid-Asp. A conjugate described in any one of the preceding clauses, comprising folic acid-Asp-Arg. A conjugate described in any one of the preceding clauses, comprising folic acid-Arg. A conjugate described in any one of the preceding clauses, wherein the linker comprises a polypeptide. A conjugate described in any one of the preceding clauses, wherein the linker comprises a polypeptide containing lysine, arginine, or aspartic acid, or a combination thereof. conjugate. A conjugate described in any one of the preceding clauses, wherein the linker comprises lysine. A conjugate described in any one of the preceding clauses, wherein the linker comprises Lys. A conjugate described in any one of the preceding clauses, wherein the linker comprises Arg-Lys. . A conjugate described in any one of the preceding clauses, wherein the linker comprises Arg-Arg-Lys. is. A conjugate described in any one of the preceding clauses, wherein the linker comprises Asp-Arg-Arg-Lys. is. The linker is a polyamine radical, for example, a polyamine of the formula NH-(CH2)2-NH A conjugate according to any one of the preceding clauses, which does not contain a diradical. P is of the formula A conjugate according to any one of the preceding clauses, which contains JPEG0007693751000001.jpg26166 or a derivative thereof containing a chelated metal. A conjugate according to any one of the preceding clauses, which contains JPEG0007693751000002.jpg26166 or a derivative thereof containing a chelated metal. The formula A conjugate according to any one of the preceding clauses, which contains JPEG0007693751000002.jpg26166 or a derivative thereof containing a chelated metal. A conjugate according to any one of the preceding clauses, which contains JPEG0007693751000002.jpg26166 or a derivative thereof containing a chelated metal. A conjugate according to any one of the preceding clauses, which contains folic acid-PEG. A conjugate according to any one of the preceding clauses, which contains folic acid-PEG2. A conjugate according to any one of the preceding clauses, which contains folic acid-PEG6. Folic acid-PEG 12 A conjugate according to any one of the preceding clauses, which contains folic acid-PEG.

[0019] The linker is [(CH2)2O] n , [(CH2)2O] n -(CH2)2-C(O) , [(CH2)2O] n -(CH2)2-C(O)NH, [(CH2)2O] n -(CH 2)2-C(O)NH-(CH2)2, [(CH2)2O] n -(CH2) n -C(O) NH-(CH2)2NH (wherein n is an integer from 1 to about 12), a conjugate according to any one of the preceding clauses. A conjugate according to any one of the preceding clauses.

[0020] The linker is [(CH2)2O]2, [(CH2)2O]6, or [(CH2)2O 12 A conjugate according to any one of the preceding clauses, which contains [(CH2)2O]2, [(CH2)2O]6, or [(CH2)2O​

[0021] The linker is (CH2)2O-(CH2)2-C(O), [(CH2)2O]2-(C H2)2-C(O), [(CH2)2O]6-(CH2)2-C(O), or [(CH 2)2O] 12 -(CH2)2-C(O), and is a conjugate described in any one of the preceding clauses.

[0022] The linker is (CH2)2O-(CH2)2-C(O)NH, [(CH2)2O]2- (CH2)2-C(O)NH, [(CH2)2O]6-(CH2)2-C(O)NH, or [(CH2)2O] 12 -(CH2)2-C(O)NH, and is a conjugate described in any one of the preceding clauses.

[0023] The linker is (CH2)2O-(CH2)2-C(O)NH-(CH2)2, [(CH 2)2O]2-(CH2)2-C(O)NH-(CH2)2, [(CH2)2O]6-( CH2)2-C(O)NH-(CH2)2, or [(CH2)2O] 12 -(CH2) 2-C(O)NH-(CH2)2, and is a conjugate described in any one of the preceding clauses.

[0024] The linker is (CH2)2O-(CH2)2-C(O)NH-(CH2)2NH, [( CH2)2O]2-(CH2)2-C(O)NH-(CH2)2NH, [(CH2)2O 6-(CH2)2-C(O)NH-(CH2)2NH, or [(CH2)2O] 12 -(CH2)2-C(O)NH-(CH2)2NH, and is a conjugate described in any one of the preceding clauses.

[0025] ​​​ The linker is NH[(CH2)2O] n 、NH[(CH2)2O] n -(CH2)2- C(O), NH[(CH2)2O] n -(CH2)2-C(O)NH, NH[(CH2) 2O] n -(CH2)2-C(O)NH-(CH2)2, NH[(CH2)2O] n -( CH2)2-C(O)NH-(CH2)2NH (where n is an integer from 1 to about 12) The conjugate according to any one of the preceding clauses, comprising

[0026] The linker is NH(CH2)2O, NH[(CH2)2O]2, NH[(CH2)2O 6, or NH[(CH2)2O] 12 The conjugate according to any one of the preceding clauses, comprising

[0027] The linker is NH(CH2)2O-(CH2)2-C(O), NH[(CH2)2O] 2-(CH2)2-C(O), NH[(CH2)2O]6-(CH2)2-C(O), or NH[(CH2)2O] 12 -(CH2)2-C(O), the conjugate according to any one of the preceding clauses, comprising

[0028] The linker is NH(CH2)2O-(CH2)2-C(O)NH, NH[(CH2)2 O]2-(CH2)2-C(O)NH, NH[(CH2)2O]6-(CH2)2-C( O)NH, or NH[(CH2)2O] 12 -(CH2)2-C(O)NH, the conjugate according to any one of the preceding clauses, comprising

[0029] ​​​The linker is NH(CH2)2O-(CH2)2-C(O)NH-(CH2)2, NH [(CH2)2O]2-(CH2)2-C(O)NH-(CH2)2, NH[(CH2) 2O]6-(CH2)2-C(O)NH-(CH2)2, or NH[(CH2)2O] 12 -(CH2)2-C(O)NH-(CH2)2, and is included in any one of the foregoing clauses The conjugate described.

[0030] The linker is NH(CH2)2O-(CH2)2-C(O)NH-(CH2)2NH, NH[(CH2)2O]2-(CH2)2-C(O)NH-(CH2)2NH, NH [(CH2)2O]6-(CH2)2-C(O)NH-(CH2)2NH, or NH[(C H2)2O] 12 -(CH2)2-C(O)NH-(CH2)2NH, and is included in any one of the foregoing clauses The conjugate described.

[0031] The linker is NH[(CH2)2O] n -(CH2)2NH (wherein n is an integer from 1 to about 12) and is included in any one of the foregoing clauses.

[0032] The linker is NH(CH2)2O-(CH2)2NH, NH[(CH2)2O]2-( CH2)2NH, NH[(CH2)2O]6-(CH2)2NH, or NH[(CH2 )2O] 12 -(CH2)2NH, and is included in any one of the foregoing clauses The conjugate.

[0033] The linker is NH[(CH2)2O] n -(CH2)2NH-C(O)-(CH2)2 -C(O) (wherein n is an integer from 1 to about 12) included in any one of the foregoing clauses The conjugate described.

[0034] The linker is NH(CH2)2O-(CH2)2NH-C(O)-(CH2)2-C( O), NH[(CH2)2O]2-(CH2)2NH-C(O)-(CH2)2-C(O ), NH[(CH2)2O]6-(CH2)2NH-C(O)-(CH2)2-C(O) , or NH[(CH2)2O] 12 -(CH2)2NH-C(O)-(CH2)2-C (O) included in any one of the foregoing clauses.

[0035] Formula JPEG0007693751000003.jpg30166 or its derivative containing a chelated metal included in any one of the foregoing clauses The conjugate described. P is a conjugate described in any one of the foregoing clauses containing a formula JPEG0007693751000004.jpg38166 or its derivative containing a chelated metal The conjugate described. Formula JPEG0007693751000005.jpg49166 or its derivative containing a chelated metal included in any one of the foregoing clauses The conjugate described.

[0036] The conjugate described in any one of the foregoing clauses, wherein the target drug is a radical of a PSMA binding ligand or a PSMA inhibitor The conjugate described. The conjugate described in any one of the foregoing clauses, wherein the target drug is a radical of a PSMA inhibitor The conjugate described.

[0037] Formula JPEG0007693751000006.jpg32166(wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) ), or JPEG0007693751000007.jpg68166(wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) ), or JPEG0007693751000008.jpg68166(wherein W is O or S), the conjugate described in any one of the preceding clauses .

[0038] A conjugate described in any one of the preceding clauses, wherein the linker contains a polypeptide . A conjugate described in any one of the preceding clauses, wherein the linker contains a polypeptide including phenylalanine, lysine, arginine, or aspartic acid, or a combination thereof . A conjugate described in any one of the preceding clauses, wherein the linker contains lysine . A conjugate described in any one of the preceding clauses, wherein the linker contains Lys . A conjugate described in any one of the preceding clauses, wherein the linker contains Arg-Lys . A conjugate described in any one of the preceding clauses, wherein the linker contains Asp-Arg-Lys . A conjugate described in any one of the preceding clauses, wherein the linker contains Arg-Asp-Arg . A conjugate described in any one of the preceding clauses, wherein the linker contains Arg-Asp-Arg-Lys . The conjugate that has been obtained. The conjugate according to any one of the preceding clauses, wherein the linker contains Phe-Arg-Asp-Arg-Lys. The conjugate according to any one of the preceding clauses. The conjugate according to any one of the preceding clauses, wherein the linker contains Phe-Phe-Arg. The conjugate according to any one of the preceding clauses. The conjugate according to any one of the preceding clauses, wherein the linker contains Phe-Phe-Arg-Asp. The conjugate according to any one of the preceding clauses. The conjugate according to any one of the preceding clauses, wherein the linker contains Phe-Phe-Arg-Asp-Arg. The conjugate according to any one of the preceding clauses. The conjugate according to any one of the preceding clauses, wherein the linker contains Phe-Phe-Arg-Asp-Arg-Lys. The conjugate according to any one of the preceding clauses. The conjugate according to any one of the preceding clauses, wherein the radical of the radionuclide or radionuclide-containing group, or its precursor, or the radical of the compound capable of binding to the radionuclide or radionuclide-containing group is the radiolabel of NOTA. The conjugate according to any one of the preceding clauses. The conjugate according to any one of the preceding clauses.

[0039] P is the conjugate according to any one of the preceding clauses, including JPEG0007693751000009.jpg30166 or its derivative containing a chelated metal. The conjugate according to any one of the preceding clauses. The conjugate according to any one of the preceding clauses. The conjugate according to any one of the preceding clauses, including the formula JPEG0007693751000010.jpg28166 or its derivative containing a chelated metal. The conjugate according to any one of the preceding clauses. The conjugate according to any one of the preceding clauses, including the formula JPEG0007693751000011.jpg33166 (wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). The conjugate according to any one of the preceding clauses. The conjugate according to any one of the preceding clauses, including the formula The conjugate described in any one of the preceding clauses, including JPEG0007693751000012.jpg33166. The linker is of the formula The conjugate described in any one of the preceding clauses, including JPEG0007693751000013.jpg20166. The linker is of the formula The conjugate described in any one of the preceding clauses, including JPEG0007693751000014.jpg22166. The linker is of the formula The conjugate described in any one of the preceding clauses, including JPEG0007693751000015.jpg22166. The conjugate described in any one of the preceding clauses, wherein one or more of the phenylalanines is L - phenylalanine. The conjugate described in any one of the preceding clauses. The formula The conjugate described in any one of the preceding clauses, including JPEG0007693751000016.jpg60166 or a derivative thereof containing a chelated metal. The conjugate described in any one of the preceding clauses. P is of the formula The conjugate described in any one of the preceding clauses, including JPEG0007693751000017.jpg38166 or a derivative thereof containing a chelated metal. The conjugate described in any one of the preceding clauses. The formula The conjugate described in any one of the preceding clauses, including JPEG0007693751000018.jpg122166 or a derivative thereof containing a chelated metal. The conjugate described in any one of the preceding clauses.

[0040] The conjugate described in any one of the preceding clauses, wherein the radionuclide is a positron - emitting radionuclide. The conjugate described in any one of the preceding clauses. The conjugate described in any one of the preceding clauses, wherein the radionuclide is a metal ion. The conjugate described in any one of the preceding clauses, wherein the radionuclide is a metal salt. An aluminum halide, such as aluminum fluoride, aluminum chloride, aluminum bromide, or aluminum iodide, contained in any one of the preceding clauses. The conjugate described in any one of the preceding clauses. Conjugate. A conjugate described in any one of the preceding clauses and containing aluminum fluoride. 18 A conjugate described in any one of the preceding clauses and containing F-aluminum fluoride. Conjugate. A conjugate described in any one of the preceding clauses and containing aluminum iodide. 125 A conjugate described in any one of the preceding clauses and containing I-aluminum iodide. Conjugate. A conjugate described in any one of the preceding clauses and containing gallium ions. 66 A conjugate described in any one of the preceding clauses and containing Ga ions. 68 A conjugate described in any one of the preceding clauses and containing Ga ions. A conjugate described in any one of the preceding clauses and containing zirconium ions. 89 A conjugate described in any one of the preceding clauses and containing Zr ions. A conjugate described in any one of the preceding clauses and containing copper ions. 64 A conjugate described in any one of the preceding clauses and containing Cu ions. The radionuclide is 131 Iodine including I, 177 Lutetium including Lu, 90 Yttrium including Y And strontium including Sr, 89 Samarium including Sm 153 Any radiotherapeutic agent or radiotherapeutic agent-containing group described in any one of the preceding clauses. The conjugate described in any one of the preceding clauses. Conjugate.

[0041] A conjugate comprising a lutetium ion, for example 177 a Lu ion, as described in any one of the preceding clauses is provided. A conjugate comprising a yttrium ion, for example 90 a Y ion, as described in any one of the preceding clauses is provided.

[0042] The conjugate of formula JPEG0007693751000019.jpg112166 or a pharmaceutically acceptable salt thereof. The conjugate of formula JPEG0007693751000020.jpg115166 or a pharmaceutically acceptable salt thereof. The conjugate of formula JPEG0007693751000021.jpg68166 or a pharmaceutically acceptable salt thereof. The conjugate of formula JPEG0007693751000022.jpg75166 or a pharmaceutically acceptable salt thereof. wherein P is of the formula JPEG0007693751000023.jpg27166 (wherein X - is the conjugate base of an acid such as trifluoromethanesulfonic acid), as described in any one of the preceding clauses is provided. The conjugate of formula JPEG0007693751000024.jpg55166 (wherein X - is the conjugate base of an acid such as trifluoromethanesulfonic acid), as described in any one of the preceding clauses is provided. wherein P is of the formula JPEG0007693751000025.jpg26166, as described in any one of the preceding clauses wherein P is of the formula JPEG0007693751000026.jpg29166, as described in any one of the preceding clauses The conjugate of formula The conjugate described in any one of the preceding clauses, including JPEG0007693751000027.jpg26166. Formula The conjugate described in any one of the preceding clauses, including JPEG0007693751000028.jpg26166.

[0043] P is the formula * The conjugate described in any one of the preceding clauses, including NH-C(CH2OH)3 Conjugate. The conjugate described in any one of the preceding clauses, including boron fluoride. 18 The conjugate described in any one of the preceding clauses, including F-boron fluoride. One or more kinds of the conjugates described in any one of the preceding clauses are included together with one Or more kinds of carriers, extenders, or pharmaceutical additives, or combinations thereof Pharmaceutical composition.

[0044] For diagnosing and / or monitoring pathogenic cell populations, such as cancer or infectious diseases One or more kinds of the conjugates described in any one of the preceding clauses, in a diagnostically effective amount, optionally together with one or more kinds of carriers, extenders, or pharmaceutical additives, or combinations thereof In a unit dose or unit dosage form composition.

[0045] For treating pathogenic cell populations, such as cancer or infectious diseases, one or more kinds of the conjugates described in any one of the preceding clauses, in a therapeutically effective amount, optionally together with one or more kinds of carriers, extenders, or pharmaceutical additives, or combinations thereof In a unit dose or unit dosage form composition. Optionally together with one or more kinds of carriers, extenders, or pharmaceutical additives, or combinations thereof

[0046] A composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, or a pharmaceutical composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, and optionally further comprising one or more carriers, bulking agents, or pharmaceutical additives, or combinations thereof. A composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, or a pharmaceutical composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, and optionally further comprising one or more carriers, bulking agents, or pharmaceutical additives, or combinations thereof. A composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, or a pharmaceutical composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, and optionally further comprising one or more carriers, bulking agents, or pharmaceutical additives, or combinations thereof. A composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, or a pharmaceutical composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, and optionally further comprising one or more carriers, bulking agents, or pharmaceutical additives, or combinations thereof. A composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, or a pharmaceutical composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, and optionally further comprising one or more carriers, bulking agents, or pharmaceutical additives, or combinations thereof. A composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, or a pharmaceutical composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, and optionally further comprising one or more carriers, bulking agents, or pharmaceutical additives, or combinations thereof.

[0047] A composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for treating a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, or a pharmaceutical composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for treating a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, and optionally further comprising one or more carriers, bulking agents, or pharmaceutical additives, or combinations thereof. A composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for treating a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, or a pharmaceutical composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for treating a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, and optionally further comprising one or more carriers, bulking agents, or pharmaceutical additives, or combinations thereof. A composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for treating a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, or a pharmaceutical composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for treating a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, and optionally further comprising one or more carriers, bulking agents, or pharmaceutical additives, or combinations thereof. A composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for treating a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, or a pharmaceutical composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for treating a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, and optionally further comprising one or more carriers, bulking agents, or pharmaceutical additives, or combinations thereof. A composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for treating a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, or a pharmaceutical composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for treating a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, and optionally further comprising one or more carriers, bulking agents, or pharmaceutical additives, or combinations thereof. A composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for treating a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, or a pharmaceutical composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for treating a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in a host animal, and optionally further comprising one or more carriers, bulking agents, or pharmaceutical additives, or combinations thereof.

[0048] Administering to the host animal an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in the host animal, or a pharmaceutical composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in the host animal, and optionally further comprising one or more carriers, bulking agents, or pharmaceutical additives, or combinations thereof. Administering to the host animal an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in the host animal, or a pharmaceutical composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in the host animal, and optionally further comprising one or more carriers, bulking agents, or pharmaceutical additives, or combinations thereof. Administering to the host animal an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in the host animal, or a pharmaceutical composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in the host animal, and optionally further comprising one or more carriers, bulking agents, or pharmaceutical additives, or combinations thereof. Administering to the host animal an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in the host animal, or a pharmaceutical composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in the host animal, and optionally further comprising one or more carriers, bulking agents, or pharmaceutical additives, or combinations thereof. Administering to the host animal an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in the host animal, or a pharmaceutical composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in the host animal, and optionally further comprising one or more carriers, bulking agents, or pharmaceutical additives, or combinations thereof. Administering to the host animal an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in the host animal, or a pharmaceutical composition comprising an effective amount of one or more of the conjugates described in any one of the preceding clauses for diagnosing and / or monitoring a disease or condition at least partially caused by a pathogenic cell population, such as cancer or an infectious disease, in the host animal, and optionally further comprising one or more carriers, bulking agents, or pharmaceutical additives, or combinations thereof. A method comprising the step of administering a composition.

[0049] In a host animal, to treat a pathogenic cell population, e.g., a disease or condition at least partially caused by cancer or an infectious disease, administering to the host animal a therapeutically effective amount of one or more of the conjugates described in any one of the preceding clauses, or administering a pharmaceutical composition comprising a therapeutically effective amount of one or more of the conjugates described in any one of the preceding clauses and optionally further comprising one or more carriers, diluents, or pharmaceutical additives, or combinations thereof. A method comprising the step.

[0050] In a host animal, to diagnose and / or monitor a disease or condition at least partially caused by a pathogenic cell population, e.g., cancer or an infectious disease, using a pharmaceutical composition comprising one or more of the conjugates described in any one of the preceding clauses, or comprising one or more of the conjugates described in any one of the preceding clauses and optionally further comprising one or more carriers, diluents, or pharmaceutical additives, or combinations thereof.

[0051] In a host animal, to manufacture a medicament for treating a disease or condition at least partially caused by a pathogenic cell population, e.g., cancer or an infectious disease, comprising one or more of the conjugates described in any one of the preceding clauses, or comprising one or more of the conjugates described in any one of the preceding clauses and In some cases, use a pharmaceutical composition further comprising one or more carriers, extenders, or pharmaceutical additives, or a combination thereof.

[0052] One or more of the conjugates described in any one of the preceding clauses, or in some cases one or more carriers, extenders, or pharmaceutical additives, or a combination thereof, and its pharmaceutical composition, an optional solvent, an optional reaction vessel, preparing one or more radionuclides, and combining the one or more radionuclides with the one or more conjugates to form an imaging agent, a diagnostic agent, or a therapeutic agent, and a set of instructions for use.

[0053] One or more of the conjugates described in any one of the preceding clauses, or in some cases one or more carriers, extenders, or pharmaceutical additives, or a combination thereof, and its pharmaceutical composition, an optional solvent, an optional reaction vessel, preparing one or more radionuclides, and combining the one or more radionuclides with the one or more conjugates to form an imaging agent, a diagnostic agent, or a therapeutic agent, and a set of instructions for use.

[0054] The compound or chemical formula is marked with ([ * ) or contains an atom or site including this mark. In each case, ([ ) means that the compound or chemical formula is a radical having an open valence at the atom or site, and it should be understood that the atom or site is the attachment position of another radical. *

[0055] In another exemplary embodiment, the conjugates, compositions, unit doses, methods, uses, or kits of any other embodiment described herein are of the compound of formula JPEG0007693751000029.jpg29166 (wherein each R is independently selected in each instance to form a carboxylic acid or its salt, ester, or amide, and R 1 , R 2 , and R 3 are each independently hydrogen and, optionally, substituted alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl), or a derivative thereof containing a chelating metal, or containing the aforementioned radicals.

[0056] In another exemplary embodiment, the conjugates, compositions, unit doses, methods, uses, or kits of any other embodiment described herein are 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), or a derivative thereof containing a chelating metal , or containing the aforementioned radicals.

[0057] In another exemplary embodiment, the conjugates, compositions, unit doses, methods, uses, or kits of any other embodiment described herein are of the compound of formula JPEG0007693751000030.jpg30166 (wherein each R is independently selected in each instance to form a carboxylic acid or its salt, ester, or amide, and R 1 , R 2 , and R 3 are each independently hydrogen and, optionally, substituted alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl), (selected from arylalkyl, heteroaryl, and heteroarylalkyl) or a derivative thereof containing a chelating metal, or any of the aforementioned radicals, for example, as an example of the compound of JPEG0007693751000031.jpg29166 (wherein JPEG0007693751000032.jpg177166), or a carboxylate or carboxamide derivative (CONH2) thereof, or any of the aforementioned radicals, or a derivative thereof containing a chelating metal.

[0058] In another exemplary embodiment, the conjugates, compositions, unit dosages, methods, uses, or kits of any other embodiment described herein are of the formula the compound of JPEG0007693751000033.jpg27166 (wherein R 4 and R 5 are selected from hydrogen and optionally substituted alkyl, cyclo alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl), or a derivative thereof containing a chelating metal, or any of the aforementioned radicals such as, for example, the compound of (wherein JPEG0007693751000034.jpg47166), or a carboxylate or carboxamide derivative (CONH2) thereof, or any of the aforementioned radicals, or a derivative thereof containing a chelating metal.

[0059] In another exemplary embodiment, the conjugates, compositions, unit dosages, methods, uses, or kits of any other embodiment described herein are of the formula the compound of JPEG0007693751000035.jpg25166 (wherein ​JPEG0007693751000036.jpg47166JPEG0007693751000037.jpg231166JPEG0007693751000038.jpg153166, or its carboxylate or carboxamide derivative (CONH2), or including any of the aforementioned radicals, or its derivatives containing a chelating metal.

[0060] In another exemplary embodiment, the conjugates, compositions, unit doses, methods, uses, or kits of any other embodiment described herein are of the formula JPEG0007693751000039.jpg120166(wherein n is an integer selected from 1, 2, 3, 4, 5, or 6), or a compound selected therefrom, or its carboxylate or carboxamide derivative (CONH2), or including any of the aforementioned radicals, or its derivatives containing a chelating metal.

[0061] As used herein, the term "radical" generally refers to a valence-free compound or chemical fragment formed after removing a hydrogen atom or a hydroxyl group from a carboxylic acid. For example, the radical JPEG0007693751000040.jpg41166(wherein each ( * ) atom is a free valence for attachment to a linker and / or a target drug) can be formed from L-NETA.

[0062] It should be understood that the aforementioned compounds and their radicals can be further functionalized by attaching a reactive group for subsequent attachment of a linker and / or a target group. As an example, the reactive intermediate is described herein for the purpose of attachment of a linker and / or a target group. Describe JPEG0007693751000041.jpg26166. In the formula, n is 0 or 1, and NX is, JPEG0007693751000042.jpg21166 and the like.

[0063] Compound JPEG0007693751000043.jpg128166 (wherein n is 1 or 3) and its metal chelate compound are not in the conjugate of the present invention It should be understood that there is none.

[0064] The compounds described herein may also contain one or more chiral centers, and may also exist as a plurality of stereoisomers. In one embodiment, it should be understood that the present invention described herein is not limited to specific stereochemical requirements, and these compounds and compositions, methods, uses, and drugs containing them can also be pure optionally, and can also be any of various stereoisomeric mixtures including racemic mixtures of enantiomers and other mixtures, other mixtures of diastereomers, etc. It should be understood that such mixtures of stereoisomers can contain a single stereochemical configuration at one or more chiral centers and remain in a state containing a mixture of stereochemical configurations at one or more other chiral centers. It should also be understood that.

[0065] Similarly, the compounds described herein can contain geometric centers such as cis, trans, E, and Z double bonds. In another embodiment, it should be understood that the present invention described herein is not limited to specific geometric isomer requirements, and these compounds and compositions, methods It should be understood that it can also be any of the mixtures. Such a mixture of geometric isomers can contain a single configuration at one or more double bonds and remain in a state containing a mixture of geometries at one or more other double bonds. It should also be understood that.

[0066] As used herein, the term "alkyl" includes, in some cases, a chain of branched carbon atoms . As used herein, the terms "alkenyl" and "alkynyl" each include, in some cases, a chain of branched carbon atoms and each contain at least one double bond or a triple bond respectively. It should be understood that alkynyl can also contain one or more double bonds . In some embodiments, alkyl is advantageously C1-C , C1- 24 , C1-C C 12 , including C1-C8, C1-C6, and C1-C4, and is further understood to be of a limited length . By way of example, alkyl groups of such particularly limited lengths, including C1-C8, C1-C6, and C1-C4 , may be referred to as lower alkyl. In some embodiments, alkenyl and / or alkynyl are each advantageously C2- C 24 , C2-C 12 , including C2-C8, C2-C6, and C2-C4, and can be further understood to be of a limited length. By way of example, alkenyl and / or alkynyl groups of such particularly limited lengths, including C2-C8, C 2-C6, and C2-C4, may be referred to as lower alkenyl and / or alkynyl. The alkyl, alkenyl, and / or alkynyl groups are shorter, the smaller the lipophilicity of the compound . can impart harmony and thus will have different pharmacokinetic behaviors will be understood from this specification. In the embodiments of the present invention described in this specification, in any case detailed description of alkyl refers to alkyl as defined in this specification and, in some cases refers to lower alkyl. In the embodiments of the present invention described in this specification in any case, detailed description of alkenyl refers to alkenyl as defined in this specification and, in some cases, refers to lower alkenyl. It should be understood that in the embodiments of the present invention described in this specification in any case, description of alkynyl refers to alkynyl as defined in this specification and, in some cases, refers to lower alkynyl. Examples of alkyl, alkenyl, and / or alkynyl groups include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl hexyl, heptyl, octyl, etc., and the corresponding groups containing one or more double and / or triple bonds, or combinations thereof or combinations thereof. The term "alkylene" as used in this specification includes, in some cases, a divalent chain of branched carbon atoms. The terms "alkenylene" and "alkynylene" as used in this specification

[0067] include, in some cases, a divalent chain of branched carbon atoms and each contains at least one double bond or triple bond. It should be understood that alkynylene can also contain one or more double bonds. In some embodiments, alkylene is preferably C1~ C C C1~C C 24 C1~C 12, including but not limited to C1-C8, C1-C6, and C1-C4, it should be further understood that they are of a certain length. By way of example, alkylene groups of such particularly limited lengths, including C1-C8, C1-C6, and C1-C4, may be referred to as lower alkylene. In some embodiments, alkenylene and / or alkynylene may each advantageously be C2-C, C2-C, C2-C8, C2-C6, and C2-C4, including but not limited to such lengths. By way of example, alkenylene and / or alkynylene groups of such particularly limited lengths, including C2-C8, C2-C6, and C2-C4, may be referred to as lower alkenylene and / or lower alkynylene. It can be further understood that the alkylene, alkenylene, and / or alkynylene groups can be of limited lengths as described above. The shorter the alkylene, alkenylene, and / or alkynylene groups, the smaller the lipophilicity that can be imparted to the compound by the drug, and thus it can be seen herein that they will have different pharmacokinetic behaviors. In the embodiments of the present invention described herein, in any case, the descriptions of alkylene, alkenylene, and alkynylene refer to alkylene, alkenylene, and alkynylene as defined herein, and in some cases, lower alkylene, alkenylene, and alkynylene. Examples of alkyl groups include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, pentylene, 1,2-pentylene, 1,3-pentylene, hexylene, heptylene, octylene, and the like. It should be further understood that they are of a certain length. By way of example, alkylene groups of such particularly limited lengths, including C1-C8, C1-C6, and C1-C4, may be referred to as lower alkylene. Including but not limited to such lengths. In some embodiments, alkenylene and / or alkynylene may each advantageously be C2-C. C2-C. 24 C2-C. 12 C2-C8, C2-C6, and C2-C4, including but not limited to such lengths. It should be further understood that they can be of limited lengths as described above. By way of example, alkenylene and / or alkynylene groups of such particularly limited lengths, including C2-C8, C2-C6, and C2-C4, may be referred to as lower alkenylene and / or lower alkynylene. Including but not limited to such lengths. The alkylene, alkenylene, and / or alkynylene groups can be of limited lengths as described above. The shorter the alkylene, alkenylene, and / or alkynylene groups, the smaller the lipophilicity that can be imparted to the compound by the drug, and thus it can be seen herein that they will have different pharmacokinetic behaviors. In the embodiments of the present invention described herein, in any case, the descriptions of alkylene, alkenylene, and alkynylene refer to alkylene, alkenylene, and alkynylene as defined herein, and in some cases, lower alkylene, alkenylene, and alkynylene. Including but not limited to such lengths. The descriptions of alkylene, alkenylene, and alkynylene refer to alkylene, alkenylene, and alkynylene as defined herein, and in some cases, lower alkylene, alkenylene, and alkynylene. And in some cases, lower alkylene, alkenylene, and alkynylene. Examples of alkyl groups include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, pentylene, 1,2-pentylene, 1,3-pentylene, hexylene, heptylene, octylene, and the like. Including but not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, pentylene, 1,2-pentylene, 1,3-pentylene, hexylene, heptylene, octylene, and the like. Including but not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, pentylene, 1,2-pentylene, 1,3-pentylene, hexylene, heptylene, octylene, and the like. Including but not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, pentylene, 1,2-pentylene, 1,3-pentylene, hexylene, heptylene, octylene, and the like.

[0068] As used herein, the term "linker" binds to two or more functional moieties of a molecule to include a chain of atoms that forms a conjugate. By way of example, the chain of atoms is C, N, O, S, Si, and P, or selected from C, N, O, and S, and P, or C, N, O, and S. The chain of atoms is covalently bonded to various functional group capabilities of conjugates such as target drugs, drugs, diagnostic agents, imaging agents, etc. The linker can have a wide variety of lengths in its continuous backbone, for example, in the range of about 2 to about 100 atoms. The atoms used to form the linker can be in any chemically appropriate manner, for example, a chain of carbon atoms forming alkylene, alkenylene, and alkynylene groups, and also forming ether, polyoxyalkylene groups, or a chain of carbon and oxygen atoms forming esters and carbonates when bonded to a carbonyl group, and also forming amines, imines, polyamines, hydrazines, hydrazones, or forming amides, ureas, semicarbazides, carbazides, etc. when bonded to a carbonyl group, a chain of carbon and nitrogen atoms, and also forming alkoxyamines, alkoxylamines, or forming urethanes, amino acids, acyloxysilamines, hydroxamic acids, etc. when bonded to a carbonyl group, a chain of carbon, nitrogen, and oxygen atoms, and also bonded with many other chains. In addition to this, in each of the foregoing exemplary embodiments, atoms that form a chain, and thus, for example, single bonds, double bonds, or triple bonds that can be radicals such as alkanes, alkenes, alkynes, imines, etc. contained in the linker are understood to be able to be saturated or unsaturated. In addition to this, the atoms forming the linker can also be cycloalkanes, cyclic in the linker. It should be understood that the atoms forming double or triple bonds may be saturated or unsaturated. In addition to this, the atoms forming the linker can also be cycloalkanes, cyclic including ethers, cyclic amines, and other divalent cyclic structures that form linkers, including arylene and heteroarylene of heterocycles, etc. It should also be understood that they can be ring-opened with each other to form a divalent cyclic structure that forms a linker, or can be part of a cyclic structure. In this latter arrangement, the length of the linker can be defined by any path that traverses one or more of its cyclic structures. It should be understood that as an example, the length of the linker is defined by the shortest path that traverses each of those cyclic structures. The linker can optionally be substituted at one or more of the available valences along the chain of atoms, for example, with any substituent on a carbon, nitrogen, silicon, or phosphorus atom. It should be understood that the linker can be bonded to two or more functional moieties of a molecule to form a conjugate with any available valence, and the two or more functional moieties of the molecule forming the conjugate do not necessarily have to be attached to the outer ends of the linker. It should also be understood that the term "cycloalkyl" as used herein includes a chain of carbon atoms at least part of which is cyclic and, in some cases, branched. Cycloalkylalkyl is to be understood as a subpopulation of cycloalkyl. It should be understood that cycloalkyl can also be polycyclic. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, 2-methylcyclopropyl, cyclopentyleth-2-yl, adamantyl, etc. It should be understood that the term "cycloalkenyl" as used herein includes a chain at least part of which is cyclic.

[0069] The term "cycloalkyl" as used herein includes a chain of carbon atoms at least part of which is cyclic and, in some cases, branched. Cycloalkylalkyl is to be understood as a subpopulation of cycloalkyl. It should be understood that cycloalkyl can also be polycyclic. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, 2-methylcyclopropyl, cyclopentyleth-2-yl, adamantyl, etc. -2-yl, and adamantyl, etc. The term "cycloalkenyl" as used herein includes a chain at least part of which is cyclic. comprises a chain of carbon atoms, optionally branched, containing at least one double bond. One or more double bonds can be present in the cyclic portion of the cycloalkenyl and / or the acyclic portion of the cycloalkenyl. It should be understood that cycloalkenylalkyl and cycloalkylalkenyl are each a sub-population of cycloalkenyl. It should be understood that cycloalkyl can also be polycyclic. Examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclohexen-2-yl, cycloheptenylpropenyl, etc. The chain forming the cycloalkyl and / or cycloalkenyl is preferably C3-C 3-C 3-C8, C3-C6, and C5-C6, including those of limited length. It should be further understood that the alkyl and / or alkenyl chains forming the cycloalkyl and / or cycloalkenyl respectively give the compound a smaller lipophilic affinity the shorter they are, and thus will have different pharmacokinetic behaviors as can be seen herein. 24 12

[0070] As used herein, the term "heteroalkyl" includes both carbon and at least one heteroatom and is optionally branched. Examples of heteroatoms include nitrogen, oxygen, and sulfur. In some variants, examples of heteroatoms also include phosphorus and selenium. As used herein, the term "cycloheteroalkyl", including heterocyclyl and heterocycle, includes both carbon and at least one heteroatom. ​​​​​​​​​​​​​A chain of atoms, such as a heteroalkyl, optionally branched, wherein a portion of the chain is cyclic. Examples of heteroatoms include nitrogen, oxygen, and sulfur. In some variations, examples of heteroatoms also include phosphorus and selenium. Examples of cycloheteroalkyl include, but are not limited to, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, quinuclidinyl, and the like.

[0071] As used herein, the term "aryl" includes monocyclic and polycyclic aromatic carbocyclic groups, each of which can be optionally substituted. Examples of the aromatic carbocyclic groups described herein include, but are not limited to, phenyl, naphthyl, and the like. As used herein, the term "heteroaryl" includes aromatic heterocyclic groups, each of which can be optionally substituted. Examples of aromatic heterocyclic groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, and the like.

[0072] As used herein, the term "optionally substituted" includes replacing a hydrogen atom on an optionally substituted radical with another functional group. Such other functional groups These include, but are not limited to, amino, hydroxyl, halo, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acid and its derivatives, carboxylic acid and its derivatives, etc. are exemplified. As examples, amino, hydroxyl, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and / or any of sulfonic acid is optionally substituted.

[0073] The terms "optionally substituted aryl" and "optionally substituted heteroaryl" used herein include replacing a hydrogen atom with another functional group on the optionally substituted aryl or heteroaryl. Such other functional groups are also referred to as aryl substituents herein and include, but are not limited to, amino, hydroxy, halo, thio, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acid and its derivatives, carboxylic acid and its derivatives, etc. As examples, amino, hydroxy, thio, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and / or any of sulfonic acid is optionally substituted.

[0074] ​​​​​​​​Examples of substituents include, but are not limited to, radical -(CH2) x Z x and the like wherein x is an integer from 0 to 6 and Z x is halogen, hydroxy, alkanoyloxy including C1-C6 alkanoyl oxy, optionally substituted aryloxy, alkyl including C1-C 6 alkyl, alkoxy including C1-C6 alkoxy, cycloalkyl including C3-C8 cyclo alkyl, cycloalkoxy including C3-C8 cycloalkoxy , alkenyl including C2-C6 alkenyl, alkynyl including C2-C6 alkynyl, C 1-C6 haloalkyl including haloalkyl, C1-C6 haloalkoxy including haloalkoxy xy, C3-C8 halocycloalkyl including halocycloalkyl, C3-C8 halocyclo alkoxy including halocycloalkoxy, amino, C1-C6 alkylamino, (C1-C 6 alkyl)(C1-C6 alkyl)amino, alkylcarbonylamino, N-(C1 -C6 alkyl)alkylcarbonylamino, aminoalkyl, C1-C6 alkylamino alkyl, (C1-C6 alkyl)(C1-C6 alkyl)aminoalkyl, alkyl carbonylaminoalkyl, N-(C1-C6 alkyl)alkylcarbonylaminoalkyl , cyano, and nitro, or Z x is -CO2R 4 and -C ONR 5 R 6 selected from (wherein R 4 、R 5 、and R 6 are each independently selected from hydrogen, C1-C6 alkyl, aryl-C1-C6 alkyl, and hetero- C1-C6 alkyl) in each case). ​

[0075] In any instance disclosed herein, the description of an integer range for any variable is to be understood to represent the recited range, all individual members of that range, and all possible sub-ranges for that variable. For example, the description that n is an integer from 0 to 8 represents that range, as well as the individual and selectable values of 0, 1, 2, 3, 4, 5, 6, 7, and 8, such as n is 0, or n is 1, or n is 2, etc. In addition to this, the description that n is an integer from 0 to 8 also represents each and every sub-range where each, as a criterion for further embodiments, can be an integer from, for example, 1 to 8, 1 to 7, 1 to 6, 2 to 8, 2 to 7, 1 to 3, 2 to 4, etc. The term "composition" as used herein generally refers to any product containing a specified amount of a specified component, and products directly or indirectly obtained from a combination of a specified amount of a specified component. It should be understood that the compositions described herein can be prepared from the isolated compounds described herein, or from salts, solutions, hydrates, solvates, and other forms of the compounds described herein. It can be seen that some functional groups, such as hydroxy, amino, and similar groups, form various physical shape complexes and / or coordination compounds with water and / or various solvents with those compounds Moreover, it should be understood that these compositions can be prepared from various amorphous forms, non-amorphous forms, partially crystalline forms, crystalline forms, and / or morphological shapes of the compounds described herein.

[0076] The term "composition" as used herein generally refers to any product containing a specified amount of a specified component, and products directly or indirectly obtained from a combination of a specified amount of a specified component. It should be understood that the compositions described herein can be prepared from the isolated compounds described herein, or from salts, solutions, hydrates, solvates, and other forms of the compounds described herein. Some functional groups, such as hydroxy, amino, and similar groups, form various physical shape complexes and / or coordination compounds with water and / or various solvents with those compounds It should also be understood that these compositions can be prepared from various amorphous forms, non-amorphous forms, partially crystalline forms, crystalline forms, and / or morphological shapes of the compounds described herein. It can be seen that some functional groups, such as hydroxy, amino, and similar groups, form various physical shape complexes and / or coordination compounds with water and / or various solvents with those compounds Moreover, it should be understood that these compositions can be prepared from various amorphous forms, non-amorphous forms, partially crystalline forms, crystalline forms, and / or morphological shapes of the compounds described herein. It can be seen that some functional groups, such as hydroxy, amino, and similar groups, form various physical shape complexes and / or coordination compounds with water and / or various solvents with those compounds Moreover, it should be understood that these compositions can be prepared from various amorphous forms, non-amorphous forms, partially crystalline forms, crystalline forms, and / or morphological shapes of the compounds described herein. It can be seen that some functional groups, such as hydroxy, amino, and similar groups, form various physical shape complexes and / or coordination compounds with water and / or various solvents with those compounds It is to be understood that these compositions can also be prepared from the various hydrates and / or solvates of the compounds described herein. Thus, such pharmaceutical compositions relating to the compounds described herein include each of the various morphological forms and / or forms of hydrates or solvates of the compounds described herein, or any combination thereof. It is to be understood.

[0077] As a specific example, the composition can include one or more carriers, extenders, and / or pharmaceutical additives. The compounds described herein or compositions containing them can be formulated in any conventional dosage form suitable for the methods described herein in an amount effective for diagnosis or treatment. The compounds described herein, including such formulations, or compositions containing them can be administered by a wide variety of conventional routes for the methods described herein and in a wide variety of dosage forms using known procedures (in general, see Re mington: The Science and Practice of Phar macy (21st Edition, 2005)).

[0078] As used herein, the term "diagnostically effective amount" refers to the activity that elicits a biological or drug response in a tissue system, animal, or human being sought by a researcher, veterinarian, physician, or other professional, including the diagnosis and / or monitoring of symptoms of a disease or disorder being treated. Examples of diagnostically effective amounts of conjugates administered to a host animal include about 1 pg / kg to about 10 mg / kg, 1 ng / kg to about 10 mg / kg, and is about 10 μg / kg to about 1 mg / kg, or about 100 μg / kg to about 500 μg / kg include.

[0079] As used herein, the term "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical that elicits a biological or drug response in a tissue system, animal, or human that is sought by a researcher, veterinarian, physician, or other expert, including alleviation of the symptoms of the disease or disorder being treated. In one aspect, a therapeutically effective amount is an amount that can treat or alleviate a disease or symptoms of a disease at a reasonable benefit / risk ratio applicable to any treatment. However, it should be understood that the total daily usage of the compounds and compositions described herein can be determined by the attending physician within the scope of reliable medical judgment. The specific dosage level that is therapeutically effective for any particular patient will depend on various factors, including the disorder being treated and the severity of the disorder, the activity of the specific compound being used, the specific compound being used, the age, weight, general health, sex, and diet of the patient, the time of administration of the specific compound being used, the route of administration, and the rate of excretion, the duration of the treatment, and other drugs used in combination with or concomitantly with the specific compound being used, and other factors well known to researchers, veterinarians, physicians, or other experts of ordinary skill. Examples of a therapeutically effective amount of the conjugate administered to a host animal include about 1 pg / kg to about 10 mg / kg, 1 ng / kg to about 10 mg / kg, or about 10 μg / kg to about 1 mg / kg, or about 100 μg / kg to about 500 μg / kg. will be determined by. is. kg to about 10 mg / kg, 1 ng / kg to about 10 mg / kg, or about 10 μg / kg to about 1 mg / kg, or about 100 μg / kg to about 500 μg / kg include.

[0080] As used herein, the term "administration" includes all means of introducing the compounds and compositions described herein into a host animal, including, but not limited to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal, etc. (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal, etc. The compounds and compositions described herein can be administered in unit dosage forms and / or in the form of preparations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and / or excipients.

[0081] As used herein, the term "amino acid" generally refers to beta, gamma, and longer chain amino acids, for example, of the formula -N(R)-(CR’R”) -N(R)-(CR’R”)-C(O)- q -C(O)- wherein R is hydrogen, alkyl, acyl, or a suitable nitrogen protecting group, and R’ and R” are each independently selected hydrogen or substituents in each case, and q is an integer such as 1, 2, 3, 4, or 5. By way of example, R’ and / or R” are, but not limited to, independently methyl, benzyl, hydroxymethyl, thiomethyl, carboxyl, carboxymethyl, guanidinopropyl, etc., and derivatives and protected derivatives thereof, corresponding to the hydrogen or side chains present on naturally occurring amino acids such as, but not limited to, these. All stereoisomeric variants are included in the foregoing formula. For example, the amino acid can be selected from alanine, aspartic acid, asparagine, cysteine, glutamic acid, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, tyrosine, and ornithine, etc. The foregoing formula includes all stereoisomeric variants. For example, the amino acid can be selected from alanine, aspartic acid, asparagine, cysteine, glutamic acid, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, tyrosine, and ornithine, etc. arginine, serine, threonine, valine, tryptophan, tyrosine, and ornithine, etc. and can be selected from, for example, alanine, aspartic acid, asparagine, cysteine, glutamic acid, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, glutamine,

[0082] In any instance disclosed herein, the description of the integer range for any variable is understood to represent the recited range, all individual members within that range, and all possible sub-ranges for that variable. For example, the description that n is an integer from 0 to 8 is understood to represent that range, as well as the individual and selectable values of 0, 1, 2, 3, 4, 5, 6, 7, and 8, such as n being 0, or n being 1, or n being 2, etc. In addition to this, the description that n is an integer from 0 to 8 also represents each and every sub-range which, as a criterion for further embodiments, can be, for example, n is from 1 to 8, from 1 to 7, from 1 to 6, from 2 to 8, from 2 to 7, from 1 to 3, from 2 to 4, etc., of integers In another embodiment, the linker described herein is a polyether, for example, including the linker of formula JPEG0007693751000044.jpg53166. In the formula, m is an integer independently selected from 1 to about 8 in each instance and p is an integer independently selected from 1 to about 10, and n is an integer independently selected from 1 to

[0083] about 3 in each instance. In one aspect, m is independently 1 to about 3 in each instance. In another aspect, n is 1 in each instance. In another aspect, p is independently about 4 to about 6 in each instance Examples herein show corresponding polypropylene polyethers as described above, which can be included in the conjugate as a linker In addition to this, mixtures of polyethylene polyethers and polypropylene polyethers are also possible In addition, corresponding polypropylene polyethers as described above are shown in the present specification as examples, and they can be included in the conjugate as a linker In addition to this, mixtures of polyethylene polyethers and polypropylene polyethers can also be included It can be seen that the compound can also be included in the conjugate as a linker. Furthermore, in this specification there are shown those containing cyclic variants of the aforementioned polyether compounds, such as tetrahydrofuranyl, 1,3-di oxane, 1,4-dioxane, and the like.

[0084] In another embodiment, the linker described herein contains a plurality of hydroxyl functional groups, such as a linker incorporating monosaccharides, oligosaccharides, polysaccharides, etc. That polyhydroxyl -containing linker is to be understood as containing a plurality of -(CROH)- groups (wherein R is hydrogen or alkyl).

[0085] In another embodiment, the linker contains one or more of the diradicals JPEG0007693751000045.jpg85166. In the formula, R is H, alkyl, cycloalkyl, or ar alkyl, m is an integer from 1 to about 3, n1 is an integer from 1 to about 5, or n1 is an integer from 2 to about 5, p is an integer from 1 to about 5, and r is an integer selected from 1 to about 3 is. In one aspect, the integer n is 3 or 4. In another aspect, the integer p is 3 or 4. In another aspect, the integer r is 1.

[0086] In another embodiment, the linker contains one or more of the diradicals JPEG0007693751000046.jpg27166. In the formula, R is H, alkyl, cycloalkyl, or ar alkyl, m is an integer from 1 to about 3, n is an integer from 1 to about 5 or from 2 to about 5 is, p is an integer from 1 to about 5, and r is an integer selected from 1 to about 3. In one aspect the integer n is 3 or 4. In another aspect, the integer p is 3 or 4. In another aspect the integer r is 1.

[0087] In another embodiment, the linker comprises one or more of a cyclic polyhydroxyl group of JPEG0007693751000047.jpg188166. In the formula, n is an integer from 2 to about 5, p is an integer from 1 to about 5 and each r is an integer independently selected from 1 to about 4. In one aspect, the integer n is 3 or 4. In another aspect, the integer p is 3 or 4. In another aspect, each integer r is independently 2 or 3. It should be understood that all stereochemical forms of such portions of the linker are described in this specification book. For example, in the above formula, this portion can be derived from ribose, xylose, glucose, mannose, galactose, or other sugars, maintaining the stereochemical configuration of the pendant hydroxyl and alkyl groups present on these molecules. In addition to this, it should be understood that various deoxy compounds are also described in the foregoing formula . As an example, the formula shows the compound of JPEG0007693751000048.jpg37166. In the formula, n is equal to or less than r. For example, when r is 2 or 3, n is 1 or 2 respectively, or 1, 2, or 3.

[0088] In another embodiment, the linker comprises a polyhydroxyl compound of the formula JPEG0007693751000049.jpg23166. In the formula, n and r are integers each selected from 1 to about 3 selected. In one aspect, the linker comprises one or more polyhydroxyl compounds of the formula JPEG0007693751000050.jpg18166. It should be understood that all stereochemical forms of such portions of the linker are described in this specification . For example, as above In the formula of the record, this part can be derived from ribose, xylose, glucose, mannose, galactose, or other sugars, and the stereochemical configuration of the pendant hydroxyls and alkyl groups present on these molecules is maintained.

[0089] In another configuration, the linker L described herein contains polyhydroxyl groups spaced apart from the backbone of the linker. In one embodiment, such a carbohydrate group or polyhydroxyl group is attached to the backbone by a triazole group to form a triazole-linked linker. As an example, such a linker contains the diradical of Formula JPEG0007693751000051.jpg49166. In the formula, n, m, and r are integers, and in each case, they are each independently selected from 1 to about 5. In one exemplary embodiment, m is independently 2 or 3 in each case. In another embodiment, r is 1 in each case. In another embodiment, n is 1 in each case. In one variant, the group attaching the polyhydroxyl group to the backbone of the linker includes, but is not limited to, various heteroaryl groups such as pyrrole, pyrazole, 1,2,4-triazole, furan, oxazole, isoxazole, thienyl, thiazole, isothiazole, oxadiazole, etc. Similarly, divalent six-membered heteroaryl groups are also shown. Other variants of the aforementioned exemplary linkers include oxyalkylene groups such as Formula JPEG0007693751000052.jpg59166. In the formula, n and r are integers, and in each case, they are each independently selected from 1 to about 5, and p is an integer selected from 1 to about 4.

[0090] In another embodiment, such a carbohydrate group or polyhydroxyl group is attached to the backbone by an amide group. attaches to the backbone to form an amide bond linker. As an example, such a linker contains the diradical of the formula JPEG0007693751000053.jpg37166. In the formula, each n is an integer independently selected from 1 to about 3, and m is independently an integer independently selected from 1 to about 22. In one exemplary embodiment, each n is independently 1 or 2. In another exemplary embodiment, m is selected from about 6 to about 10, and as an example it is 8. In one variant, the group that attaches the polyhydroxyl group to the backbone of the linker is various functional groups including, but not limited to, esters, ureas, carbamates, acylhydrazones, etc. Similarly, cyclic variants are also shown. Other variants of the aforementioned exemplary linker forms include oxyalkylene groups of the formula JPEG0007693751000054.jpg44166, etc. In the formula, n is an integer independently selected from 1 to about 5 in each case and p is an integer selected from 1 to about 4.

[0091] In another embodiment, the linker contains one or more of the diradicals JPEG0007693751000055.jpg140166JPEG0007693751000056.jpg94166 . In the formula, R is H, alkyl, cycloalkyl, or arylalkyl, each m is an integer independently selected from 1 to about 3, each n is an integer independently selected from 1 to about 6, p is an integer from 1 to about 5, and r is from 1 to about 3 selected integer. In one variant, each n is independently 3 or 4. Another variant, the integer p is 3 or 4. In another variant, the integer r is 1.

[0092] In another embodiment, the linker contains the diradical Includes one or more of JPEG0007693751000057.jpg39166. In the formula, R is H, alkyl, cycloalkyl, or arylalkyl, each m is an integer independently selected from 1 to about 3, each n is an integer independently selected from 2 to about 6, p is an integer from 1 to about 5, and r is an integer selected from 1 to about 3. In one variant, each n is independently 3 or 4. In another variant, the integer p is 3 or 4. In another variant, the integer r is 1. And each m is an integer independently selected from 1 to about 3, each n is an integer independently selected from 2 to about 6, p is an integer from 1 to about 5, and r is an integer selected from 1 to about 3. In one variant, each n is independently 3 or 4. In another variant, the integer p is 3 or 4. In another variant, the integer r is 1. An integer independently selected from 2 to about 6, p is an integer from 1 to about 5, and r is an integer selected from 1 to about 3. In one variant, each n is independently 3 or 4. In another variant, the integer p is 3 or 4. In another variant, the integer r is 1. Selected integer. In one variant, each n is independently 3 or 4. In another variant, the integer p is 3 or 4. In another variant, the integer r is 1. In another variant, the integer p is 3 or 4. In another variant, the integer r is 1.

[0093] In another embodiment, the linker is a diradical Includes one or more of JPEG0007693751000058.jpg128166. In the formula, each m is an integer independently selected from 1 to about 3, each n is an integer independently selected from 1 to about 6, p is an integer from 1 to about 5, and r is an integer selected from 1 to about 3. In one variant, each n is independently 3 or 4. In another variant, the integer p is 3 or 4. In another variant, the integer r is 1. An integer, each n is an integer independently selected from 1 to about 6, p is an integer from 1 to about 5, and r is an integer selected from 1 to about 3. In one variant, each n is independently 3 or 4. In another variant, the integer p is 3 or 4. In another variant, the integer r is 1. Selected integer. In one variant, each n is independently 3 or 4. In another variant, the integer p is 3 or 4. In another variant, the integer r is 1. Or 4. In another variant, the integer p is 3 or 4. In another variant, the integer r is 1. Is.

[0094] In another embodiment, the linker is a diradical JPEG0007693751000059.jpg42166 Includes one or more of. In the formula, each m is an integer independently selected from 1 to about 3, each n is an integer independently selected from 2 to about 6, p is an integer from 1 to about 5, and r is an integer selected from 1 to about 3. In one variant, each n is independently 3 or 4. In another variant, the integer p is 3 or 4. In another variant, the integer r is 1. An integer, each n is an integer independently selected from 2 to about 6, p is an integer from 1 to about 5, and r is an integer selected from 1 to about 3. In one variant, each n is independently 3 or 4. In another variant, the integer p is 3 or 4. In another variant, the integer r is 1. Selected integer. In one variant, each n is independently 3 or 4. In another variant, the integer p is 3 or 4. In another variant, the integer r is 1. Or 4. In another variant, the integer p is 3 or 4. In another variant, the integer r is 1. Is.

[0095] In another embodiment, the linker is a diradical It includes one or more of JPEG0007693751000060.jpg136166. In the formula, each m is an integer independently selected from 1 to about 3, p is an integer from 1 to about 5, and r is an integer selected from 1 to about 3. In another variant form, the integer p is 3 or 4. In another variant form, the integer r is 1. In another embodiment, the linker is a combination of backbone and branched side-chain motifs exemplified by JPEG0007693751000061.jpg26166 (wherein n is an integer independently selected from 0 to about 3 in each case). The above formula is intended to represent cyclic sugars with 4-membered, 5-membered, 6-membered

[0096] rings and even larger ring sizes. In addition to this, it should be understood that the above formula can also be modified to represent deoxy sugars (one or more of the hydroxy groups present in the formula are replaced by hydrogen, alkyl, or amino). In addition to this, it should also be understood that the corresponding carbonyl compounds (one or more of the hydroxy groups are oxidized to the corresponding carbonyl) are also described by the above formula. In addition to this, in this exemplary embodiment, the pyranose contains both a carboxyl functional group and an amino functional group, and these can be (a) inserted into the backbone and can also (b) provide a starting point for the synthesis of branched side-chains in variant forms of this embodiment. Any of those pendant hydroxyl groups can be used to attach other chemical reagents, including additional sugars, to prepare the corresponding oligosaccharides. Other variant forms of this embodiment are also shown, including inserting the pyranose or other sugar into the backbone at just one carbon, i.e., spiro arrangements and similar arrangements at a geminal pair of carbons. For example, the linker can be attached to the backbone at a geminal pair of carbons.​​​​​​​​​​​ One or both ends of the linker, or the reagent P, or the ligand B, can be inserted into the sugar incorporated into the backbone and bonded in a 1,1, or 1,2, or 1,3, or 1,4, or 2,3, or other arrangement.

[0097] In another embodiment, the linker contains one or more of the amino groups of the formula JPEG0007693751000062.jpg136166. In the formula, each n is independently an integer selected from 1 to about 3 in each case. In one aspect, each n is independently 1 or 2 in each case. In another aspect, the integer n is 1 in each case.

[0098] In another embodiment, the linker is a sulfate ester, such as an alkyl ester of sulfuric acid. As an example, this linker has the formula JPEG0007693751000063.jpg110166. In the formula, each n is independently an integer selected from 1 to about 3 in each case. As an example, each n is independently 1 or 2 in each case.

[0099] In such polyhydroxyl, polyamino, carboxylic acid, sulfuric acid, etc., it should be understood that these linkers containing free hydrogen bonded to heteroatoms can protect one or more of their free hydrogen atoms with appropriate hydroxyl protecting groups, amino protecting groups, or acid protecting groups, or alternatively can be protected as the corresponding prodrugs. The latter is selected as a prodrug that releases the parent drug under specific uses, such as general or specific physiological conditions.

[0100] The stereochemical arrangements shown herein in each of the foregoing examples are merely illustrative. It should be understood that other stereochemical configurations are also depicted. For example, in one variant, corresponding unnatural amino acid stereoisomers such as JPEG0007693751000064.jpg64166 (wherein, as above, each n is an integer independently selected from 2 to about 5, p is an integer from 1 to about 5, and r is an integer from 1 to about 4) can also be included in the conjugates described herein.

[0101] In the foregoing embodiments ( * ) it should be further understood that vacant positions such as the atom marked () are sites for the attachment of the target drug B or the reagent (P). In addition to this, it should be understood that such attachment of either or both of B and A may be direct or via an intervening linker. Examples of additional linkers are described in U.S. Patent No. 7,601,332 the specification of which is incorporated herein by reference.

[0102] Examples of divalent radicals forming part of the linker. JPEG0007693751000065.jpg79166JPEG0007693751000066.jpg210166

[0103] It should be understood that the divalent linker can be constructed to form the linker described herein in any chemically relevant manner, either directly or via intervening heteroatoms.

[0104] In another embodiment, the multivalent linkers described herein are carbonyl, thiocarbonyl, alkylene, cycloalkylene, alkylene cycloalkyl, alkylene carbonyl yl, cycloalkylene carbonyl, carbonyl alkyl carbonyl, 1 alkylene sulf Sinimid-3-yl, 1-(carbonylalkyl)succinimid-3-yl, alkyl Lensulfooxyl, sulfonylalkyl, alkylene sulfonyloxylalkyl, alkylene Sulfonylalkyl, carbonyltetrahydro-2H-pyranyl, carbonyltetrahydro Rofuranyl, 1-(carbonyltetrahydro-2H-pyranyl)succinimid-3-yl , and 1-(carbonyltetrahydrofuranyl)succinimid-3-yl. It contains a linker selected from the group consisting of.

[0105] In another embodiment, the compounds described herein contain one or more amino acids. Included.

[0106] The compounds described herein can be used for both human clinical medicine and veterinary applications. Therefore, the host animal harboring a pathogenic cell population and administered the compounds described herein can be a human, or in the case of veterinary applications, an experimental animal, an agricultural animal, a domestic animal, or a wild animal. The present invention includes, but is not limited to, humans and Experimental animals such as rodents (e.g., mice, rats, hamsters, etc.), rabbits, monkeys, chimpanzees, etc. Domestic animals such as dogs, cats, and rabbits, agricultural animals such as cows, horses, pigs, sheep, goats, etc. And wild animals in captivity such as bears, pandas, lions, tigers, leopards, elephants, zebras, giraffes, gorillas, dolphins, and whales, etc. It can be applied to host animals. The compounds, compositions, methods, and uses described herein diagnose and treat diseases at least partially caused by pathogenic cell populations that can cause various pathologies in host animals. Also applicable. The compounds, compositions, methods, and uses described herein can be applied to host animals including, but not limited to, humans, Experimental animals such as rodents (e.g., mice, rats, hamsters, etc.), rabbits, monkeys, chimpanzees, etc., domestic animals such as dogs, cats, and rabbits, agricultural animals such as cows, horses, pigs, sheep, goats, etc., and captive wild animals such as bears, pandas, lions, tigers, leopards, elephants, zebras, giraffes, gorillas, dolphins, and whales, etc.

[0107] The compounds, compositions, methods, and uses described herein can be used to diagnose and treat diseases at least partially caused by pathogenic cell populations that can cause various pathologies in host animals. Also applicable. is / are useful for monitoring. As used herein, the term "pathogenic cell" or "pathogenic cell population" generally refers to cancer cells, infectious agents such as bacteria and viruses, cells infected with bacteria or viruses, inflammatory cells, activated macrophages that may cause disease states, and any other type of pathogenic cell that selectively expresses, express in a specific form, or overexpress the binding site of the target drug described herein.

[0108] By way of example, a pathogenic cell population may be a carcinogenic cancer cell population including benign and malignant tumors, or it may be non-carcinogenic. A cancer cell population may occur naturally, or it may appear as a result of a mutation in the germ line of the host animal or a process such as somatic mutation, or it may be chemically, virally, or radiation-induced. The present invention can be used for diagnosing, monitoring, and / or treating such cancers including carcinomas, sarcomas, lymphomas, Hodgkin's disease, melanomas, mesotheliomas, Burkitt's lymphoma, nasopharyngeal carcinoma, leukemias, and myelomas. Cancer cell populations include, but are not limited to, oral cancer, thyroid cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, pharyngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, ovarian cancer, cervical cancer, uterine cancer, breast cancer, testicular cancer, prostate cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer.

[0109] By way of example, cancer cell populations also include fibromyalgia, rheumatoid arthritis, osteoarthritis, ulcerative colitis, Crohn's disease, psoriasis, osteomyelitis, multiple sclerosis, atherosclerosis, pulmonary fibrosis, sarcoidosis, systemic sclerosis, graft-versus-host disease (GVHD), systemic lupus erythematosus, Sjogren's syndrome ​​​​​​inflammation of the skin, such as psoriasis, chronic inflammation, trauma, such as head or spinal cord trauma They are activated monocytes or macrophages that are involved in pathological conditions such as inflammation and embolism caused by It also says:

[0110] The conjugates described herein can be used to bind, for example, a wide variety of vitamins or receptor-binding vitamins. It can be formed from analogs / derivatives, linkers, and imaging and radiotherapeutic agents. The conjugates described herein can be used to generate vectors that are accessible for binding on pathogenic cells. Selective expression of receptors for targeted drugs such as tyrosine kinases can be used to select pathogenic cell populations in the host animal. The vitamin molecule portion that can be used as a targeting drug (B) can be selectively targeted. Examples of nutrients include carnitine, inositol, lipoic acid, pyridoxal, ascorbic acid, Niacin, pantothenic acid, folic acid, riboflavin, thiamine, biotin, vitamin B 12 , and the fat-soluble vitamins A, D, E, and K. These vitamins and receptors The receptor-binding analogs and derivatives are linked to imaging agents or radioactive agents via a bivalent linker (L). Illustrative targeting entities capable of binding to therapeutic agents are constructed and described herein. Form conjugates of targeted drugs (B) or radiotherapeutic drugs. The term vitamin is used unless otherwise specified. Unless otherwise specified, vitamin analogs and / or derivatives are understood to be included. In addition, pteroic acid, a derivative of folic acid, biocytin, biotin sulfoxide, and oxybiopeptide are also Biotin and its analogues, such as other biotin receptor binding compounds, are vitamins The vitamins described herein are considered to be vitamin analogs, vitamin derivatives, and the like. A vitamin analog or derivative is one in which the vitamin analog or derivative is covalently bonded to a divalent ligand. It should be understood that it refers to a vitamin incorporating a heteroatom that binds to an anchor (L).

[0111] Examples of the vitamin molecular moiety include folic acid, biotin, riboflavin, thiamine, vitamin B 12 , and receptor-binding analogs and derivatives of these vitamin molecules, and other related receptor-binding molecules.

[0112] In one embodiment, the target group B is folic acid, an analog of folic acid, or a derivative of folic acid. As used in this specification, the term folic acid is used both individually and collectively to refer to folic acid itself and / or such analogs and derivatives of folic acid that can bind to the folic acid receptor. It should be understood.

[0113] Exemplary embodiments of vitamin analogs and / or derivatives include folic acid, any folic acid analog and derivative such as folinic acid, pteropolyglutamic acid, tetrahydropterin, any folic acid receptor-binding pteridine such as dihydrofolic acid and tetrahydrofolic acid, and their deaza and dideaza analogs. The terms "deaza" and "dideaza" analogs refer to analogs recognized in the art in which one or two nitrogen atoms in the naturally occurring folic acid structure, or an analog thereof, or a derivative thereof are replaced by carbon atoms. For example, deaza analogs include 1-deaza, 3-deaza, 5-deaza, 8-deaza, and 10-deaza analogs of folic acid, folinic acid, pteropolyglutamic acid, and folic acid receptor-binding pteridines such as tetrahydropterin, dihydrofolic acid, and tetrahydrofolic acid. Dideaza analogs include, for example, those of folic acid 1,3-dideaza, 1,5-dideaza, 1,8-dideaza, 1,10-dideaza, 3,5-dideaza, 3,8-dideaza, 3,10-dideaza, 5,8-dideaza, 5,10-dideaza, and 8,10-dideaza analogs. 1,5-dideaza, 5,10-dideaza, 8,10-dideaza, and 5,8-dideaza analogs of folic acid, pteropolyglutamic acid, and tetrahydropterin, dihydrofolic acid , tetrahydrofolic acid, and other folate receptor-binding pteridines are exemplified. Other folates useful as complexes forming the ligands of the present invention are the folate receptor-binding analogs aminopterin, amethopterin (also known as methotrexate), N -methylfolic acid, 2-deamino-hydroxyfolic acid, deaza analogs such as 1-deazamethopterin or 3-deazamethopterin, and 3’,5’-dichloro-4-amino-4-de oxy-N 10 -methylpteroylglutamic acid (dichloromethotrexate). The foregoing folate analogs and / or derivatives are typically referred to as "folates" in reflection of their binding ability to folate receptors, and such ligands are effective in promoting transmembrane transport, for example, via endocytosis mediated by folic acid as described in the present specification, when conjugated with an exogenous molecule. 10 Additional folate analogs that bind to folate receptors are described in U.S. Patent Application Publication No. 2005 / 02279 85 and U.S. Patent Application Publication No. 2004 / 0242582, the disclosures of which are incorporated herein by reference. As an example, radicals of such folate analogs have the general formula JPEG0007693751000067.jpg21166 wherein X and Y are each independently halo, R , OR

[0114] , SR , and NR R R R wherein X and Y are each independently halo, R 2 , OR 2 , SR 3 , and NR 4 R 5 selected from the group consisting of U, V, and W are each independently (R 6a )C=, N=, (R 6a )C(R 7a ), and N(R 4a ) and represent a divalent molecular moiety selected from the group consisting of Q is selected from the group consisting of C and CH, T is selected from the group consisting of S, O, N, NH, and -C=C-, A 1 and A 2 are each independently oxygen, sulfur, C(Z), C(Z)O, OC(Z ), N(R 4b ), C(Z)N(R 4b ), N(R 4b )C(Z), OC(Z)N(R 4 b ), N(R 4b )C(Z)O, N(R 4b )C(Z)N(R 5b ), S(O), S(O )2, N(R 4a )S(O)2, C(R 6b )(R 7b ), N(C≡CH), N(CH2 C≡CH), C1-C 12 alkylene, and C1-C 12 alkyleneoxy from the group selected (where Z is oxygen or sulfur), R 1 is hydrogen, halo, C1-C 12 alkyl, and C1-C 12 alkoxy from the group selected, R 2 , R 3 , R 4 , R 4a , R 4b , R 5 , R 5b , R 6b , and R 7b are each independently hydrogen, halo, C1-C12 Alkyl, C1-C 12 Alkoxy , C1-C 12 Alkanoyl, C1-C 12 Alkenyl, C1-C 12 Alkynyl, (C 1-C 12 Alkoxy)carbonyl, and (C1-C 12 Alkylamino)carbonyl selected from the group consisting of, R 6 and R 7 are each independently hydrogen, halo, C1-C 12 alkyl, and C1 -C 12 alkoxy selected from the group consisting of, or R 6 and R 7 together form a carbonyl group, and R and R 6a and R 7a are each independently hydrogen, halo, C1-C 12 al kyl, and C1-C 12 alkoxy selected from the group consisting of, or R 6a and R 7 a together form a carbonyl group, L is one or more, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, and n, p, r, s, and t are each independently either 0 or 1. It should be understood that the term folic acid as used herein refers to both the individual folic acid used for conjugate formation, or

[0115] either a folic acid or a folic acid analog or derivative capable of binding to a folic acid or folic acid receptor. In another embodiment, the target group is a PSMA ligand or inhibitor, for example of the formula

[0116] JPEG0007693751000068.jpg is a derivative of pentanedioic acid. In the formula, X is RP(O)(OH)CH2- (U.S. Patent No. 5,968,915), RP(O)(OH)N(R 1 )- (U.S. Patent No. 5,86 3,536), RP(O)(OH)O- (U.S. Patent No. 5,795,877 specification), RN(OH)C(O)Y- or RC(O)NH(OH)Y- (where Y is -C R1R2-, -NR3-, or -O-) (U.S. Patent No. 5,962,521), RS(O)Y, RSO2Y or RS(O)(NH)Y (where Y is -CR1R2-, -NR3-, or -O-) (U.S. Patent No. 5,902,817), and RS- alkyl (where R is, for example, hydrogen, alkyl, aryl, or arylalkyl, any of which may be optionally substituted) (J.Med.Chem. 46:1 989 - 1996 (2003)).

[0117] In each of the foregoing formulas, R, R1, R2, and R3 are each independently hydrogen, C1 - C9 straight or branched chain alkyl, C2 - C9 straight or branched chain alkenyl, C3 - C8 cycloalkyl, C5 - C7 cycloalkenyl, and aryl. In addition to this, in each case, each of R, R1, R2, and R3 is optionally substituted with one or more groups selected from, for example, C3 - C8 cycloalkyl, C5 - C7 cycloalkenyl, halo, hydroxy, nitro, trifluoromethyl, C1 - C6 straight or branched chain alkyl, C2 - C6 straight or branched chain alkenyl, C1 - C4 alkoxy, C2 - C4 alkenyloxy, phenoxy , benzyloxy, amino, aryl. substituted with may also be. In one aspect, aryl is 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, benzyl, and phenyl, and in each case aryl is optionally substituted with one or more groups selected from halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched alkyl, C2-C6 straight or branched alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino, and may be substituted with one to three groups as an example. In each variant form of the above formula, R is not hydrogen. yl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, benzyl, and phenyl, and in each case aryl is optionally, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched alkyl, C2-C6 straight or branched alkenyl, C1 -C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino, and may be substituted with one or more groups selected from one to three groups as an example. In each variant form of the above formula, R is not hydrogen.

[0118] Examples of PSMA ligands (U.S. Patent No. 5,968,915) include 2-[[methylhydroxyphosphinyl]methyl]pentanedioic acid, 2-[[ethylhydroxyphosphinyl]methyl]pentanedioic acid, 2-[[propylhydroxyphosphinyl]methyl]pentanedioic acid, 2-[[butylhydroxyphosphinyl]methyl]pentanedioic acid, 2-[[cyclohexylhydroxyphosphinyl]methyl]pentanedioic acid, 2-[[phenylhydroxyphosphinyl]methyl]pentanedioic acid, 2-[[2-(tetrahydrofuranyl)hydroxyphosphinyl]methyl]pentanedioic acid , 2-[[(2-tetrahydropyranyl)hydroxyphosphinyl]methyl]pentanedioic acid, 2-[[((4-pyridyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid, 2-[[((2-pyridyl)methyl)hydroxyphosphinyl]methyl]pentanedioic acid, 2-[[(phenylmethyl)hydroxyphosphinyl]methyl]pentanedioic acid, 2-[[((2-phenylethyl)methyl)hydroxyphosphinyl]methyl]pentane Diacid, 2-[[((3-phenylpropyl)methyl)hydroxyphosphinyl]methyl]penta dioic acid, 2-[[((3-phenylbutyl)methyl)hydroxyphosphinyl]methyl]pentane Diacid, 2-[[((2-phenylbutyl)methyl)hydroxyphosphinyl]methyl]pentane Diacid, 2-[[(4-phenylbutyl)hydroxyphosphinyl]methyl]pentanedioic acid, and Beauty 2-[[(aminomethyl)hydroxyphosphinyl]methyl]pentanedioic acid Examples include:

[0119] Examples of PSMA ligands (U.S. Pat. No. 5,863,536) include: N-[methylhydroxyphosphinyl]glutamic acid, N-[ethylhydroxyphosphine N-[propylhydroxyphosphinyl]glutamic acid, N-[buthyl N-[phenylhydroxyphosphinyl]glutamic acid, N-[phenylhydroxyphosphinyl] Glutamic acid, N-[(phenylmethyl)hydroxyphosphinyl]glutamic acid, N- [((2-phenylethyl)methyl)hydroxyphosphinyl]glutamic acid, and N -Methyl-N-[phenylhydroxyphosphinyl]glutamic acid Examples include:

[0120] Examples of PSMA ligands (U.S. Pat. No. 5,795,877) include: 2-[[methylhydroxyphosphinyl]oxy]pentanedioic acid, 2-[[(Ethylhydroxyphosphinyl)oxy]pentanedioic acid, 2-[[(Propylhydroxyphosphinyl)oxy]pentanedioic acid, 2-[[(Butylhydroxyphosphinyl)oxy]pentanedioic acid, 2-[[(Phenylhydroxyphosphinyl)oxy]pentanedioic acid, 2-[[((4-Pyridyl)methyl)hydroxyphosphinyl]oxy]pentanedioic acid, 2-[[((2-Pyridyl)methyl)hydroxyphosphinyl]oxy]pentanedioic acid, 2-[[(Phenylmethyl)hydroxyphosphinyl]oxy]pentanedioic acid, and 2-[[((2-Phenylethyl)methyl)hydroxyphosphinyl]oxy]pentane dioic acid are included.

[0121] Examples of PSMA ligands (U.S. Patent No. 5,962,521) include 2-[[(N-Hydroxy)carbamoyl]methyl]pentanedioic acid, 2-[[(N-Hydroxy-N-methyl)carbamoyl]methyl]pentanedioic acid, 2-[[(N-Butyl-N-hydroxy)carbamoyl]methyl]pentanedioic acid, 2-[[(N-Benzyl-N-hydroxy)carbamoyl]methyl]pentanedioic acid, 2-[[(N-Hydroxy-N-phenyl)carbamoyl]methyl]pentanedioic acid, 2-[[(N-Hydroxy-N-2-phenylethyl)carbamoyl]methyl]pentane dioic acid, 2-[[(N-Ethyl-N-hydroxy)carbamoyl]methyl]pentanedioic acid, 2-[[(N-Hydroxy-N-propyl)carbamoyl]methyl]pentanedioic acid, 2-[[(N-Hydroxy-N-3-phenylpropyl)carbamoyl]methyl]pentane dioic acid, 2-[[(N-Hydroxy-N-4-pyridyl)carbamoyl]methyl]pentanedioic acid, 2-[[(N-Hydroxy)carboxamide]methyl]pentanedioic acid, 2-[[N-Hydroxy(methyl)carboxamide]methyl]pentanedioic acid, 2-[[N-Hydroxy(benzyl)carboxamide]methyl]pentanedioic acid, 2-[[N-Hydroxy(phenyl)carboxamide]methyl]pentanedioic acid, 2-[[N-Hydroxy(2-phenylethyl)carboxamide]methyl]pentanedioic acid , 2-[[N-Hydroxy(ethyl)carboxamide]methyl]pentanedioic acid, 2-[[N-Hydroxy(propyl)carboxamide]methyl]pentanedioic acid, 2-[[N-Hydroxy(3-phenylpropyl)carboxamide]methyl]pentanedio ic acid, and 2-[[N-Hydroxy(4-pyridyl)carboxamide]methyl]pentanedioic acid are included.

[0122] Examples of PSMA ligands (U.S. Patent No. 5,902,817) include 2-[(Sulfinyl)methyl]pentanedioic acid, 2-[(Methylsulfinyl)methyl]pentanedioic acid, 2-[(Ethylsulfinyl)methyl]pentanedioic acid, 2-[(Propylsulfinyl)methyl]pentanedioic acid, 2-[(Butylsulfinyl)methyl]pentanedioic acid, 2-[(Phenylsulfinyl)methyl]pentanedioic acid, 2-[[(2-Phenylethyl)sulfinyl]methyl]pentanedioic acid, 2-[[(3-Phenylpropyl)sulfinyl]methyl]pentanedioic acid, 2-[[(4-Pyridyl)sulfinyl]methyl]pentanedioic acid, 2-[(Benzylsulfinyl)methyl]pentanedioic acid, 2-[(Sulfonyl)methyl]pentanedioic acid, 2-[(Methylsulfonyl)methyl]pentanedioic acid, 2-[(Ethylsulfonyl)methyl]pentanedioic acid, 2-[(Propylsulfonyl)methyl]pentanedioic acid, 2-[(Butylsulfonyl)methyl]pentanedioic acid, 2-[(Phenylsulfonyl)methyl]pentanedioic acid, 2-[[(2-Phenylethyl)sulfonyl]methyl]pentanedioic acid, 2-[[(3-Phenylpropyl)sulfonyl]methyl]pentanedioic acid, 2-[[(4-Pyridyl)sulfonyl]methyl]pentanedioic acid, 2-[(Benzylsulfonyl)methyl]pentanedioic acid, 2-[(Sulfoximino)methyl]pentanedioic acid, 2-[(Methylsulfoximino)methyl]pentanedioic acid, 2-[(Ethylsulfoximino)methyl]pentanedioic acid, 2-[(Propylsulfoximino)methyl]pentanedioic acid, 2-[(Butylsulfoximino)methyl]pentanedioic acid, 2-[(Phenylsulfoximino)methyl]pentanedioic acid, 2-[[(2-Phenylethyl)sulfoximino]methyl]pentanedioic acid, 2-[[(3-Phenylpropyl)sulfoximino]methyl]pentanedioic acid, 2-[[(4-Pyridyl)sulfoximino]methyl]pentanedioic acid, and 2-[(Benzylsulfoximino)methyl]pentanedioic acid are included.

[0123] Examples of PSMA ligands include, JPEG0007693751000069.jpg73166.

[0124] In another embodiment, the PSMA ligand is a urea of two amino acids. In one aspect, these amino acids include one or more additional carboxylic acids. In another embodiment, these amino acids include one or more additional phosphoric acids, phosphonic acids, phosphinic acids, sulfonic acids, or boronic acids. In another aspect, the amino acids include one or more thiol groups or derivatives thereof. In another aspect, the amino acids include one or more biological equivalents of carboxylic acids, such as tetrazole, etc.

[0125] In another embodiment, the PSMA ligand is a compound of formula JPEG0007693751000070.jpg25166. In the formula, R 1 is JPEG0007693751000071.jpg82166.

[0126] In another exemplary embodiment, the binder is a urea of an aminodicarboxylic acid such as aspartic acid, glutamic acid, etc. and another aminodicarboxylic acid or an analog thereof, such as a binder of formula JPEG0007693751000072.jpg21166. In the formula, Q is an aminodicarboxylic acid such as aspartic acid, glutamic acid, etc. or an analog thereof, and n and m are each independently selected from integers between 1 and about 6, and the * (

[0127] As an example, the PSMA ligand is a compound of formula JPEG0007693751000073.jpg85166.

[0128] In another embodiment, the PSMA ligand is 2-[3-(1-carboxy-2-mercapto -Ethyl)-ureido]-pentanedioic acid (MUPA) or 2-[3-(1,3-dicarboxy -propyl)-ureido]-pentanedioic acid (DUPA).

[0129] Other examples of PSMA ligands include kiscaic acid, aspartic acid glutamic acid (Asp -Glu), Glu-Glu, Gly-Glu, γ-Glu-Glu, beta-N-acetyl -L-aspartic acid-L-glutamic acid (β-NAAG) and other peptide analogs. are included.

[0130] In another embodiment, the PSMA ligand comprises a urea or thiourea of lysine and an amino acid or one or more carboxylic acid derivatives thereof, including but not limited to urea or thiourea of lysine and aspartic acid or glutamic acid or homoglutamic acid. are mentioned.

[0131] In another embodiment, the PSMA ligand comprises a urea or thiourea of L-lysine and L-glutamic acid.

[0132] In another embodiment, the PSMA ligand comprises a compound selected from JPEG0007693751000074.jpg62166.

[0133] In another embodiment, the PSMA ligand comprises JPEG0007693751000075.jpg25166.

[0134] The compounds, linkers, intermediates, and conjugates described herein are disclosed in International Publication No. WO 2009 / 002993, International Publication No. WO 2004 / 069159, and ​​WO 2007 / 022494 pamphlet, and WO 2006 / 0125 27 pamphlet, and US Patent Application No. 13 / 837539 (filed on March 15, 2013) (the entire disclosure content of each of the above is incorporated herein by reference) can be prepared using conventional methods, including those described therein. Yes.

[0135] Each publication cited in this specification is incorporated herein by reference.

[0136] In another embodiment, a method for diagnosing and / or monitoring a disease or medical condition is described , the method comprising the step of administering to a patient to be evaluated for a medical condition an effective amount of a conjugate of formula B-L-P. This method involves allowing sufficient time for the conjugate to bind to the target tissue and diagnosing and / or monitoring the disease or medical condition outside the body, for example by positron emission tomography. Including.

[0137] Examples of such radionuclides include positron-emitting isotopes having an appropriate half-life and toxicity profile. In various embodiments, the radioisotope has a half-life greater than 30 minutes, greater than 70 minutes, greater than 80 minutes, greater than 90 minutes, greater than 100 minutes, less than 8 hours, less than 6 hours, less than 4 hours, or less than 3 hours. In other embodiments, the radio isotope has a half-life of about 30 minutes to about 4 hours, about 70 minutes to about 4 hours, about 80 minutes to about 4 hours, about 90 minutes to about 4 hours, about 100 minutes to about 4 hours, about 30 minutes to about 6 hours, about 70 minutes to about 6 hours, about 80 minutes to about 6 hours, about 90 minutes to about 6 hours, about 100 minutes to about 6 hours, about 3 0 minutes to about 8 hours, about 70 minutes to about 8 hours, about 80 minutes to about 8 hours, about 90 minutes to about 8 hours of. has a half-life of about 100 minutes to about 8 hours.

[0138] The radionuclide includes one or more positron-emitting isotopes, such as, but not limited to, 89 Zr, 45 Ti, 51 Mn, 64 Cu, 61 Cu, 63 Zn, 82 Rb, 6 8 Ga, 66 Ga, 11 C, 13 N, 15 O, 124 I, 34 Cl, and 18 selected from F Isotopes can be mentioned. In another embodiment, the radionuclide is a halide, such as For example, a positron-emitting halide. In another embodiment, the radionuclide is a metal ion, such as A positron-emitting metal ion. In another embodiment, the radionuclide is a gallium ion, such as A positron-emitting gallium ion. In another embodiment, the radionuclide is 89 Zr, 64 Cu , 68 Ga, 66 Ga, 124 I, and 18 Selected from F. In another exemplary embodiment The radioactive isotope is 89 Zr, 64 Cu, 68 Ga, 124 I, and 18 Selected from F In another embodiment, the radioactive isotope is 68 Ga or 89 Zr or 18 F. In another embodiment, in each of the above and below embodiments described herein, the radioactive Isotope is 68 ​It is Ga. In another embodiment, in each of the above and below embodiments described herein, the radioisotope is In each of the above and below embodiments described herein, the radioisotope is 18 F. In another embodiment, in each of the above and below embodiments described herein, the radioisotope is In each of the above and below embodiments described herein, the radioisotope is 89 Zr. In another In each of the above and below embodiments described herein, the radioisotope is In each of the above and below embodiments described herein, the radioisotope is 64 Cu. The fluorine isotopes described herein can also be selected from various combinations of 18 F and 19 F. It should also be understood that the selection of suitable isotopes can include factors such as a positron-emitting isotope half-life sufficient to allow preparation of the diagnostic composition in a pharmaceutically acceptable carrier before administration to the patient, and a residual half-life sufficient to produce an activity sufficient to allow in vitro measurement by a PET scan. It should be understood that these are examples of factors that can be included. Further, a suitable isotope should have a half-life short enough to limit exposing the patient to unnecessary radiation. In an exemplary embodiment, F having a half-life of 110 minutes provides an appropriate time and acceptable deterioration rate for the preparation of the diagnostic composition. Further, when F decays, it converts to O. Examples of positron-emitting isotopes having suitable half-lives include 18 18 18 34 45 51 61 63 82

[0139] 34 34 Cl (half-life is about 32 minutes) 、 45 Ti (half-life is about 3 hours), 51 Mn (half-life is about 45 minutes), 61 Cu (half-life is about 3.4 hours), 63 Zn (half-life is about 38 minutes), 82 Rb (half-life is about 2 minutes),68 G a (half-life is about 68 minutes), 66 Ga (half-life is about 9.5 hours), 11 C (half-life is about 20 minutes), 15 O (half-life is about 2 minutes), 13 N (half-life is about 10 minutes), or 18 F (half-life is about 110 minutes) may be mentioned.

[0140] In another embodiment, the radionuclide is a radiotherapeutic agent. Examples of radionuclides for radiotherapy include 177 isotopes of lutetium such as Lu, 90 isotopes of yttrium such as Y, 67 Cu and 64 isotopes of copper such as Cu, etc. may be mentioned.

[0141] The radionuclide can be covalently attached to the conjugate to an aryl or heteroaryl aromatic group including groups such as benzamidyl, benzyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, naphthyl, benzothiazolyl, benzimidazolyl, benzo oxazolyl, etc. In one exemplary embodiment, the radioisotope is F, and this radio 18 nuclide contains an aryl group to which the radioisotope is covalently attached. The radionuclide can also be non-covalently attached to the conjugate, for example, within a chelate. These methods also include any other methods of cancer diagnosis already developed and known in the art, including methods using other already developed diagnostic agents, and methods utilizing X-ray co

[0142] mputer tomography (CT), magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMR I), ultrasound imaging, and single photon emission computed tomography (SPECT), and can be combined with any other method of cancer diagnosis already developed and known in the art. ​They can also be used in combination.

[0143] The methods described herein, i.e., each of the processes and syntheses described herein In some applications of the process, either substantially complete fluorination or only partial fluorination is required. It can be appreciated that in some cases it may be desirable to use methods and compositions as described herein. The method can be carried out in various alternative embodiments. In those embodiments in which oxidation is desired, the methods and syntheses described herein are based on stoichiometric It is understood that the present invention can be carried out using less than about 100% of the fluorinating agent. Some of the methods described herein, i.e., each of the processes and synthetic methods described herein, In the examples, substantially complete radiofluorination or It can be seen that either partial or partial radiofluorination may be desirable. Thus, the methods and synthesis methods described herein may be carried out in a variety of alternative embodiments. Thus, in those embodiments in which only partial radiofluorination is desired, the present invention The methods and syntheses described herein use less than a stoichiometric amount of radioactive fluorinating agent (the remainder is optional). By choice 19 It is understood that this can be carried out using the formula (F).

[0144] The following examples further illustrate certain embodiments of the present invention; however, the following illustrative examples are by no means intended to be limiting. They should not be construed as limiting the invention in any way. EXAMPLES

[0145] General: Water was distilled and then filtered using a Milli-Q water filtration system (Millipore Co., Ltd.). Passed through rp., Milford, MA) for deionization (18 MΩ / cm 2 ) and used. Unless otherwise specified, all chemicals and solvents were purchased from Sigma (St. Louis, M O) and used without further purification. Amino acids were purchased from Chem-Impex I nt (Chicago, IL). 2,2'-(7-(2-((2,5-Dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7-triazonane -1,4-diyl)diacetic acid (NOTA-NHS) was purchased from CheMatech (France ). N10-TFA-pteroylglutamic acid was provided by Endocyte, Inc. High-performance liquid chromatography (HPLC) analysis and purification of the DUPA-NOTA precursor were performed on an Agilent G6130B instrument. Radioactive HPLC was performed using an X select CSH C18 (250×10 mm) column and a γ-counter with MeCN and 0.1% formic acid as the mobile phase. JPEG0007693751000076.jpg101166

[0146] Example: C-NETA tert-Butyl [2-hydroxy-1-(4-nitrobenzyl)ethyl]carbamate (QC04011) was prepared from commercially available methyl 2-amino-3-(4-nitrophenyl)pro panoate by NaBH4 reduction and Boc protection. Sequential des-Martin oxidation and reductive amination of QC04001 gave the compound protected with tris-Boc QC04013. This was converted to QC04014 after Boc deprotection in 4M HCl dissolved in dioxane. QC04014 was reacted with tert-butyl bromoacetate ​Treatment, followed by hydrogenolytic cleavage of the NO2 group, gave QC04016. The co Further reaction with succinic anhydride gave the corresponding di-functional C-NETA (QC04018) as the tert-butyl ester. JPEG0007693751000077.jpg24166

[0147] Example: Di-tert-butyl [1,4,7] triazanonane-1,4-dicarboxylate ( QC04001) QC04001 was prepared according to a modified procedure of the previously reported synthetic procedures [19 - 21]. A solution of 1,4,7-triazonane trihydrochloride (TACN ·3HCl, 1.85 g, 7.7 mmol, M.W.: 238.6) dissolved in CHCl3 (25 mL) was added portionwise with DIPE A (4.0 mL, 3.0 g, 23.1 mmol, M.W.: 129.24, d: 0.74 2) and BOC-ON (3.77 g, 15.3 mmol, M.W.: 246.26). The resulting mixture was stirred for 5 days and the solvent was evaporated under vacuum. The residue was partitioned between 1 0% NaOH solution (10 mL) and diethyl ether (30 mL). The ether layer was separated and washed several times with 10% NaOH solution (10 mL) and water (10 mL). The ether layer was dried (MgSO4), filtered, and concentrated under vacuum to give QC04001 (2.5 1 3 g, quantitative). This was used without further purification. 1H NMR (400 MH z, CDCl3) δ = 3.47~3.50 (m, 2H), 3.42~3.45 (m, 2H ), 3.38 (br, s, 1H), 3,28~3.34 (m, 2H), 3.16~3.2 13 C NMR (101 MHz, CDCl3) δ = 156.08, 155.85 (C=O), 79 .80, 79.70 ( t- Bu), 53.20, 52.62, 52.52, 51.78, 50.50, 49.41, 49.63, 48.39, 48.23, 47.83, 47.4 6 (TACN ring from 53.20 - 47.6), 28.60 ( t- Bu). JPEG0007693751000078.jpg19166

[0148] Example: tert-Butyl [2-hydroxy-1-(4-nitrobenzyl)ethyl]carbamate (QC04011)

[19] -butyl (QC04011)

[19] A small modification to the reported procedure

[19] was made, and the HCl salt of methyl 2-amino-3-(4-nitrophenyl )propionate was used directly without neutralization with Et3N, and this 2-amino-3-(4-nitrophenyl)propionic acid methyl hydrochloride (6.22 g, 23.9 mmol) dissolved in MeOH (70 mL) was added portionwise with NaBH4 (2.86 g, 7 1.4 mmol). The reaction was monitored by TLC and LC-MS. This mixture was heated to reflux (in a water bath at about 70 °C) and additional NaBH4 was added portionwise as necessary until most of the starting material had disappeared (a total of about 6 grams of NaBH4 was required) . After evaporation of the solvent, the residue was treated with H2O (70 mL) and extracted with DCM / IPA (3 / 1) . The combined organic layers were dried, filtered, and concentrated in vacuo to give the white solid QC04 010 (4.4 g, 94%) which was used without further purification. . The combined organic layers were dried, filtered, and concentrated in vacuo to give the white solid QC04 010 (4.4 g, 94%) which was used without further purification.

[0149] Example: QC04010 (4.4 g, 22.7 mmol) was dissolved in CH3CN (30 Dissolved in (mL), and BOC-ON (11.2 g, 27.2 mmol, 1.2 equiv) was added little by little. To the above mixture, DIPEA (5.24 mL, 3.76 g, 29.2 m mol, M.W.: 129.24, d: 0.742) was added, and the resulting mixture was stirred for 4 hours and evaporated. The residue was partitioned between ethyl ether (50 mL) and 10% NaOH solution (20 mL ). The ether layer was separated and successively washed with 10% NaOH solution (10 mL) and water (10 m L). The ether layer was dried, filtered, and concentrated under vacuum. The residue was washed with ether (20 mL) to obtain QC04011 (5.31 g, 75%). This was used without further purification. To prepare an analytical sample, this residue was purified by column chromatography on SiO2 eluting with hexane / ethyl acetate (3 / 1 to 1 / 1 containing 1% MeOH) to obtain pure QC04011 as a white solid. H NMR (400 MHz, CDCl3) δ = 8.15 (d, J = 8.8 MHz, 2H), 7.4 0 (d, J = 8.8 MHz, 2H), 4.84 (d, J = 6.8 MHz, 1H), 3.9 0 (s, 1H), 3.68 (dd, J = 3.1 MHz, 1H), 3.57 (dd, J = 3 .1 MHz, 1H), 2.98 (d, J = 6.0 MHz, 2H), 1.39 (s, 9H) ; 1 H NM C NMR (101 MHz, CDCl3) δ = 156.0, 146.4, 146. 2, 130.1, 123.5, 79.8, 63.3, 53.1, 37.3, 28.0. ; 13 JPEG0007693751000079.jpg17166

[0150] Example: (1-(4-Nitrophenyl)-3-oxopropan-2-yl)carbamic acid tert-butyl​​​​​ QC04011 (1.27 g, 4.3 mmol) was dissolved in CH2CL2 (40 mL). It was cooled to 0 °C and Dess-Martin periodinane (1.70 g, 5.16 mmol, 1.2 equiv) was added all at once. After stirring at 0 °C for 15 minutes, the reaction mixture was warmed to 23 °C and stirred for 45 minutes. The reaction was quenched by the addition of basic aqueous Na2S2O3 (50 / 50 v / v aqueous Na2S2O3 and aqueous Na2HCO3), and the resulting mixture was stirred vigorously for 15 minutes. After extraction with CH2Cl2 (3×), the organic phase was washed successively with water and brine and dried over Na2SO4, filtered, and concentrated in vacuo to afford QC04012 which was used without further purification. JPEG0007693751000080.jpg23166

[0151] Example: Reductive amination of QC04012 and QC04001 to prepare QC04013, namely 7-(2-{[(tert-butoxy)carbonyl] amino}-3-(4-nitrophenyl)propyl)-1,4,7-triazonane-1,4-dicarboxylic acid 1,4-di-tert-butyl (QC04013) Compound QC04012 (theoretically 4.3 mmol) was added to a solution of QC04001 (1.40 g, 4.3 mmol) dissolved in DCE (100 mL) at 0 °C. The resulting solution was stirred for 10 minutes, and sodium triacetoxyborohydride (1.28 g, 6.02 mmol, 1.4 equiv) was added portionwise over 30 minutes. 4 This mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated, treated with saturated aqueous NaHCO3 (50 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford QC04013 as a yellow solid (1.90 g, 95%). The organic layer was concentrated, treated with saturated aqueous NaHCO3 (50 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4, filtered , Concentrated in vacuo. The residue was purified by flash chromatography (SiO2, Hex / EA = 3 / 1) to give QC04013 (2.31 g based on a theoretical 2.61 g, 88.5% in 2 steps) as a pale yellow semi-solid. 1 1H NMR (400 MHz, CDCl3) δ = 8.11 (2H, d, J = 7.6 Hz), 7.35 (2H, d, J = 7 .6 Hz) 5.28 (1H, s, br), 3.54~3.88 (2H, m), 3.39~ 3.54 (2H, m), 3.32~3.40 (1H, m), 3.15~3.32 (2H, m), 2.79~3.15 (4H, m), 2.37~2.73 (6H, m), 1.43 ( 9H, s), 1.42 (9H, s), 1.38 (9H, s); 13 13C NMR (101 M Hz, CDCl3) δ = 156.15, 155.99, 155.70, 155.56, 1 47.00, 146.95, 146.81, 146.76, 130.36, 123.73 , 123.65, 123.60, 80.07, 79.99, 79.92, 79.81, 7 9.57, 79.46, 60.79, 60.47, 55.52, 54.33, 54.06 , 53.64, 53.15, 53.28, 51.54, 50.80, 50.71, 50. 42, 49.87, 49.07, 48.12, 39.67, 39.45, 28.74, 2 8.61. MS m / z: MS-API: C 30 H 50 N5O8 ([M + H] + ) calculated for: 608.4, found: 608.3. JPEG0007693751000081.jpg20166

[0152] Example: 1-(4-Nitrophenyl)-3-(1,4,7-triazonan-1-yl)pro lopan-2-amine QC04013 (2.31 g, 3.8 mmol) was dispersed in 30 mL of 4M HCl / diox ane, and the resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was quickly added to cold Et2 O to precipitate a white solid. This solid was recovered and dried in air to obtain pure product Q C04014 (1.71 g in quantitative yield) as an off-white solid. MS m / z: MS-API: C 15 H 26 N5O2 ([M+H] + ) Calculated: 308. 2, Found: 308.2. JPEG0007693751000082.jpg34166

[0153] Example: Introduction of Tri-tert-butyl Acetate 1b QC04014 (78 mg, 0.19 mmol) dissolved in DMF (2 mL) and D IPEA (0.272 mL, 202 mg, 1.56 mmol, 8.2 equiv, M.W.: 1 29.24, d: 0.742) solution, NaI (233.8 mg, 1.56 mmol, 8.2 equiv, M.W.: 149.89) and tert-butyl bromoacetate (0.126 mL, 168 mg, 0.86 mmol, 4.5 equiv, M.W.: 195.05, d: 1. 321) were slowly added at room temperature. The resulting mixture was warmed to 60 - 70 °C and stirred for 20 hours . After completion, monitored by TLC and LC-MS, the reaction was quenched with water and extracted with Et2O. The combined organic solvents were successively washed with water and brine and dried over Na2 SO4. After filtration, the solvent was evaporated under vacuum, and the resulting dark oil residue was purified by Si Flash chromatography on O2 (DCM / MeOH=100 / 1 to 100 / 4) QC04015 (14 mg, 10%) and QC04016 (10 mg, 10%) were purified as yellow oils by 15' (61 mg, 49.4%) was obtained. MS m / z: MS-API: C 39 H 66 N5O 10 ([M+H] + ) Calculated value: 764.5, actual value: 764.4. JPEG0007693751000083.jpg37166

[0154] Example: QC04015 (20 mg, 0.039 mmol) dissolved in MeOH (2 mL) To a solution of 10% Pd / C catalyst (5 mg) was added. The resulting mixture was Hydrogenolysis by stirring together at 1 atm (approximately 15 psi) for 14 hours at ambient temperature. The reaction mixture was diluted with excess DCM and filtered through Celite, and the filtrate was Concentration in vacuo gave QC04016 (13 mg, 67.5%). MS m / z:MS -API:C 39 H 68 NO8([M+H] + ) Calculated value: 734.5, measured value :734.4.

[0155] Examples directed at folic acid JPEG0007693751000084.jpg26166 Example: 2-(4-(N-((2-amino-4-oxo-3,4-dihydropteridine- 6-yl)methyl)-2,2,2-trifluoroacetamido)benzamido)pentane (S)-5-tert-butyl 1-methyl diacetate (QC02023) HCl·H2N-Glu(OtBu)-OMe (350 mg, 1.38 mmol), N dissolved in DMSO (6.0 mL)10 -TFA-pteroylglutamic acid (560 mg, 1.3 mmol) and DIPEA (1.2 mL, 6.85 mmol) were added to a solution at 23 °C under N2. After stirring at 23 °C for 15 minutes, PyBOP (720 mg, 1.0 mmol) was added and the reaction mixture was stirred at 23 °C for 24 hours. Volatiles were removed under reduced pressure to obtain a crude product as a semi-solid. This was further purified by three solid extractions with Hex / EA (1 / 1) to obtain QC02023 as a yellowish-white solid in quantitative yield. This was used without further purification. λ max = 280 nm; LC-MS (Agilent G6 130B Quadrupole LC / MS): Mobile phase: buffer (pH 7)-CH3CN; Column: analytical C18 column; Method: 0 - 100% CH3CN - 15 minutes, t R = 5. 62 minutes. MS m / z: MS-API: C 26 H 29 F3N7O7 ([M + H] + ) calculated value for: 608.2, measured value: 608.1. JPEG0007693751000085.jpg28166

[0156] Example: (S)-4-(4-(N-((2-Amino-4-oxo-3,4-dihydro pteridin-6-yl)methyl)-2,2,2-trifluoroacetamido)benzamide) -5-methoxy-5-oxopentanoic acid (QC02024) 224 mg of QC02023 was treated with TFA / DCM (15 mL, 1 / 3) at 23 °C. The reaction was stirred at 23 °C and monitored by TLC. After 1.5 hours, the starting material was no longer observed by TLC. Volatiles were removed under reduced pressure to obtain a semi-solid residue. This This was treated with cold Et2O to give a pale white precipitate. This was collected by filtration and dried in air to give (S)-4-(4-(N-((2-amino-4-oxo-3,4-dihydro pteridin-6-yl)methyl)-2,2,2-trifluoroacetamido)benz amide)-5-methoxy-5-oxopentanoic acid (QC02024) (169 mg, 83% for 2 steps). λ = 280 nm; LC-MS (Agilent max G6130B Quadrupole LC / MS): Mobile phase: buffer (pH 7)-CH 3CN; Column: analytical C18 column; Method: 0 - 100% CH3CN - 15 min, t = R 3.40 min. MS m / z: MS-API: C 22 H 21 F3N7O7 ([M + H] + ) Calculated for: 552.1, Found: 552.1. 1 1H NMR (400 MHz, DM SO) δ = 12.16 (s, br, 1H), 8.88 (d, J = 7.2 Hz, 1H), 8 .65 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8. 0 Hz, 2H), 7.16 (s, br, 1H), 5.14 (s, 2H), 4.38 - 4. 55 (m, 1H), 3.64 (s, 3H), 2.28 - 2.40 (m, 2H), 2.00 - 2.12 (m, 1H), 1.87 - 2.00 (m, 1H); 13 13C NMR (101 M Hz, DMSO) δ = 173.91, 172.36, 165.93, 161.03, 15 6.11, 155.76 (d, J = 35.8 HZ), 154.19, 149.40, 14 4.45, 141.80, 134.30, 128.89, 128.62, 128.29, ​117.91 (d, J = 48.5 Hz), 53.90, 52.23, 52.06, 30. 26, 25.81; 19 19F NMR (377 MHz, CDCl3) δ = 62.87. JPEG0007693751000086.jpg42166

[0157] Example: Pte-γGlu-Lys-OH (EC1777) EC1777 was prepared using the following solid-phase peptide synthesis.

[0158] [Table 1]

[0159] Fmoc-Lys-resin (1.0 mg, 0.5 mmol) was placed in a peptide synthesis vessel and washed with DMF (3 × 10 mL). The first Fmoc deprotection was carried out for 10 minutes per cycle using a 20% piperidine solution dissolved in DMF (3 × 10 mL). After washing with DMF (3 × 10 mL) and i-PrOH (3 × 10 mL), a Kaiser test was performed to determine the completion of the reaction. After another DMF wash (3 × 10 mL), an amino acid solution (2.0 equivalents) dissolved in DMF, PyBOP (2.0 equivalents), and DIPEA (3.0 equivalents) was added to the vessel, and the solution was bubbled with argon for 1 hour. This coupling solution was filtered, and the resin was washed with DMF (3 × 10 mL) and i-PrOH (3 × 10 mL), and a Kaiser test was performed to determine the completion of the reaction. The above process was also continuously carried out for additional couplings. Cleavage of the resin was carried out with a reaction mixture consisting of 95% CF3CO2H, 2.5% H2O, and 2.5% triisopropylsilane. This cleavage reaction mixture DMF (3 × 10 mL) was used for washing. The first Fmoc deprotection was carried out for 10 minutes per cycle using a 20% piperidine solution dissolved in DMF (3 × 10 mL). After washing with DMF (3 × 10 mL) and i-PrOH (3 × 10 mL), a Kaiser test was performed to determine the completion of the reaction. After another DMF wash (3 × 10 mL), an amino acid solution (2.0 equivalents) dissolved in DMF, PyBOP (2.0 equivalents), and DIPEA (3.0 equivalents) was added to the vessel, and the solution was bubbled with argon for 1 hour. This coupling solution was filtered, and the resin was washed with DMF (3 × 10 mL) and i-PrOH (3 × 10 mL), and a Kaiser test was performed to determine the completion of the reaction. The above process was also continuously carried out for additional couplings. Cleavage of the resin was carried out with a reaction mixture consisting of 95% CF3CO2H, 2.5% H2O, and 2.5% triisopropylsilane. This cleavage reaction mixture dissolved in DMF (3 × 10 mL) was used for 10 minutes per cycle. After washing with DMF (3 × 10 mL) and i-PrOH (3 × 10 mL), a Kaiser test was performed to determine the completion of the reaction. After another DMF wash (3 × 10 mL), an amino acid solution (2.0 equivalents) dissolved in DMF, PyBOP (2.0 equivalents), and DIPEA (3.0 equivalents) was added to the vessel, and the solution was bubbled with argon for 1 hour. This coupling solution was filtered, and the resin was washed with DMF (3 × 10 mL) and i-PrOH (3 × 10 mL), and a Kaiser test was performed to determine the completion of the reaction. The above process was also continuously carried out for additional couplings. Cleavage of the resin was carried out with a reaction mixture consisting of 95% CF3CO2H, 2.5% H2O, and 2.5% triisopropylsilane. This cleavage reaction mixture 3 × 10 mL) and i-PrOH (3 × 10 mL), a Kaiser test was performed to determine the completion of the reaction. After another DMF wash (3 × 10 mL), an amino acid solution (2.0 equivalents) dissolved in DMF, PyBOP (2.0 equivalents), and DIPEA (3.0 equivalents) was added to the vessel, and the solution was bubbled with argon for 1 hour. This coupling solution was filtered, and the resin was washed with DMF (3 × 10 mL) and i-PrOH (3 × 10 mL), and a Kaiser test was performed to determine the completion of the reaction. The above process was also continuously carried out for additional couplings. Cleavage of the resin was carried out with a reaction mixture consisting of 95% CF3CO2H, 2.5% H2O, and 2.5% triisopropylsilane. This cleavage reaction mixture to determine the completion of the reaction. After another DMF wash (3 × 10 mL), an amino acid solution (2.0 equivalents) dissolved in DMF, PyBOP (2.0 equivalents), and DIPEA (3.0 equivalents) was added to the vessel, and the solution was bubbled with argon for 1 hour. This coupling solution was filtered, and the resin was washed with DMF (3 × 10 mL) and i-PrOH (3 × 10 mL), and a Kaiser test was performed to determine the completion of the reaction. The above process was also continuously carried out for additional couplings. Cleavage of the resin was carried out with a reaction mixture consisting of 95% CF3CO2H, 2.5% H2O, and 2.5% triisopropylsilane. This cleavage reaction mixture dissolved in DMF, PyBOP (2.0 equivalents), and DIPEA (3.0 equivalents) was added to the vessel, and the solution was bubbled with argon for 1 hour. This coupling solution was filtered, and the resin was washed with DMF (3 × 10 mL) and i-PrOH (3 × 10 mL), and a Kaiser test was performed to determine the completion of the reaction. The above process was also continuously carried out for additional couplings. Cleavage of the resin was carried out with a reaction mixture consisting of 95% CF3CO2H, 2.5% H2O, and 2.5% triisopropylsilane. This cleavage reaction mixture equivalents) was added to the vessel, and the solution was bubbled with argon for 1 hour. This coupling solution was filtered, and the resin was washed with DMF (3 × 10 mL) and i-PrOH (3 × 10 mL), and a Kaiser test was performed to determine the completion of the reaction. The above process was also continuously carried out for additional couplings. Cleavage of the resin was carried out with a reaction mixture consisting of 95% CF3CO2H, 2.5% H2O, and 2.5% triisopropylsilane. This cleavage reaction mixture filtered, and the resin was washed with DMF (3 × 10 mL) and i-PrOH (3 × 10 mL), and a Kaiser test was performed to determine the completion of the reaction. The above process was also continuously carried out for additional couplings. Cleavage of the resin was carried out with a reaction mixture consisting of 95% CF3CO2H, 2.5% H2O, and 2.5% triisopropylsilane. This cleavage reaction mixture to determine the completion of the reaction. The above process was also continuously carried out for additional couplings. Cleavage of the resin was carried out with a reaction mixture consisting of 95% CF3CO2H, 2.5% H2O, and 2.5% triisopropylsilane. This cleavage reaction mixture was also continuously carried out for additional couplings. Cleavage of the resin was carried out with a reaction mixture consisting of 95% CF3CO2H, 2.5% H2O, and 2.5% triisopropylsilane. This cleavage reaction mixture consisting of 95% CF3CO2H, 2.5% H2O, and 2.5% triisopropylsilane was used. This cleavage reaction mixture 10 mL) was poured onto the resin, bubbled with argon for 30 minutes, and then filtered into a clean flask Additional cleavage was carried out continuously twice at 10 - minute intervals with fresh cleavage reaction mixture. The combined filtrate was poured onto cold diethyl ether and the formed precipitate was recovered by centrifuging at 4000 rpm for 5 minutes (3X). The precipitate was obtained after decantation and drying of the solid under vacuum. Deprotection of the trifluoro - acetyl group was achieved by dissolving the crude precipitate in H2O (15 mL), basifying it to pH 9 with Na2CO3 while bubbling with argon. At the completion of the reaction confirmed by LCMS, 2M HCl was used to acidify the solution to pH 3 and the desired linker was purified by preparative HPLC (mobile phase A = 10 mM ammonium acetate (pH = 5), organic phase B = acetonitrile, method: from 10% B to 100% B in 30 minutes) to give EC1777 (112 mg, 39%). The combined filtrate was poured onto cold diethyl ether and the formed precipitate was recovered by centrifuging at 4000 rpm for 5 minutes (3X). The precipitate was obtained after decantation and drying of the solid under vacuum. Deprotection of the trifluoro - acetyl group was achieved by dissolving the crude precipitate in H2O (15 mL), basifying it to pH 9 with Na2CO3 while bubbling with argon. At the completion of the reaction confirmed by LCMS, 2M HCl was used to acidify the solution to pH 3 and the desired linker was purified by preparative HPLC (mobile phase A = 10 mM ammonium acetate (pH = 5), organic phase B = acetonitrile, method: from 10% B to 100% B in 30 minutes) to give EC1777 (112 mg, 39%). (3X). The precipitate was obtained after decantation and drying of the solid under vacuum. Deprotection of the trifluoro - acetyl group was achieved by dissolving the crude precipitate in H2O (15 mL), basifying it to pH 9 with Na2CO3 while bubbling with argon. At the completion of the reaction confirmed by LCMS, 2M HCl was used to acidify the solution to pH 3 and the desired linker was purified by preparative HPLC (mobile phase A = 10 mM ammonium acetate (pH = 5), organic phase B = acetonitrile, method: from 10% B to 100% B in 30 minutes) to give EC1777 (112 mg, 39%). (3X). The precipitate was obtained after decantation and drying of the solid under vacuum. Deprotection of the trifluoro - acetyl group was achieved by dissolving the crude precipitate in H2O (15 mL), basifying it to pH 9 with Na2CO3 while bubbling with argon. At the completion of the reaction confirmed by LCMS, 2M HCl was used to acidify the solution to pH 3 and the desired linker was purified by preparative HPLC (mobile phase A = 10 mM ammonium acetate (pH = 5), organic phase B = acetonitrile, method: from 10% B to 100% B in 30 minutes) to give EC1777 (112 mg, 39%). (3X). The precipitate was obtained after decantation and drying of the solid under vacuum. Deprotection of the trifluoro - acetyl group was achieved by dissolving the crude precipitate in H2O (15 mL), basifying it to pH 9 with Na2CO3 while bubbling with argon. At the completion of the reaction confirmed by LCMS, 2M HCl was used to acidify the solution to pH 3 and the desired linker was purified by preparative HPLC (mobile phase A = 10 mM ammonium acetate (pH = 5), organic phase B = acetonitrile, method: from 10% B to 100% B in 30 minutes) to give EC1777 (112 mg, 39%). (3X). The precipitate was obtained after decantation and drying of the solid under vacuum. Deprotection of the trifluoro - acetyl group was achieved by dissolving the crude precipitate in H2O (15 mL), basifying it to pH 9 with Na2CO3 while bubbling with argon. At the completion of the reaction confirmed by LCMS, 2M HCl was used to acidify the solution to pH 3 and the desired linker was purified by preparative HPLC (mobile phase A = 10 mM ammonium acetate (pH = 5), organic phase B = acetonitrile, method: from 10% B to 100% B in 30 minutes) to give EC1777 (112 mg, 39%). (3X). The precipitate was obtained after decantation and drying of the solid under vacuum. Deprotection of the trifluoro - acetyl group was achieved by dissolving the crude precipitate in H2O (15 mL), basifying it to pH 9 with Na2CO3 while bubbling with argon. At the completion of the reaction confirmed by LCMS, 2M HCl was used to acidify the solution to pH 3 and the desired linker was purified by preparative HPLC (mobile phase A = 10 mM ammonium acetate (pH = 5), organic phase B = acetonitrile, method: from 10% B to 100% B in 30 minutes) to give EC1777 (112 mg, 39%). (3X). The precipitate was obtained after decantation and drying of the solid under vacuum. Deprotection of the trifluoro - acetyl group was achieved by dissolving the crude precipitate in H2O (15 mL), basifying it to pH 9 with Na2CO3 while bubbling with argon. At the completion of the reaction confirmed by LCMS, 2M HCl was used to acidify the solution to pH 3 and the desired linker was purified by preparative HPLC (mobile phase A = 10 mM ammonium acetate (pH = 5), organic phase B = acetonitrile, method: from 10% B to 100% B in 30 minutes) to give EC1777 (112 mg, 39%). 1 1H NMR (500 MHz, DMSO - d6) major signals: δ 8.60 (s, 1H), 7.58 (d , 2H), 6.60 (d, 2H), 4.45 (s, 2H). [M + H] + = calculated 570 .23, found 570.582. JPEG0007693751000088.jpg41166

[0160] Example: Pte - γGlu - Lys - NOTA In a dry flask, EC1777 (30.5 mg, 0.054 mmol, 1.0 equivalent), 1,1,3,3 - tetramethylguanidine (13.45 μL, 0.107 mmol, 2. 0 equivalents), and DMSO (2.5 mL) were sonicated under argon for 1 hour. To this solution, DIPEA (0.19 mL, 1.07 mmol, 20 equivalents) was added, followed by additional Time, ultrasonic treatment was performed. To the clear solution, p-SCN-Bn-NOTA·3HCl (33 m g, 0.059 mmol, 1.1 eq) was added and monitored by LCMS until the reaction was complete and purified using preparative HPLC (mobile phase A = 10 mM ammonium acetate (pH = 5), organic phase B = acet onitrile, method: 10% B to 100% B in 30 minutes) to obtain EC1778 ( 16 mg, 29%). 1 1H NMR (500 MHz, DMSO-d6) main signals : δ 8.60 (s, 1H), 7.58 (d, 2H), 7.29 (d, 2H), 7.07( d, 2H), 6.61 (d, 2H), 4.45 (s, 2H), 4.20 (t, 1H). [M+H] + = calculated value 1020.39, measured value 1020.63.

[0161] Example: Pte-γGlu-Lys-NOTA was reacted with Al 18 F3·3H2O using the published method (one-step method), or AlCl3·3H2O, subsequently reacted with Na 18 F (two-step method) to prepare Pte-γGlu-Lys-N OTA-Al- 18 F. JPEG0007693751000089.jpg46166

[0162] Example: N10-TFA-Pte-γGlu-OtBu-Arg(Pbf)-Arg(P bf)-Lys(Mtt)-resin (3) The general procedure described for the synthesis of resin-bound folic acid-peptide resin (1) was followed for the coupling of 2X Fmoc -L-Arg(pbf)-OH, Fmoc-Glu-OtBu, and N10-TFA- Pte-OH with Fmoc-L-Lys(Mtt)-Wang resin. was followed. JPEG0007693751000090.jpg58166

[0163] Example: Pte-γGlu-Arg-Arg-Lys-Bn-NOTA(4)(EC22 17) Place N10-TFA-Pte-γGlu-OtBu-Arg(Pbf) -Arg(Pbf)-Lys(Mtt)-resin (0.28 g, 0.07 mmol) into a peptide synthesis vessel , and wash it with DCM (3 × 10 mL). Add a 2% CF3CO2H / DCM solution to the vessel , and perform selective Mtt deprotection by bubbling with argon for 10 minutes. After filtration, wash the resin with dichloromethane and then with a fresh solution of 2% CF3CO2H / DCM. Repeat this process until no yellow solution is formed , and perform a Kaiser test. After DMF washing (3 × 10 mL), add p-SCN-Bn-NOTA.3H Cl (50 mg, 0.09 mmol, 1.2 equivalents) and DIPEA (80 μL, 0.4 5 mmol, 6.0 equivalents) dissolved in DMF to the vessel, and bubble the solution with argon for 2 hours. Filter the coupling solution, wash the resin with DMF (3 × 10 mL) and i-PrOH (3 × 10 mL) , and perform a Kaiser test to determine the completion of the reaction. Cleavage / overall tert-butyl ester deprotection of the resin was performed with a reaction mixture consisting of 95% CF3CO2H, 2.5% H2O, and 2.5 % triisopropylsilane. Pour this cleavage reaction mixture (10 mL) onto the resin , bubble with argon for 60 minutes, and then filter and transfer it to a clean flask. Perform additional cleavage with a fresh cleavage reaction mixture continuously twice, with 20 minutes of bubbling each time. Pour the combined filtrate onto cold diethyl ether , and centrifuge the formed precipitate at 4000 rpm for 5 minutes( 0 ), and collect the precipitate 3X) It was recovered by centrifugation. The precipitate was obtained after decantation and drying of the solid under vacuum. Deprotection of the trifluoro-acetyl group was achieved by dissolving the crude precipitate in H2O (15 mL ), which was basified to pH 9 with Na2CO3 while bubbling with argon. At the completion of the reaction confirmed by LCMS, 2M HCl was used to acidify the solution to pH 5, and the desired linker was purified by preparative HPLC (mobile phase A = 10 mM ammonium acetate (pH = 5), organic phase B = acetonitrile, method: 10% B to 100% B in 30 minutes) to obtain EC2217 (35 mg, 35%). (pH = 5), organic phase B = acetonitrile, method: 10% B to 100% B in 30 minutes) to obtain EC2217 (35 mg, 35%). 0%B) to obtain EC2217 (35 mg, 35%). 1 1H NMR (50 0 MHz, DMSO-d6) main signals: δ 8.61 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.17 - 7.03 (m, 2H), 6.99 (d, J = 8.0 Hz , 2H), 6.66 (d, J = 8.5 Hz, 2H), 4.52 - 4.45 (m, 1H), 4.17 (dt, J = 8.9, 4.6 Hz, 2H), 4.12 (s, 1H) 4.07 - 3 .97 (m, 1H). [M + H] + = calculated value 1332.59, measured value 1332.87. JPEG0007693751000091.jpg45166

[0164] Example: N10-TFA-Pte-γGlu-OtBu-Asp(OtBu)-Arg( Pbf)-Arg(Pbf)-Lys(Mtt)-resin (5) The general procedure described for the synthesis of the resin-bound folic acid-peptide resin (1) was repeated with 2X Fmoc -L-Arg(pbf)-OH, Fmoc-L-Asp(OtBu)-OH, Fmoc- Glu-OtBu, and N10-TFA-Pte-OH, using Fmoc-L-Lys(M It was followed for coupling with Wang resin. JPEG0007693751000092.jpg61166

[0165] Example: Pte-γGlu-Asp-Arg-Arg-Lys-Bn-NOTA(6)( EC2218) Pte-γGlu-Asp-Arg-Arg-Lys-Bn-NOTA (EC2218) was prepared in 18% yield according to the method described for folic acid-peptide-NOTA(4). 1 H NMR (500 MHz, DMSO-d6) main signals: δ 8.58 (s, 1H), 7 .52 (d, J = 9.0 Hz, 2H), 7.14~7.08 (m, 4H), 6.61 (d , J = 9.0 Hz, 2H), 4.16~4.09 (m, 2H), 4.06 (dd, J = 1 , J = 10.0, 4.3 Hz, 1H), 3.90 (dd, J = 7.8, 4.7 Hz, 1H). [M +H] +H] + = Calculated value 1449.64, Measured value 1449.76. JPEG0007693751000093.jpg38166

[0166] Example: N10-TFA-Pte-γGlu-OtBu-Arg(Pbf)-Lys(M tt)-resin(7) The general procedure described for the synthesis of resin-bound folic acid-peptide resin(1) was followed for the coupling of Fmoc-L- Arg(Pbf)-OH, Fmoc-Glu-OtBu, and N10-TFA-Pte -OH with Fmoc-L-Lys(Mtt)-Wang resin. It was followed. JPEG0007693751000094.jpg50166

[0167] Example: Pte-γGlu-Arg-Lys-Bn-NOTA(8)(EC2219) Pte-γGlu-Arg-L was prepared according to the method described for folic acid-peptide-NOTA(4). ys-Bn-NOTA(EC2219) was prepared in 20% yield. 1H NMR(50 0 MHz, DMSO-d6) main signals: δ 8.68(s, 1H), 7.60(d, J = 8.4 Hz, 3H), 7.27~6.97(m, 4H), 6.77~6.69(m, 2H ), 4.28~f4.19(m, 2H), 4.08(dd, J = 9.0, 5.4 Hz, 1 H), 4.01(dd, J = 8.5, 5.4 Hz, 1H). [M + H] + = calculated value 117 8.51, measured value 1178.7. JPEG0007693751000095.jpg66166

[0168] Example: Pte-γGlu-Arg-Arg-Lys-NOTA(9)(EC2222) N10-TFA-Pte-γGlu-OtBu-Arg(Pbf) -Arg(Pbf)-Lys(Mtt)-resin(0.5 g, 0.12 mmol) was placed in a peptide synthesis vessel and washed with DCM(3×10 mL). 2% CF3CO2H / DCM solution was added to the vessel and selective Mtt deprotection was carried out by bubbling with argon for 10 minutes. After filtration, the resin was washed with dichloromethane and then with fresh 2% CF3CO2H / DCM solution. This process was repeated until no more yellow solution was produced, and the Kaiser test was performed. After washing with DMF(3×10 mL), NOTA-bis(tBu) ester(0 .10 g, 0.24 mmol, 2.0 equivalents), PyBOP(0.14 g, 0.26 mmo l, 2.2 equivalents), and DIPEA(64 μL, 0.36 mmol, 3.0 equivalents) were added to the vessel and the solution was bubbled with argon for 2 hours. The coupling solution was filtered and the resin was washed with DM .10 g, 0.24 mmol, 2.0 equivalents), PyBOP(0.14 g, 0.26 mmol, 2.2 equivalents), and DIPEA(64 μL, 0.36 mmol, 3.0 equivalents) were added and the solution was bubbled with argon for 2 hours. The coupling solution was filtered and the resin was washed with DM l, 2.2 equivalents), and DIPEA(64 μL, 0.36 mmol, 3.0 equivalents) were added and the solution was bubbled with argon for 2 hours. The coupling solution was filtered and the resin was washed with DM F(3×10 mL). Washed with F(3×10 mL) and i-PrOH(3×10 mL), and the Kaiser test was performed to determine the completion of the reaction. Cleavage of the resin / overall tert-butyl ester deprotection was carried out with a reaction mixture consisting of 95% CF3CO2H, 2.5% H2O, and 2.5% triisopropylsilane. This cleavage reaction mixture (10 mL) was poured onto the resin, bubbled with argon for 1 hour , and then filtered and placed in a clean flask. Further cleavage was carried out continuously twice with fresh cleavage reaction mixture every 10 minutes of bubbling. The combined filtrate was poured onto cold diethyl ether , and the formed precipitate was collected by centrifugation at 4000 rpm for 5 minutes (3X). The precipitate was obtained after decantation and drying of the solid under vacuum. Deprotection of the trifluoro -acetyl group was achieved by dissolving the crude precipitate in H2O (15 mL), which was basified to pH 9 with Na2CO3 while bubbling with argon. When the completion of the reaction was confirmed by LCMS , the solution was acidified to pH 5 with 2M HCl, and the desired linker was purified by preparative HPLC (mobile phase A = 10 mM ammonium acetate (pH = 5), organic phase B = acetonitrile, method: from 10% B to 100% B in 30 minutes) to obtain EC22 22 (28 mg, 20%). 1H NMR (500 MHz, DMSO-d6) main signal: δ 8.60 (s, 1H), 7.51 (d, J = 8.1 Hz, 2H), 6.64( d, J = 8.4 Hz, 2H), 4.21~4.09 (m, 2H), 4.09~4.03( m, 1H), 3.98~3.88 (m, 1H), 3.50 (s, 1H). [M + H] = Calculated value 1167.57, measured value 1167.8. JPEG0007693751000096.jpg43166 JPEG0007693751000096.jpg43166 = Calculated value 1167.57, measured value 1167.8. d, J = 8.4 Hz, 2H), 4.21~4.09 (m, 2H), 4.09~4.03( m, 1H), 3.98~3.88 (m, 1H), 3.50 (s, 1H). [M + H] + = Calculated value 1167.57, measured value 1167.8. JPEG0007693751000096.jpg43166

[0169] Example: 18-4-(N-((2-amino-4-oxo-3,4-dihydro pteridin-6-yl)methyl)-2,2,2-trifluoroacetamide)benzamide)-2,2 -dimethyl-4,15-dioxo-3,8,11-trioxa-5,14-diazanonade canoic acid (S)-methyl ester (QC07010) QC02024 (100 mg, 0.181 mmol) was added to a solution of Mono-Boc-PEG-NH2 (45 mg, 0.181 m mol) and DIPEA (0.158 mL, 0.905 mmol) dissolved in DM SO (2 mL) under N2 at 23 °C. After stirring at 2 3 °C for 15 minutes, PyBOP (94.2 mg, 0.181 mmol) was added, and the reaction mixture was stirred at 23 °C for 24 hours. The volatiles were removed under reduced pressure, and the crude material was further purified by S PE purification and successively extracted with ACN (2×), EA (1×), and Et2O (1×) to obtain the pure product QC07010 (127 mg, 90%). λ = 2 max 80 nm; LC-MS (Agilent G6130B Quadrupole LC / MS): Mobile phase: buffer (pH 7)-CH3CN; Column: analytical C18 column; Method: 0~100 CH3CN - 15 minutes, tR = 5.06 minutes. MS m / z: MS-API: C 33H43F3N9O10 ([M+H] ) calculated value for: 782.3, measured value: 78 + 2.2. 1H NMR (400 MHz, DMSO) δ = 11.59 (s, br, 1H), 8.92 (d, J = 7.2 Hz, 1H), 8.64 (s, 1H), 7.85~8.02 ([[]] m, 3H), 7.64 (d, J = 8.0 Hz, 2H), 6.75 (t, J = 5.2 Hz, 1H), 1H), 5.13 (s, 2H), 4.33 - 4.48 (m, 1H), 3.64 (s, 3H ), 3.46 (s, 4H), 3.30 - 3.41 (s, 4H), 3.14 - 3.23 (m , 2H), 3.01 - 3.08 (m, 2H), 2.19 - 2.30 (m, 2H), 2.0 2 - 2.12 (m, 1H), 1.89 - 2.00 (m, 1H), 1.35 (s, 9H); 13C NMR (101 MHz, DMSO) δ = 172.43, 171.46, 165. 73, 160.87, 156.80, 155.70 (d, J = 35.5 Hz), 155. 67, 154.17, 149.49, 144.20, 141.73, 134.30, 12 8.82, 128.55, 128.23, 116.20 (d, J = 290.0 Hz), 7 7.65, 69.58, 69.50, 69.193, 69.192, 53.88, 52. 52, 51.96, 38.89, 38.62, 31.65, 28.23, 26.32; 1 9F NMR (377 MHz, CDCl3) δ = -62.87。 JPEG0007693751000097.jpg45166

[0170] Example: 2-(4-(N-((2-Amino-4-oxo-3,4-dihydropteridin- 6-yl)methyl)-2,2,2-trifluoroacetamido)benzamide)-5-( (2-(2-(2-Aminoethoxy)ethoxy)ethyl)amino)-5-oxopentane acid (S)-methyl (QC07011) QC07010 (274 mg, 0.35 mmol) was treated with TFA / DCM (4 mL, 1 / 3 ) at 23 °C. The reaction mixture was stirred at 23 °C and monitored by LC-MS. After 1.5 h, TLC indicated that all starting materials had disappeared. This mixture was taken up in CH3 The mixture was diluted with CN and evaporated to dryness by rota-vap. The remaining TFA (boiling point 72. 4 °C) was removed by azeotropic distillation with ACN to give the product QC07011 in quantitative yield. This was used without further purification. max = 280 nm; LC-MS (Agile nt G6130B Quadrupole LC / MS): Mobile phase: Buffer (pH7) -ACN; Column: analytical C18 column; Method: 0-100 ACN 15 min, t R =3 .84 min. MS m / z: MS-API: C 28 H 35 F3N9O8([M+H] + ) Calculated value: 682.2, actual value: 682.2. JPEG0007693751000098.jpg45166

[0171] Example: (S)-2,2'-(7-(4-(4-(N-((2-amino-4-oxo-3 ,4-Dihydropteridin-6-yl)methyl)-2,2,2-trifluoroacetamido Benzamide)-3,7,18-trioxo-2,11,14-trioxa-8,1 7-diazanonadecan-19-yl)-1,4,7-triazonane-1,4-diyl)di Acetic acid (QC07013) QC07011 (15.7 mg, 0.023 mmol) dissolved in DMSO (0.5 mL) l) was treated with NOTA-NHS (18.2 mg, 0.028 mmol), followed by DIPEA ( The reaction was stirred at 23 °C and analyzed by LC-MS. The majority of the starting material was converted to QC07013 within 5 hours. -C 18 Purification by HPLC gave the pure product QC07013 (13 mg, 58.5%). Got it.max = 280 nm; LC-MS (Agilent G6130B Quadr upole LC / MS): Mobile phase: Buffer (pH 7) - CH3CN; Method: 0 - 100 CH3CN - 15 min, t R = 3.74 min. MS m / z: MS-API: C 40 H 54 F3N 12 O 13 ([M + H] + ) Calculated value for: 967.4, Measured value: 967.2; HPLC (Agilent Preparative C18 Column): Mobile phase : Buffer (pH 7) - CH3CN; Method: 0 - 100 CH3CN - 30 min, t R = 10 .75 min. JPEG0007693751000099.jpg60166

[0172] Example: (S)-2,2'-(7-(1-(4-(((2-amino-4-oxo-3,4 -dihydropteridin-6-yl)methyl)amino)phenyl)-3-carboxy-1, 6,17-trioxo-10,13-dioxa-2,7,16-triazaoctadecane- 18-yl)-1,4,7-triazonane-1,4-diyl)diacetic acid (FA-PEG1- NOTA, QC07017) QC07013 (20.8 mg, 0.022 mmol) was stirred in 1.2 mL of 1M NaO H (aqueous) at 23 °C and the reaction was monitored by LC-MS. After 15 min, all starting materials were converted to the product and the crude material was purified by RP-C18 HPLC to give Q C07017 (11.3 mg, 60%). λ max = 280 nm; HPLC (Ag ilent Preparative C18 Column): Mobile phase: Buffer (pH 7) - CH3CN; Method: 0 - 30% CH3CN for 30 minutes, tR = 11.49 minutes. LC - MS (Agilent G6130B Quadrupole LC / MS): Mobile phase: Buffer (pH 7) - CH3CN; Method: 0 - 100% CH3CN for 15 minutes, tR = 2.7 2 minutes. MS m / z: MS - API: C37H53N12O12([M + H] + ) corresponding to Calculated value: 857.4, Measured value: 857.2. 1H NMR (400 MHz, DMSO) δ = 8.62 (s, 1H), 8.28 (t, J = 5.6 Hz, 1H), 7.99 (t, J = 5.6 Hz, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.76 - 7.80 ( s, br, 2H), 7.58 (d, J = 8.8 Hz, 2H), 7.00 (t, J = 6.0 Hz, 1H), 6.62 (d, J = 8.8 Hz, 2H), 4.47 (d, J = 5.2 Hz , 2H), 4.13 - 4.18 (m, 1H), 3.43 (s, 4H), 3.31 - 3.4 1 (m, 4H), 3.29 - 3.32 (m, 2H), 3.10 - 3.24 (m, 4H), 3.03 - 3.10 (s, br, 2H), 2.90 - 3.03 (s, br, 2H), 2. 10 - 2.14 (m, 2H), 1.97 - 2.05 (m, 1H), 1.84 - 1.9 (m , 1H); 13C NMR (101 MHz, DMSO) δ = 174.33, 172.21 , 171.17, 170.35, 165.70, 161.85, 156.19, 154. 95, 150.56, 148.45, 148.32, 128.62, 127.87, 12 1.84, 111.38, 69.44, 69.30, 69.08, 68.70, 60.9 5, 57.48, 53.11, 50.85, 49.41, 48.91, 45.88, 38 .60, 38.18, 32.04, 27.52. JPEG0007693751000100.jpg102166

[0173] Example: Solid-phase synthesis (SPS) of FA-PEG6-EDA-NH2 precursor (QC03019) ) 1,2-Diaminoethane trityl resin (1.2 mmol / g, 100 mg, 0.12 m mol) was swollen with dichloromethane (DCM, 3 mL), followed by dimethylformamide (DMF, 3 mL). After swelling the resin in DMF, a solution of fluorenylmeth oxycarbonyl (Fmoc)-PEG6-OH (1.5 equivalents), HATU (1.5 equivalents ), and DIPEA (2.0 equivalents) was added. Stirred with argon for 2 hours, and the resin was washed with DMF (3 × 3 mL) and i-PrOH (3 × 3 mL). The above procedure was used to conjugate Fmoc-Glu -(OtBu)-OH and N 10 -TFA-Ptc-OH, and the last 2 coupling steps were repeated. The reaction mixture of trifluoroacetic acid (TFA):H2 O:triisopropylsilane (95:2.5:2.5) was used to cleave the final product from the resin and concentrated under vacuum. The concentrated product was precipitated in diethyl ether and dried under vacuum. Then it was incubated in saturated Na2CO3 and monitored by LC-M S. After 1 hour, the mixture was neutralized to pH = 7 with 2M HCl (aqueous), and separated by extraction RP-C HPLC (solvent gradient: 0%B to 50%B in 30 minutes; A = 10 mM NH4 OAc (pH = 7), B = CH3CN). Acetonitrile was removed under vacuum, 18 and the residue was lyophilized to obtain QC03019 as a yellow solid (59 mg, 60%). Analytical RP-C HPLC:t for RP-C 18 HPLC:t R= 4.22 minutes (A = 10 mM NH4OAc (pH = 7) ; B = CH3CN, solvent gradient: 0% B to 50% B in 15 minutes); preparative RP-C 18 HPLC : t R = 11.7 minutes (A = 10 mM NH4OAc (pH = 7), B = CH3CN, solvent gradient: 0% B to 50% B in 30 minutes); λ max = 280 nm; HPLC (Agilent Preparative C18 Column): mobile phase: buffer (pH 7)-CH 3CN; method: 0 to 30% CH3CN - 30 minutes, t R = 11.7 minutes. LC-MS (Agi lent G6130B Quadrupole LC / MS): mobile phase: buffer (pH 7)-CH3CN; method: 0 to 50% CH3CN - 15 minutes, t R = 4.22 minutes. MS m / z: MS-API: C 36 H 55 N 10 O 12 ([M + H] + ) calculated value for: 81 9.4, measured value: 819.2. 1 H NMR (DMSO-d6 / D2O) δ = 8.63( s, 1H), 7.64 (d, J = 8.8 Hz, 2H), 6.64 (d, J = 8.8 Hz, 2H), 4.48 (s, 2H), 4.12~4.21 (m, 1H), 3.58 (t, J= 6.4 Hz, 2H), 3.41~3.53 (m, 24H), 3.18~3.25 (m, 2 H), 3.11~3.18 (m, 2H), 2.28 (t, J = 6.4, 2H), 2.15 (t, J = 7.4, 2H), 2.03 (m, 1H), 1.88 (m, 1H) ppm. JPEG0007693751000101.jpg43166

[0174] Example: FA-PEG6-NOTA QC03019 (9.5 mg, 0.011 mmol) dissolved in DMSO (0.40 mL at a concentration of 0.0029 M) was added to NOTA-NHS (8.6 mg, 0.013 mmol), followed by the addition of DIPEA (7.0 μL, 0.039 mmol). The reaction mixture was stirred at 23 °C and monitored by LC-MS. Most of the starting material was converted to the corresponding product in 5 hours. The crude material was purified by RP-C 18 HPLC to obtain the pure product QC07029 (5.5 m g, 45%). Analytical RP-C 18 HPLC: t R = 3.91 min (A = 10 mM NH4OAc (pH = 7.0); B = CH3CN, solvent gradient: 0% B - 50% B in 15 min ); Preparative RP-C 18 HPLC: t R = 10.51 min (A = 10 mM NH4OAc (p H = 7.0), B = CH3CN, solvent gradient: 0% B - 50% B in 30 min); λ max = 2 80 nm; HPLC (Agilent Preparative C18 Column ): Mobile phase: buffer (pH 7) - CH3CN; Method: 0 - 30% CH3CN - 30 min, t R = 10.51 min. LC-MS (Agilent G6130B Quadrupole LC / MS): Mobile phase: buffer (pH 7) - ACN; Method: 0 - 50% ACN - 15 min , t R = 3.91 min; MS m / z: MS-API: C 48 H 74 N 13 O 17 ([M + H] + ) calculated: 1104.5, found: 1104.4. JPEG0007693751000102.jpg63166

[0175] Example: FA-NOTA-Al- 18 F radioactive tracer [2] FA-NOTA-Al- 18 Two methods for the formation of F are described herein. 18 The conditions including the pH value, the concentration of substances, and the temperature for the chelation reaction with F-Al can be changed FA-NOTA-Al- 18 A general method for F is described below.

[0176] Method a): Dissolve the FA-NOTA precursor in 2 mM NaOAc (pH 4.5) and 0.5 m L ethanol, and treat it with freshly prepared Al 18 F3·3H2O (1 .5 equivalents). Adjust the pH to 4.5 - 5.0 and keep the pH at 4.5 - 5.0 while refluxing the reaction mixture for 15 - 30 minutes. After cooling to room temperature, load the crude material onto a cartridge and elute the radioactive tracer into a vial. After sterile filtration and dilution to the appropriate radioactivity (5 - 1 0 mCi) and specific radioactivity (>1 Ci / μmol), the radioactive tracer is ready for in vivo PET imaging.

[0177] Method b): Dissolve the FA-NOTA precursor in 2 mM NaOAc (pH 4.5), and treat it with AlCl3·3H2O (1.5 equivalents). Adjust the pH to 4.5 - 5.0 and keep the pH at 4.5 - 5.0 while refluxing the reaction mixture for 15 - 30 minutes. Purify the crude material by RP-HPLC to obtain the 18 FA-NOTA-Al- OH intermediate ready for F-labeling. Treat an appropriate amount of FA-NOTA-Al-OH with 18 Na F saline and ethanol After cooling to room temperature, the crude material was loaded into the cartridge, and the radioactive tracer was eluted into the vial. After sterile filtration and dilution to the appropriate radioactivity (5 - 10 mCi) and specific radioactivity (>1 Ci / μ mol), the radioactive tracer was ready for in vivo PET imaging. JPEG0007693751000103.jpg60166

[0178] Example: Standard protocol for the formation of folic acid - NOTA - Al 18 F radioactive tracer This 18 resin containing F was first washed with 1.5 mL of ultrapure water and then 18 F was eluted from the resin by using 1.0 mL of 18 F 100 μL of the elution solution containing was added to a stem vial filled with 10 μL of acetic acid, 25 μL of AlCl3 (2 mM dissolved in 0.1 M NaOAc (pH 4) buffer), and 125 μL of 0.1 M NaO Ac (pH 4) buffer. The entire mixture was incubated for 2 minutes and then 125 μL of 0.25 mg of folic acid - NOTA precursor (1) dissolved in 0.1 M NaO Ac (pH 4) buffer was transferred to the same stem vial. The reaction mixture was immediately heated at 100 °C for 15 minutes. After cooling to room temperature, the crude material was mixed with 0.7 mL of 0.1% folic acid and purified by radio - HPLC on an Xselect CSH C18 (250×10 mm ) column using Me

[0179] CN and 0.1% folic acid as the mobile phase. The fraction at 11.5 minutes was collected to obtain a pure radioactive tracer with an approximately 98% radiochemical purity (RCP) at approximately 40 - 50% ​​​Obtained with radiochemical yield (RCY). Specific activity (SA) of 70 ± 18.4 GBq / μmol of folic acid-NOTA-Al 18 F((2), Al 18 F-QC07017) of this whole Radiochemical synthesis was achieved in about 37 minutes. After sterile filtration and appropriate dilution with isotonic saline to the desired radioactivity, folic acid-NOTA-Al F(2) radioactive tracer was ready for PET imaging examination. 18

[0180] Using the same strategy, F with a specific activity (SA) of 49 ± 17.1 GBq / μmol A-PEG 12 -NOTA-Al 18 Radiochemical synthesis of the F radioactive tracer (QC07043) was achieved in about 35 minutes. The radiochemical purity was excellent and was 100% after radioactive HPLC purification, but its overall radiochemical yield (RCY) was relatively low, about 25 - 30%

[0181] 12 -NOTA-Al 18 F radioactive tracer was ready for PET imaging examination. JPEG0007693751000104.jpg101166

[0181] Example: FA-PEG 12 -EDA-NH2 (QC07042)

[11] solid-phase synthesis (S PS) 1,2-diaminoethane trityl resin (1.2 mmol / g, 50 mg, 0.06 mmol ol) was swollen with dichloromethane (DCM, 3 mL), followed by dimethylformamide (DMF, 3 mL). After swelling the resin in DMF, fluorenylmethoxy carbonyl (Fmoc)-PEG 12-OH (1.5 equivalents), HATU (1.5 equivalents ), and a solution of DIPEA (2.0 equivalents) were added. Stirred with argon for 2 hours, and the resin was washed with DMF (3 × 3 mL) and i-PrOH (3 × 3 mL). Fmoc-Glu -(OtBu)-OH and N 10 -TFA-Ptc-OH were conjugated, and the above procedure was repeated for 2 more coupling steps. Trifluoroacetic acid (TFA):H2 O:triisopropylsilane reaction mixture (95:2.5:2.5) was used to cleave the final product from the resin and concentrated under vacuum. The concentrated product was precipitated in diethyl ether and dried under vacuum. Then it was incubated in saturated Na2CO3 and monitored by LC-M S. After 1 hour, the mixture was neutralized to pH = 7 with 2M HCl (aqueous) and separated by preparative RP-C 18 HPLC (solvent gradient: 0%B to 50%B in 30 minutes; A = 10 mM NH4 OAc (pH = 7), B = CH3CN). Acetonitrile was removed under vacuum and the residue was lyophilized to obtain pure QC07042 as a yellow solid (32.5 mg, 50%) . Analytical RP-C 18 HPLC: t R = 4.76 minutes (A = 10 mM NH4OAc (pH = 7.0); B = CH3CN, solvent gradient: 0%B to 50%B in 15 minutes); Preparative RP -C 18 HPLC: t R = 13.75 minutes (A = 10 mM NH4OAc (pH = 7.0) , B = CH3CN, solvent gradient: 0%B to 50%B in 30 minutes); UV-Vis: λ max = 280 nm; Preparative RP-C 18 HPLC: HPLC (Agilent Preparat ive C18 Column): Mobile phase: Buffer (pH 7) - CH3CN; Method: 0~ 50 CH3CN, 30 minutes, t R = 13.75 minutes. LC-MS of the product mobile phase (Agil ent G6130B Quadrupole LC / MS): Buffer (pH 7) - CH 3CN; Method: 0~50 CH3CN, 15 minutes, t R = 4.76 minutes. MS m / z: MS -API: C 48 H 79 N 10 O 18 ([M + H] + ) Calculated value for: 1083.6, Measured value: 1083.4. JPEG0007693751000105.jpg43166

[0182] Example: FA-PEG12-EDA-NH2-NOTA (QC07043) FA-PEG12- dissolved in DMSO (0.25 mL having a concentration of 0.025 M) EDA-NH2 (QC07042, 4.78 mg, 0.004 mmol, M.W.: 10 82.5), NOTA-NHS (3.5 mg, 0.005 mmol, 1.2 equivalents), then DIPEA (2.7 μL, 0.039 mmol) was added. The entire mixture was stirred at 23 °C and monitored by LC-MS. After 4 hours, LC-MS showed that almost all of the starting material had been converted to the product. The crude material was then purified by preparative RP-HPLC to obtain pure FA-PEG12-EDA-NH2-NOTA (QC07043, 4.09 mg, 68 %). Analytical RP-C 18 HPLC: t R = 6.21 minutes (A = 10 mM NH4O Ac (pH = 7.0); B = CH3CN, solvent gradient: 0%B~30%B in 15 minutes); Preparative RP-C 18HPLC: t R = 15.60 minutes (A = 10 mM NH4OAc (pH = 7. 0), B = CH3CN, solvent gradient: 0% B to 30% B in 30 minutes); UV-Vis: λ ma x = 280 nm; LC-MS: LC-MS of the product mobile phase (Agilent G6130 B Quadrupole LC / MS): buffer (pH 7) - CH3CN; method: 0 to 8.00 (m, 1H), 7.55 (d, J = 6.4 Hz, 1H), 7.54 (s, br, 2H), 6.81 - 6.93 (m, 1H), 6.62 (d, J = 8.0 Hz, 2H), 4 .45 (d, J = 4.4 Hz, 2H), 3.95 - 4.03 (m, 1H), 3.64 - 3 .70 (m, 2H), 3.56 - 3.63 (m, 6H), 3.38 - 3.50 (m, 28 H), 3.33 - 3.36 (m, 6H), 3.20 - 3.24 (m, 4H), 3.09 - 3.18 (m, 10H), 3.04 - 3.09 (m, 4H), 2.50 (s, 12H, D MSO residue peak overlapping), 2.27 - 2.34 (m, 2H), 2.02 - 2. 12 (m, 2H), 1.99 - 2.01 (m, 2H). JPEG0007693751000106.jpg63166

[0183] Examples: C-NETA and folic acid-C-NETA Coupling between QC04018 and compound (6) promoted by PyBOP, followed by T Deprotection of the tert-butyl ester by TFA gave folic acid-C-NETA. This folic acid-C-NETA was used to evaluate the labeling efficiency of Al 18 F and 68 Ga, and also evaluate in vivo PET imaging. JPEG0007693751000107.jpg28166

[0184] Example: Methyl 3-cyano-4-(dimethylamino)benzoate (QC07002) [1] To a stirred solution of methyl 3-cyano-4-fluorobenzoate (5 g, 27 .9 mmol) in DMSO (6 mL) was added dimethylamine hydrochloride (2.75 g, 33.7 mmol) , followed by potassium carbonate (8.1 g, 58.6 mmol). The reaction mixture was stirred at room temperature overnight and concentrated. The residue was dissolved in dichloromethane (50 mL), washed with water (2 × 25 mL) and brine, dried over Na2SO4, and concentrated in vacuo to give methyl 3-cyano- 4-(dimethylamino)benzoate (QC07002) in quantitative yield and used without further purification. JPEG0007693751000108.jpg31166

[0185] Example: 2-Cyano-4-(methoxycarbonyl)-N,N,N-trimethylbenzenaminium trifluoromethanesulfonate (QC07003) To a stirred solution of methyl 3-cyano-4-(dimethylamino)benzoate (3.4 g, 16.7 mmol) in anhydrous dichloromethane (17 mL) was added methyl trifluoromethanesulfonate (10 g, 60.9 mmol, M.W. 164.1) dropwise. The reaction mixture was stirred at room temperature for 16 h and another portion of methyl trifluoromethanesulfonate (10 g, 6 0.9 mmol, M.W. 164.1) was added. The reaction mixture was stirred for another 16 h and tert-butyl methyl ether (20 mL) was slowly added. The suspension was filtered and the recovered solid was washed with tert-butyl methyl ether. The crude product was purified by RP-C 18 ​​​​​​Purified by HPLC (gradient of acetonitrile / water 1:99 to 80:20) to give product Q C07003 (3.69 g) was obtained in 60% yield. RP-C for analysis 18 HPLC: t R = 0.49 min (A = 10 mM NH4OAc (pH = 7.0); B = CH3CN, solvent gradient : 0% B to 100% B in 15 min); λ max = 275 nm; LC-MS (Agilen t G6130B Quadrupole LC / MS): mobile phase: buffer (pH 7)- CH3CN; column: analytical C 18 column; method: 0 to 100 CH3CN - 15 min, t R = 0.49 min. MS m / z: MS-API: C 12 H 15 N2O2 ([M] + ) calculated value for: 219.1, measured value: 219.0. 1H NMR (400 MHz, D2O) δ = 8.67 (d, J = 2.1 Hz, 1H), 8.44 (dd, J = 9.1, 2.1 Hz , 1H), 8.15 (d, J = 9.1 Hz, 1H), 3.93 (s, 3H), 3.87( , 9H) ppm. s JPEG0007693751000109.jpg28166

[0186] Example: 4-Carboxy-2-cyano-N,N,N-trimethylbenzenaminium trifluoromethanesulfonate (QC07004) A solution of QC07003 (3.6 g, 9. 8 mmol) dissolved in water (83 mL) and TFA (83 mL) was heated at 120 °C for 48 h. The reaction mixture was concentrated in vacuo and the pale green oil was treated with diethyl ether to give a suspension. The solid was collected by filtration and washed with diethyl ether and dried in vacuo to give 4-carboxy- trifluoromethanesulfonate Boxy-2-cyano-N,N,N-trimethylbenzeneaminium QC07004(2. 8 g, 82%) was obtained. RP-C for analysis 18 HPLC: t R = 0.61 min (A = 10 mM NH4OAc (pH = 7.0); B = CH3CN, solvent gradient: 0% B to 100 % B in 15 min); λ max = 240 nm; LC-MS (Agilent G6130B Quad rupole LC / MS): mobile phase: buffer (pH 7)-CH3CN; column: analytical C 18 column; method: 0 to 100 CH3CN, 15 min, t R = 0.61 min. MS m / z: MS-API: C 11 H 13 N2O2 ([M] + ) calculated value: 205.1, actual measurement: 205.1. 1H NMR (400 MHz, DMSO) δ = 8.58 (d, J = 2 .07 Hz, 1H), 8.39~8.49 (m, 1H), 8.23~8.35 (m, 1H ), 3.85 (s, 9H). JPEG0007693751000110.jpg51166

[0187] Example: FA-PEG1-TMA precursor (QC07005) QC07004 (62 mg, 0.17 mmol) was added to a solution of QC07011 (0.14 mmol) and DIPEA (87 μL, 1.75 mmol) dissolved in DMSO (2.0 mL) under N2 at 23 °C. After stirring at 23 °C for 15 min, PyBOP( 91 mg, 0.17 mmol) was added and the reaction mixture was stirred at 23 °C for 24 h. Volatile substances were removed under reduced pressure to obtain a crude product. This was further purified by RP-HPLC (C ) to 18 give Purified to obtain pure compound QC07005 as a yellowish-white solid (125.1 mg, 72%) obtained. RP-C for analysis 18 HPLC: t R = 4.17 min (A = 10 mM NH4OAc( pH = 7.0); B = CH3CN, solvent gradient: 0% B to 100% B in 15 min); λ max = 280 nm; LC-MS (Agilent G6130B Quadrupole L C / MS): mobile phase: buffer (pH 7)-CH3CN; column: analytical C 18 column; meth od: 0 to 100 CH3CN - 15 min, t R = 4.17 min. MS m / z: MS-API : C 28 H 35 F3N9O8([M] + ) calculated value for: 868.3, measured value: 868 .2。 JPEG0007693751000111.jpg47166

[0188] Example: One-pot 19 General procedure for F introduction and deprotection 8.3 μL of freshly prepared KF-Kryptofix (1 / 1.5) (0.0012 mmol, 0.144 M) solution was azeotropically dried with CH3CN at 90 - 100 °C and then. To 1.2 mg (0.0012 mmol, 1.0 equivalent) of this, QC07005 dissolved in 50 uL of anhydrous DMSO was added at a precursor concentration of 0.024 M. The resulting mixture was immediately immersed in an oil bath preheated to 7 0 - 75 °C and maintained at 70 - 75 °C for 10 min. After cooling to room temperature 200 μL of 1 M NaOH (aqueous) was added at a concentration of 0.8 M NaOH (aqueous). The reaction was monitored by LC-MS and found to be complete after 5 min. This was used Neutralized with 1 M HCl (aqueous) and analyzed by LC-MS (QC07006). Also , the overall labeling efficiency was approximately 30% based on LC-MS analysis. RP-C for analysis 18 HP LC: A = 10 mM NH4OAc (pH = 7.0); B = CH3CN, solvent gradient: 15 min from 0% B to 100% B); λ max = 280 nm; LC-MS: method: 0 to 100 C H3CN-15 min, t R = 5.13 min. MS m / z: MS-API: C 36 H 37 F4 N 10 O9 ([M+H] + ) calculated value: 829.3, measured value: 829.1. JPEG0007693751000112.jpg94166

[0189] Example: Folic acid- 18 F-boronic acid PET imaging agent Example directed to PSMA JPEG0007693751000113.jpg95166

[0190] Example: EC1380(10) H-Glu(O t Bu)-O t Bu·HCl (2.48 g, 8.41 m mol) and 4-nitrophenyl chloroformate (1.86 g, 9.25 mmol, 1.1 equivalent) were added and dissolved in CH2Cl2 (30 mL) under an argon atmosphere. This stirred solution was cooled to 0 °C, and then DIPEA (4.50 mL, 25.2 mmol, 3 equivalents) was added dropwise one by one. The reaction mixture was left to warm to room temperature and stirred for 1 hour. To this stirred solution , H-Lys-(Z)-O t Bu (4.39 g, 11.8 mmol, 1.4 equivalents) and DIPEA (4.50 mL, 25.2 mmol, 3 equiv) was added and stirred for 1 h. Upon completion the reaction mixture was quenched with saturated NaHCO3 and extracted three times with CH2Cl2. The organic extracts were combined, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The product was purified using silica gel chromatography with petroleum ether and ethyl acetate. The Cbz-protected amine was transferred to a round-bottom flask with 10% Pd / C (10 wt% equiv) and dissolved in MeOH (30 mL) under a hydrogen atmosphere (1 atm) and stirred for 3 h. Upon completion the reaction mixture was filtered through celite and the solvent was removed under reduced pressure to afford the crude amine. This amine was dissolved in CH2Cl2 (30 mL) under an argon atmosphere and cooled to 0 °C. To the cooled solution, 4-nitrophenyl chloroformate (2.2 g, 10.9 mmol, 1.3 equiv) and DIPEA (6.0 mL, 33.6 mmol, 4 equiv) were successively added and stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NH4Cl and extracted three times with ethyl acetate. The organic extracts were combined, dried over Na2SO4, filtered, and the solvent was removed under vacuum to afford the product which was purified using silica gel chromatography to give the desired active amine EC 1380 (2.54 g, 46%).

[0191] JPEG0007693751000114.jpg39166

[0191] Example: Glu(O t Bu)-O t Bu-Lys-O t Bu-AMPAA-Asp(O t Bu)-Asp(O t Bu)-Lys(Mtt)-resin (11) The general procedure described for the synthesis of the resin-bound folic acid peptide resin (1) was followed for 2X Fmoc- L-Asp(O t Bu)-OH, Fmoc-AMPAA-OH, Fmoc-L-Lys( Z)-O t Bu, and Fmoc-(L)-Glu(O t Bu) of Fmoc-L-Ly s(Mtt)-Wang resin was followed for coupling. This resin-bound penta -peptide was subjected to standard Fmoc deprotection, washing, and Kaiser test. Once again, after washing with DMF (3 × 10 mL), the EC1380 solution (2.0 equivalents) dissolved in DMF and DIPEA (3.0 equivalents) were added to the vessel, and the solution was bubbled with argon for 2 hours. The coupling solution was filtered, and the resin was washed with DMF (3 × 10 mL) and i-PrO H (3 × 10 mL), and the Kaiser test was performed to determine the completion of the reaction. JPEG0007693751000115.jpg45166

[0192] Example: Glu-Lys-AMPAA-Asp-Asp-Lys-Bn-NOTA(12 ) Glu-Lys-AMPAA-Asp-Asp-Lys-Bn-NOTA(EC220 9) was prepared in 47% yield according to the method described for folic acid-peptide-NOTA(4). 1 H NMR (500 MHz, DMSO-d6) main signals: δ7.25~7. 18(m, 2H), 7.14(d, J = 8.1 Hz, 1H), 7.12~7.06(m, 5H), 4.47(ddd, J = 17.8, 7.5, 5.6 Hz, 2H), 4.11~4 .08(m, 3H), 4.08~4.02(m, 2H), 3.98(dd, J = 8.2, 5.1 Hz, 1H). [M + H] + = Calculated value 1319.50, Measured value 1319.70. JPEG0007693751000116.jpg36166

[0193] Example: Glu(O t Bu)-O t Bu-Lys-O t Bu-Aoc-Phe-Phe- Arg(Pbf)-Asp(O t Bu)-Arg(Pbf)-Lys(Mtt)-resin( 13) The general procedure described for the synthesis of the resin-bound folic acid peptide resin (1) was followed for the coupling of Fmoc-L-A rg(Pbf)-OH, Fmoc-L-Asp(O t Bu)-OH, Fmoc-L-Ar g(Pbf)-OH, 2X Fmoc-Phe-OH, Fmoc-Aoc-OH, Fmo c-L-Lys(Z)-O t Bu, Fmoc-(L)-Glu(O t Bu), and EC 1380 for the coupling with Fmoc-L-Lys(Mtt)-Wang resin was followed. JPEG0007693751000117.jpg51166

[0194] Example: Glu-Lys-Aoc-Phe-Phe-Arg-Asp-Arg-Lys- NOTA(14) Glu-Lys-Aoc-Phe-Phe-Arg-Asp-Arg-Lys-NOT A(EC2390) was prepared in 3 7% yield according to the method described for folic acid-peptide-NOTA(4). 1 1H NMR (500 MHz, DMSO-d6) main signals: δ 7.25~7.14 (m, 6H), 7.16~7.08 (m, 3H), 4.47 (dd, J = 9.0, 4.7 Hz, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.36( dd, J = 10.4, 4.4 Hz, 1H), 4.27 (t, J = 6.9 Hz, 1H), 4 .16 (t, J = 5.6 Hz, 1H), 3.97~3.88 (m, 2H). [M+H] + = Calculated value 1639.84, measured value 1640.22. JPEG0007693751000118.jpg32166

[0195] Example: DUPA-EAOA-Phe-Arg-Lys-NH2 (2-[3-(3-ben zyloxycarbonyl-1-tert-butoxycarbonyl-propyl)-ureido] pen tandioic acid di-tert-butyl ester (2)) [1,2] L-Glutamic acid di-tert-butyl ester hydrochloride (1) (1.0 g, 3.39 mmol) and triphosgene (329.8 mg, 1.12 mmol) in DCM (25.0 mL) at -78 °C, triethylamine (TEA, 1.0 mL, 8.19 mmol) was added. After stirring at -78 °C for 2 hours under argon, DCM (5.0 mL) solution of L-Glu(OBn)-OtBu (1.2 g, 3.72 mmol) and TEA (600 μL, 4.91 mmol) was added. The reaction mixture was left to reach room temperature (rt) over 1 hour and stirred overnight at ambient temperature. The reaction was quenched with 1M HCl and the organic layer was washed with brine and dried over Na2SO4. The crude product was purified using flash chromatography (hexane:EtOAc = 1:1) to give the intermediate (2) (1.76 g, 90.2%) as a colorless oil. This was crystallized using hexane:DCM . Rf = 0.67 (hexane:EtOAc = 1:1). 1 H NMR (CDC l3): δ 1.43 (s, 9H, CH3-tBu); 1.44 (s, 9H, CH3-tB u); 1.46 (s, 9H, CH3-tBu); 1.85 (m, 1H, Glu-H); 1 .87 (m, 1H, Glu-H); 2.06 (m, 1H, Glu-H); 2.07 (m, 1H, Glu-H); 2.30 (m, 2H, Glu-H); 2.44 (m, 2H, Glu -H); 4.34 (s (broad), 1H, RH); 4.38 (s (broad), 1H, R-H); 5.10 (s, 2H, CH2-Ar); 5.22 (s (broad), 2H, urea -H); 7.34 (m, 5H, Ar-H). EI-HRMS (m / z): C 30 H 47 Calculated value for (M + H) for C + H

[0196] Example: 2-[3-(1,3-bis-tert-butoxycarbonyl-propyl)-ure ido]pentanedioic acid 1-tert-butyl ester, DUPA_1 To a solution of (2) (250 mg, 432 mmol) dissolved in DCM, 10% Pd / C was added. The reaction mixture was hydrogenated at room temperature under 1 atm for 24 h. The Pd / C was filtered through celite and washed with DCM. The crude product was purified using flash chromatography (hexane:EtOAc = 40:60) to give DUPA_1 (169 mg, 80.2%) as a colorless oil. This was crystallized using hexane:DCM. R f = 0.5 8 (hexane:EtOAc = 40:60). 1 1H NMR (CDCl3): δ 1.46 ( m, 27H, CH3-tBu); 1.91 (m, 2H, Glu-H); 2.07 (m, 1 H, Glu-H); 2.18 (m, 1H, Glu-H); 2.33 (m, 2H, Glu- H); 2.46 (m, 2H, Glu-H), 4.31 (s (broad), 1H, RH), 4.35 (s (broad), 1H, R-H); 5.05 (t, 2H, urea-H); EI- HRMS (m / z): C 23 H 41 N2O9 for (M + H) + Calculated value: 489.28 12, Measured value: 489.2808. JPEG0007693751000119.jpg90166

[0197] Reagents and conditions: (a) (i) 20% piperidine / DMF, room temperature, 10 minutes, (ii) Fm oc-Arg(Boc)2-OH, HBTU, HOBt, DMF-DIPEA, 2 hours, (b) (i) 20% piperidine / DMF, room temperature, 10 minutes, (ii) Fmoc-Phe-O H, HBTU, HOBt, DMF-DIPEA, 2 hours, (c) (i) 20% piperidine / DMF, room temperature, 10 minutes, (ii) Fmoc-8-amino-octanoic acid (EAO), HB TU, HOBt, DMF / DIPEA, 2 hours, (d) (i) 20% piperidine / DMF , room temperature, 10 minutes, (ii) (tBuO)3-DUPA-OH, HBTU, HOBt, DI PEA, 2 hours, (e) TFA / H2O / TIPS (95:2.5:2.5), 1 hour.

[0198] Example: DUPA-EAOA-Phe-Arg-Lys-NH2 Fmoc-Lys(Boc)-Wang resin (0.43 mM) was swollen with DCM (3 mL), followed by dimethylformamide (DMF, 3 mL). To this resin was added a solution of 20% piperidine dissolved in DMF (3 × 3 m L), and argon was bubbled for 5 minutes. The resin was Washed with DMF (3 × 3 mL) and isopropyl alcohol (i-PrOH, 3 × 3 mL). The formation of free amine was determined by the Kaiser test. After swelling the resin in DMF, a solution of Fmoc-Arg(Boc)2-OH (2.5 eq), HBTU (2.5 eq), HOBt (2.5 eq), and DIPEA (4 eq) dissolved in DMF was added. Argon was bubbled for 2 h and the resin was washed with DMF (3 × 3 mL) and i-PrOH (3 × 3 mL). The coupling efficiency was evaluated by the Kaiser test. The above procedure was repeated for 3 more coupling steps to introduce phenylalanine (Phe), 8-amino-octanoic acid (EAO), and DUPA successively. The final compound was cleaved from the resin using a trifluoroacetic acid (TFA):H2O:triisopropylsilane reaction mixture (95:2.5:2.5) and concentrated under vacuum. The concentrated product was precipitated in cold diethyl ether and dried under vacuum. The crude product was purified by preparative RP-HPLC ((λ) 210 nm, solvent gradient: 0% B to 50% B in a 30-min run, mobile phase: A) 0.1% TFA (pH = 2), B) acetonitrile (ACN)). ACN was removed under vacuum and the pure fraction was lyophilized to obtain DUPA-EAOA-Phe-Arg-Lys-NH2 as a white solid. UV / vis: λ = 205 nm. Analytical RP-HPLC: t = 6.2 min (A = 0.1% TFA; B = CH3CN, solvent gradient: 0% B to 50% B in 15 min); ESI-MS (m / z): (M + H) for C H N O It was washed. The formation of the free amine was judged by the Kaiser test. After swelling the resin in DMF, a solution of Fmoc-Arg(Boc)2-OH (2.5 equivalents), H BTU (2.5 equivalents), HOBt (2.5 equivalents), and DIPEA (4 equivalents) dissolved in DMF was added. Argon was bubbled for 2 hours and the resin was washed with DMF (3 × 3 mL) and i-PrOH (3 × 3 mL). The coupling efficiency was evaluated by the Kaiser test. Phenylalanine (Phe), 8-amino-octanoic acid (EAO), and DUPA were introduced successively by repeating the above procedure for 3 more coupling steps. Trifluoroacetic acid (TFA):H2O:triisopropylsilane reaction mixture (95:2.5:2 .5) was used to cleave the final compound from the resin and concentrated under vacuum. The concentrated product was precipitated in cold diethyl ether and dried under vacuum. Preparative RP-HPLC ((λ) 21 0 nm, solvent gradient: 0% B to 50% B in a 30-minute run, mobile phase: A) 0.1% TFA (p H = 2), B) acetonitrile (ACN)) was used to purify the crude product. ACN was removed under vacuum and the pure fraction was freeze-dried to obtain DUPA-EAOA-Phe-Arg-Lys- NH2 as a white solid. UV / vis: λ = 205 nm. Analytical RP-H PLC: t = 6.2 minutes (A = 0.1% TFA; B = CH3CN, solvent gradient: 0 max % B to 50% B in 15 minutes); ESI-MS (m / z): C R 40 65 10 13 + H 65 N 10 O 13 for (M + H) +Calculated value: 893.5, measured value: 893.4. JPEG0007693751000120.jpg96166

[0199] Example: DUPA-EAOA-Phe-Arg-Lys-NH2-NOTA DUPA-EAOA-Ph dissolved in DMSO (0.20 mL at a concentration of 0.028 M) e-Arg-Lys-NH2 (QC8001, 5.0 mg, 0.0056 mmol, M. W.: 893.0), NOTA-NHS (5.5 mg, 0.0084 mmol, 1.5 equivalents), followed by DIPEA (2.9 μL, 0.017 mmol) was added. The reaction mixture was stirred at 23 °C and monitored by LC-MS, and most of the starting materials were converted to the corresponding products in 5 hours. The crude material was purified by RP-C 18 HPLC. ACN was removed under vacuum, and the pure fraction was lyophilized to obtain pure DUPA-EAOA-Phe-Arg-Lys-NH2-NO TA (QC08002, 3.3 mg, 50%). Analytical RP-C HPLC: t 18 = 5.98 min (A = 0.1% TFA; B = CH3CN, solvent gradient: 0% B to 5 R 0% B in 15 min); Preparative RP-C HPLC: t 18 = 16.16 min (A = 0.1% TFA; B = R CH3CN, solvent gradient: 0% B to 50% B in 30 min); UV-vis: λ = 201 max nm; HPLC (Agilent Preparative C18 Column); Mobile phase: A = 0.1% TFA, B = CH3CN; Method: 0 - 50 CH3CN - 30 min, t = 16.16 min; LC-MS (Agilent G6130B Quadrupol R ​e LC / MS): Mobile phase: A = 0.1% TFA, B = CH3CN; Method: 0 - 50 °C H3CN - 30 min, t R = 5.98 min, MS m / z: MS - API: C 52 H 84 N1 3O 18 ([M + H] + ) Calculated value for: 1178.6, Measured value: 1178.4. JPEG0007693751000121.jpg41166

[0200] Example: DUPA - EAOA - Phe - Arg - Lys - NH2 - NOTA - Al 18 F Method a) Dissolve DUPA - EAOA - Phe - Arg - Lys - NH2 - NOTA in 2 mM NaOAc (pH 4.5) and 0.5 mL of ethanol, and treat it with freshly prepared Al 18 F3·3H2O (1.5 equivalents). Adjust the pH to 4.5 - 5.0 and reflux the reaction mixture for 15 - 30 minutes while maintaining the pH at 4.5 - 5.0 After cooling to room temperature, load the crude material onto a cartridge and elute the radioactive tracer into a vial After sterile filtration, dilute it to the appropriate radioactivity (5 - 10 mCi) and specific radioactivity (> 1 Ci / μ mol), and then the radioactive tracer is ready for in vivo PET imaging .

[0201] Method b) Dissolve DUPA - EAOA - Phe - Arg - Lys - NH2 - NOTA in 2 mM NaOAc (pH 4.5) and treat it with AlCl3·3H2O (1.5 equivalents). Adjust the pH to 4.5 - 5.0 and reflux the reaction mixture for 15 - 30 minutes while keeping the pH at 4.5 - 5.0 Purify the crude material by RP - HPLC to obtain the 18 F - labeled DUPA-EAOA-Phe-Arg-Lys-NH2-NOTA-A ready for labeling To obtain the l-OH intermediate. An appropriate amount of DUPA-EAOA-Phe-Arg-Lys-NH 2-NOTA-Al-OH is treated with Na 18 F salts solution and ethanol (1 / 1, v / v) and the whole mixture is heated at 100 - 110 °C for 15 minutes. After cooling to room temperature , the crude material is loaded into a cartridge and the radioactive tracer is eluted into a vial. After sterile filtration, it is diluted to an appropriate radioactivity (5 - 10 mCi) and specific activity (>1 Ci / μmol), and then the radioactive tracer is ready to be used for in vivo PET imaging diagnosis. JPEG0007693751000122.jpg37166

[0202] Reagents and conditions: (a) Fmoc-Phe-OH, HBTU, HOBt, DMF-DIP EA, 2 h, (b) (i) 20% piperidine / DMF, room temperature, 10 min, (ii) Fmo c-Phe-OH, HBTU, HOBt, DMF / DIPEA, 2 h, (c) (i) 2 0% piperidine / DMF, room temperature, 10 min, (ii) Fmoc-8-amino-octane (E AO) acid, HBTU, HOBt, DMF / DIPEA, 2 h, (d) (i) 20% piper idine / DMF, room temperature, 10 min, (ii) (tBuO)3-DUPA-OH, HBTU, HOBt, DIPEA, 2 h, (e) TFA / H2O / TIPS (95:2.5:2. 5), 1 h.

[0203] Example: Solid-phase peptide synthesis (S PPS) of DUPA-EAOA-Phe-Phe-EDA-NH2 [2,3] For DUPA-EAOA-Phe-Arg-Lys-NH2 (QC08001), this As described in the specification, DUPA-EAOA-Phe-Phe-EDA-NH2 was prepared A commercially available Trt-EDA resin was swollen with DCM (3 mL), followed by dimethylformamide ( DMF, 3 mL), and a solution of Fmoc-Phe-OH (2.5 equivalents), HBTU (2.5 equivalents), HOBt (2.5 equivalents), and DIPEA (4 equivalents) dissolved in DMF was added thereto. Argon was bubbled for 2 hours, and the resin was washed with DMF (3 × 3 mL) and i-Pr OH (3 × 3 mL). The coupling efficiency was evaluated by the Kaiser test. A solution of 20% piperidine dissolved in DMF (3 × 3 mL) was added to the resin, and argon was bubbled for 5 minutes. The resin was washed with DMF (3 × 3 mL) and isopropyl alcohol (i- PrOH, 3 × 3 mL). The formation of free amine was judged by the Kaiser test. The above procedure was repeated for 3 more coupling steps to continuously introduce the second phenylalanine (Phe), 8-amino-octanoic acid (EAO), and DUPA. The final compound was cleaved from the resin using a trifluoroacetic acid (TFA):H2O:triisopropylsilane reaction mixture (95:2.5:2.5) and concentrated under vacuum. The concentrated product was precipitated in cold diethyl ether and dried under vacuum. Preparative RP-H PLC ((λ) 210 nm, solvent gradient: 0% B to 100% B in a 30-minute run, mobile phase: A ) 10 mM NH4OAc (pH = 7, buffer), B) acetonitrile (ACN)) was used to purify the crude product. ACN was removed under vacuum, and the pure fraction was lyophilized to obtain DUPA -EAOA-Phe-Phe-EDA-NH2 as a white solid. Analytical RP-C HPLC: t The above procedure was repeated for 3 more coupling steps to continuously introduce the second phenylalanine (Phe), 8-amino-octanoic acid (EAO), and DUPA. The final compound was cleaved from the resin using a trifluoroacetic acid (TFA):H2O:triisopropylsilane reaction mixture (95:2.5:2.5) and concentrated under vacuum. The concentrated product was precipitated in cold diethyl ether and dried under vacuum. Preparative RP-H PLC ((λ) 210 nm, solvent gradient: 0% B to 100% B in a 30-minute run, mobile phase: A ) 10 mM NH4OAc (pH = 7, buffer), B) acetonitrile (ACN)) was used to purify the crude product. ACN was removed under vacuum, and the pure fraction was lyophilized to obtain DUPA -EAOA-Phe-Phe-EDA-NH2 as a white solid. Analytical RP-C HPLC: t -EAOA-Phe-Phe-EDA-NH2 was obtained as a white solid. Analytical RP-C 18 HPLC: t R= 3.99 min (A = 10 mM NH4OAc (pH = 7.0); B = CH3CN, solvent gradient: 0% B - 100% B in 15 min); preparative RP-C 18 HPLC: t R = 16.05 min (A = 10 mM NH4OAc (pH = 7.0); B = CH3CN, solvent gradient: 0% B - 100% B in 30 min); UV-vis: λ max = 209 nm; LC- MS: LC-MS of the product mobile phase (Agilent G6130B Quadrupole LC / MS): buffer (pH 7) - CH3CN; method: 0 - 100 ACN - 15 min, t R = 3.99 min, MS m / z: MS-API: C 39 H 56 N7O 11 ([M + H + ) calculated value for: 798.4, measured value: 798.3; C 39 H 55 N7O 11 K( [M + H] + ) calculated value for: 836.4, measured value: 836.3. HPLC (Agil ent Preparative C18 Column); mobile phase: buffer (pH 7) - CH3CN; method: 0 - 100 ACN - 30 min, t R = 16.05 min. JPEG0007693751000123.jpg78166

[0204] Example: DUPA-EAOA -Phe-Phe-EDA-NH2 (QC08008, 5.9 mg, 0.0074 mmol, M.W.: 797.4) dissolved in DMSO (0.25 ml at a concentration of 0.025 M) was added with NOTA-NHS (7.3 mg, 0.011 mmol, 1.5 eq), followed by 4 drops of DIPEA. The mixture was stirred at 23 °C and LC-MS ​Monitored by. After 4 hours, LC-MS showed that almost all of the starting material had been converted to the product. The crude material was then purified by preparative RP-HPLC to obtain pure DUPA-EA OA-Phe-Phe-NOTA (QC08009, purity by HPLC at 210 nm 97%, 4.50 mg (56%) relative to the theoretical 8.02 mg. Analytical RP -C 18 HPLC: t R = 3.45 min (A = 10 mM NH4OAc (pH = 7.0); B = CH3CN, solvent gradient: 0% B to 100% B in 15 min); Preparative RP-C 18 HPLC : t R = 10.09 min (A = 10 mM NH4OAc (pH = 7.0); B = CH3CN , solvent gradient: 0% B to 100% B in 30 min); UV-vis: λ max = 211 nm; L C-MS: LC-MS of the product mobile phase (Agilent G6130B Quadrup ole LC / MS): Buffer (pH 7)-CH3CN; Method: 0 to 100 ACN-1 5 min, t R = 3.45 min, MS m / z: MS-API: C 51 H 75 N 10 O 16 ( M + H] + ) Calculated value for: 1083.5, Measured value: 1083.3. HPLC (Agi lent Preparative C18 Column); Mobile phase: Buffer (pH 7 )-CH3CN; Method: 0 to 100 ACN-30 min, t R = 10.09 min. 1 H NM R (400 MHz, DMSO-d6) δ = 10.13 (br, 1H), 8.98 (br, 1H), 8.43 (br, 1H), 7.90 (br, 3H), 7.30~7.10 (m, 10H), 6.37(br, 1H), 6.28(br, 1H), 4.60~4.52(m , 1H), 4.32~4.44(m, 1H), 4.24~4.31(m, 2H), 3.9 5~4.03(m, 2H), 3.85~3.92(m, 2H), 3.28(s, 4H), 3.25(s, 2H), 3.09(m, 1H), 3.05(m, 1H), 2.92~3. 02(m, 4H), 2.54~2.67(m, 12H), 2.31~2.38(m, 2H ), 2.19~2.31(m, 3H), 2.11~2.18(m, 2H), 2.02~2 .10(m, 3H), 1.52~1.72(m, 4H), 1.25~1.37(m, 4H ), 1.05~1.13(m, 2H). JPEG0007693751000124.jpg73166

[0205] Example: DUPA - EAOA - Phe - Arg - Lys - NOTA - 64 Radiochemical synthesis of Cu radioactive tracer In the preparation of NOTA - Cu for nuclear medicine / radiotherapy, NOTA - based chelates 64 / 67 have also been reported and used [14 - 16]. The corresponding DUPA - NOTA - 6 4 Cu was prepared for the dual purposes of diagnostic imaging and therapy (also called theranostics s). DUPA - EAOA - Phe - Arg - Lys - NOTA - A - 64 Cu was prepared according to a standard protocol with minor modifications [4, 14 - 16]. Locally prepared 64 CuCl2 using 0.1 M ammonium acetate (pH 5.5) was added to a reaction tube containing the DUPA - NOTA precursor 64 ​. Subsequently, the resulting mixture was heated at 95 °C for 15 minutes. After cooling to room temperature, it was purified by radio-HPLC on a C18 column using MeCN and 0.1% TFA as the mobile phase to obtain the crude material, and the target radio-tracer was obtained with a radiochemical purity (RCP) of approximately 90%. Sterile filtration and dilution with isotonic saline to the desired radioactivity yielded a radio-tracer ready for PET imaging. using MeCN and 0.1% TFA as the mobile phase on a C18 column to purify the crude material, and the target radio-tracer was obtained with a radiochemical purity (R CP) of approximately 90%. Sterile filtration and dilution with isotonic saline to the desired radioactivity yielded a radio-tracer ready for PET imaging . JPEG0007693751000125.jpg66166

[0206] Example: DUPA-EAOA-Phe-Phe-NOTA- 64 Cu / Al- 18 F radio chemical synthesis JPEG0007693751000126.jpg70166

[0207] Example: DUPA-EAOA-Phe-Phe-NOTA- 68 Ga radio chemical synthesis

[0208] Example: 68 General procedure for Ga labeling 68 Ga was eluted from the Ge / 68 Ga generator with 0.1 N HCl. A predetermined amount of 68 Ga dissolved in 0.1 N HCl was added to a solution of DUPA 68 -NOTA dissolved in acetate buffer (pH 4.8). The labeling mixture was incubated at room temperature, and the labeling efficiency was examined by radio HPLC. The radiolabeled product was purified by radio-HPLC, and the D UPA-NOTA- Ga peak sample was collected. After sterile filtration and dilution to the appropriate radioactivity (5 - 1 68 0 mCi) and specific radioactivity (> 1 Ci / μmol), the radio-tracer was obtained. - Preparation for in vivo PET imaging was completed. JPEG0007693751000127.jpg77166

[0209] Example: Radiochemical synthesis of DUPA-C-NETA-based seranostics JPEG0007693751000128.jpg70166

[0210] Example: Preparation of NOTA derivatives In this specification, bifunctional conjugates (also called theranostics) are described. The compounds described in this specification can firmly chelate both radionuclides such as F and 18 F and also 68 Ga for PET imaging diagnosis, and radionuclides for radiotherapy 177 Lu and 90 Y. C-NETA, a derivative of NOTA, has been reported to chelate Al 18 F with an efficiency approximately twice that of NOTA (87%)

[17] . Furthermore, C-NETA has also been reported to chelate commonly used radiotherapy nuclides such as 177 Lu and 90 Y with high labeling efficiency

[18] . Therefore, it can be seen from this specification that C-NETA serves as a bifunctional chelating agent that can be used for both PET imaging diagnosis and radiotherapy (the radionuclides thereof are metals or metal halides, such as . Al F, 18 F, 68 Ga, 177 Lu, or 90 Y).

[0211] Example: Coupling between QC04018 and QC08008 promoted by PyBOP Subsequently, deprotection of the tert-butyl ester with TFA gives DUPA-C-NETA is obtained. Using DUPA-C-NETA, the labeling efficiencies of Al 18 F, 68 Ga, 177 Lu, and and 90 Y are determined, and in vivo PET imaging and radiotherapy are evaluated.

[0212] Examples of the method Example: The specificity of the binding of the radionuclide-containing conjugate to FR is evaluated against KB xenograft homogenate and Ca151 xenograft homogenate. 18 F-AIF-QC07 017 and 18 F-AIF-QC07043 are evaluated for concentration-dependent binding and separated into specific binding and non-specific binding. No significant non-specific binding was observed in the KB homogenate . In the Ca151 homogenate, a small amount of non-specific binding was observed, 18 and for F-AIF -QC07017, a specific / non-specific binding ratio > 3:1 was obtained at all concentrations up to about 30 nM, and for 18 F-AIF-QC07043, a specific / non-specific binding ratio > 2:1 was obtained at all concentrations up to about 20 nM . In the A549 homogenate, a small amount of non-specific binding was observed, and for 18 F-AIF-QC07043, a specific / non-specific binding ratio > 2:1 was obtained at all concentrations up to about 10 nM . Scatchard analysis was also performed. Competitive binding and saturation binding of F-A 18 IF-QC07017 by self-competition were observed in human tumor xenografts (KB and Ca151). 18 F-AIF-QC07 017 and 18 ​Both F-AIF-QC07043 bound to one site with high affinity in all cell xenografts. The high ratio of Bmax / Kd indicated high specific binding affinity for the KB xenograft. Moderate binding affinity was observed for the Ca151 xenograft, and the lowest binding affinity was observed for the A549 xenograft. Without being bound by theory, it is believed herein that the moderate expression of FR in the Ca151 xenograft is the main cause of the lower binding affinity.

[0213]

Table 2

[0214]

Table 3

[0215] Example: μPET imaging was performed on nude mice with KB tumor xenografts under standard and competitive conditions to evaluate the in vivo binding specificity of F-AIF-QC07017(2) to FR. Nude mice with KB tumor xenografts on the left shoulder were injected with 0.30 - 0.40 mCi of (2). 100 μg of folic acid was given to the competitive group and the corresponding amount of phosphate buffer was injected into the treatment group 10 minutes before the intravenous injection of (2). The time-course observation of PET images obtained at various time points revealed that the data obtained 60 - 90 minutes after tracer injection gave the best visual PET imaging. The uptake of (2) was completely inhibited by competition with folic acid, while the KB tumor in the treatment group became clearly visible. This indicates that in vivo, (2) binds specifically to FR 18 ​​​​​​​​​​​​​​Demonstrate the high specificity of the binding. Without being bound by theory, the high radioactivity found in the kidneys is due to uptake via FR expressed in proximal tubular cells in the kidneys and potential accumulation of the radioactive tracer by renal excretion, as considered herein. This is further demonstrated by the biodistribution studies described in this specification. No significant uptake was observed in other organs except the liver. A significant blocking effect on liver uptake was observed under competitive conditions.

[0216] Example: Ex vivo biodistribution studies of the compounds described in this specification in nude mice with KB tumor xenografts in the left shoulder under both reference and competitive conditions demonstrate high and specific uptake in FR( +) tumors. The radioactivity levels of F-AIF-QC07017 and 18 F-AIF-QC07043 were determined in whole blood, plasma, heart, kidneys, liver, 18 lungs, muscle, spleen, KB xenograft tumor tissue, and A549 xenograft tumor tissue (Figures 1A, 1B, and 1C). The highest signal was observed in the kidneys. Accumulation in the liver was observed to a much lesser extent. Without being bound by theory, the highest accumulation of radioactivity in the kidneys, along with relatively low uptake of the radioactive tracer in the hepatobiliary system, i.e., the liver, bile, and intestine / feces, demonstrates that renal excretion is the dominant excretion pathway, as considered herein. Excluding the kidneys, the accumulation in KB xenograft tumor tissue was the greatest and significantly greater than that in the liver. The accumulation in A549 xenograft tumor tissue was equivalent to that in the liver. The accumulation in both KB xenograft tumor tissue and A549 xenograft tumor tissue was blocked under competitive conditions with folic acid (Figures 2A and 2B). 18 F-AIF -QC07017 and 18 the FR specificity of F-AIF-QC07043 was equivalent in both the single tumor tissue and the A549 xenograft tumor tissue to eta rfolatide (EC20), which is a compound in clinical trials.

[0217] [Table 4]

[0218] [Table 5]

[0219] Example: in vitro evaluation of the DUPA-EAOA-Phe-Phe-NOTA- 68 Ga radiotracer ( 68 Ga-QC08009) 67 Ga has 68 a longer half-life than Ga (about 3.3 days vs. about 68 minutes, respectively). Thus, 67 Ga is used as a substitute for 68 G a in the in vitro evaluation of Kd values and tissue imaging diagnosis. 67 It should be understood that the Kd values and tissue imaging diagnosis observed for 68 Ga are predictive of those for Ga. DUPA 67 -EAOA-Phe-Phe-NOTA- 67 Ga ( Ga-NOTA-LC-PSM A(2)) was prepared with nearly quantitative radiochemical yield. In vitro studies in both the PSMA(-) cell line (PC3) 5±2.16nM. PC3 is a PSMA(-) cell line, and LnCaP is a PSM A(+) cell line, and PIP-PC3 had higher PSMA expression. Transfected cell line: PIP-PC3 cells 68 Ga-QC08009 uptake is The amount of LnCaP and PIP-PC3 was small and did not change when competed. R 68 Ga-QC08009 uptake was significant, with the highest uptake in PIP-PC3 cells. In both cases, LnCaP and PIP-PC3 uptake 68 Ga -QC08009 uptake is blocked by a competing ligand. Imaging in clinical trials It is a drug 67 Compared with Ga-DKFZ-PSMA (11), 67 Ga-NOTA-LC -PSMA(2) demonstrated excellent binding to PSMA(+) prostate cancer tissue.

[0220] Example: DUPA-EAOA-Phe-Phe-NOTA- 68 Ga radioactive tracer ( 68 In vivo PET imaging and BioD assay of Ga-QC08009 In mice bearing PSMA(+)LnCaP xenografts 68 In vivo micro-PET / CT scans with the Ga-NOTA-LCPSMA(2) radiotracer showed uptake of 4.29% ID of PSMA(+) tumors. One hour after injection, the majority of the radiotracer was found in the bladder. Without being bound by theory, it is believed herein that the data establish that the primary route of excretion is urinary. In addition to this, a small amount of accumulation of the radiotracer was observed in the kidney compared to other tissues. Without being bound by theory, it is believed that the relatively high expression of PSMA in mouse kidney compared to other tissues may explain the increased uptake of PSMA in the kidney. 68It is believed herein that it explains at least in part the reason for the small accumulation of the Ga-NOTA-LC-PSMA(2) radiotracer. This specification includes the following content. <Appendix 1> The conjugate of the formula B-L-P (wherein B is a radical of a targeting drug selected from a vitamin receptor-binding ligand, a PSMA-binding ligand, and a PSMA inhibitor; L is a divalent linker; P is a radical of an imaging agent or a radiotherapy drug such as a radionuclide or a radionuclide-containing group, or a precursor thereof, or a radical of a compound capable of binding to a radionuclide or a radionuclide-containing group such as a metal chelate group) or a pharmaceutically acceptable salt thereof. <Appendix 2> The conjugate according to Appendix 1, comprising folic acid-Asp. <Appendix 3> The conjugate according to Appendix 1, comprising folic acid-Arg. <Appendix 4> The conjugate according to Appendix 1, wherein the linker comprises a polypeptide containing lysine, arginine, or aspartic acid, or a combination thereof. <Appendix 5> The conjugate according to Appendix 1, wherein the linker does not contain the diradical of the formula NH-(CH -NH. 2 ) 2 <Appendix 6> The conjugate according to Appendix 1, comprising the formula or a derivative thereof containing a chelating metal. JPEG0007693751000133.jpg24170 <Appendix 7> The conjugate according to Appendix 1, comprising folic acid-PEG. <Appendix 8> The conjugate according to Appendix 7, comprising the formula or a derivative thereof containing a chelating metal. JPEG0007693751000134.jpg28170 <Appendix 9> The conjugate according to Appendix 7, comprising the formula or a derivative thereof containing a chelating metal. JPEG0007693751000135.jpg39170 <Appendix 10> The conjugate according to Appendix 1, wherein the targeting drug is a radical of a PSMA-binding ligand or a PSMA inhibitor. <Appendix 11> The formula (wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or JPEG0007693751000136.jpg32170 (wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 JPEG0007693751000137.jpg65170 ), or (wherein W is O or S), contained in the conjugate according to Appendix 10. JPEG0007693751000138.jpg62170 <Appendix 12> The conjugate according to Appendix 10, wherein the linker comprises a polypeptide containing phenylalanine, lysine, arginine, or aspartic acid, or a combination thereof. <Appendix 13> The conjugate according to Appendix 10, comprising the formula or a derivative thereof containing a chelating metal. JPEG0007693751000139.jpg27170 <Appendix 14> The conjugate according to Appendix 10, comprising the formula (wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). JPEG0007693751000140.jpg33170 <Appendix 15> The conjugate according to Appendix 10, wherein the linker comprises the formula . JPEG0007693751000141.jpg17170 <Appendix 16> The conjugate according to Appendix 10, wherein the linker comprises the formula . JPEG0007693751000142.jpg21170 <Appendix 17> The formula ​ JPEG0007693751000143.jpg123170 Or, the conjugate according to Supplementary Note 14, comprising a chelated metal or a derivative thereof. <Supplementary Note 18> The conjugate according to any one of Supplementary Notes 1 to 17, wherein the radionuclide is a positron-emitting radionuclide. <Supplementary Note 19> The conjugate according to any one of Supplementary Notes 1 to 17, wherein the radionuclide is a radiotherapeutic agent.

Claims

1. The conjugate of the formula B-L-P (wherein B is a radical of a PSMA-binding ligand of the formula: [[Chemical Formula 1]] [[Chemical Formula 1]] and L is a bivalent linker, and P is selected from the group consisting of [[Chemical Formula 2]] [[Chemical Formula 2]] [[Chemical Formula 2]] [[Chemical Formula]] [[Chemical Formula]] and the bivalent linker L does not contain a diradical of the formula NH-(CH ) ２ ) ２ -NH and contains two or more amino acids selected from lysine, arginine, aspartic acid, glutamic acid, or combinations thereof) or a pharmaceutically acceptable salt thereof.

2. Wherein P is [[Chemical Formula 3]] The conjugate according to claim 1.

3. P-L is [[Chemical Formula 4]] The conjugate according to claim 1 or 2.

4. Wherein P is [[Chemical Formula 5]] The conjugate according to claim 1.

5. P-L is [[Chemical Formula 6]] The conjugate according to claim 1 or 4.

6. The conjugate according to any one of claims 1 to 5, wherein P further comprises a radionuclide.

7. The conjugate according to claim 6, wherein the radionuclide comprises a metal or a metal halide.

8. The conjugate according to claim 7, wherein the radionuclide comprises a positron-emitting radionuclide or a radiation therapy agent.

9. The positron-emitting radionuclide or the radiation therapy agent is ６６ Ga, ６８ Ga, １８ F, １７７ Lu, ９０ Y, ６４ Cu, ６１ Cu, ８９ Zr, ４５ Ti, ５１ Mn, ６３ Zn, ８２ Rb, １２４ I, １１ C, １３ N, or １５ O, and is the conjugate according to claim 8.

10. The conjugate according to claim 7, wherein the radionuclide comprises 18F.

11. The conjugate according to claim 10, wherein the radionuclide comprises Al 18F.

12. The conjugate according to claim 1, wherein the divalent linker L comprises *NH[(CH2)2O]n*, *NH[(CH2)2O]n-(CH2)2NH*, *NH[(CH2)2O]n-(CH2)2-C(O)*, *NH[(CH2)2O]n-(CH2)2-C(O)NH*, *NH[(CH2)2O]n-(CH2)2-C(O)NH-(CH2)2*, or *NH[(CH2)2O]n-(CH2)2-C(O)NH-(CH2)2NH*, where n is an integer from 1 to about 12.

13. The divalent linker L is *NH(CH ２ ) ２ O-(CH ２ ) ２ NH*, *NH[(CH ２ ) ２ O] ２ -(CH ２ ) ２ NH*, *NH[(CH ２ ) ２ O] ６ -(CH ２ ) ２ NH*, or *NH[(CH ２ ) ２ O] １２ -(CH ２ ) ２ NH* containing conjugate according to claim 1.

14. The divalent linker L is *NH[(CH ２ ) ２ O] ２ -(CH ２ ) ２ NH* containing conjugate according to claim 1.

15. The divalent linker L contains lysine, conjugate according to claim 1.

16. The divalent linker L contains arginine, conjugate according to claim 1.

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