Compounds 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 division of U.S. Provisional Patent Application No. 61 / 904,387, filed November 14, 2013. No. 61 / 904,400 filed November 14, 2013, and Regarding the U.S. Patent Act Section 119(e) of the specification of No. 61 / 909,822 filed on November 27th The disclosures of each of which are incorporated herein by reference in their entirety. To be incorporated.

[0002] The invention described herein uses 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 identify 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 method that detects the two emitted gamma rays traveling in exactly opposite directions. Therefore, it is possible to determine their original location and thereby the origin of the emitted gamma rays. Computer analysis can reconstruct a three-dimensional image of all positron emitters. According to reports, compared with other radiological imaging modalities such as SPECT, PET has higher detection sensitivity (about two orders of magnitude), better spatial resolution (about 5 mm), and Larger signal-to-noise ratio and greater suitability for preclinical and clinical applications In addition, it demonstrates excellent tracer quantification in both standard SPECT and MRI. Acquiring PET images takes approximately 90 minutes, compared to the approximately 90 minutes required for a diagnostic body scan. It can be done routinely in about 20 minutes. , generally below nanomolar (10 -10 ~10 -12 ) concentration of radioactive tracer is required. This has been reported to minimize possible damage to other biological systems. Finally, PET allows quantitative dynamic imaging, which is targeted through receptor occupancy. Facilitates kinetic studies of target engagement Vitamin receptors and / or prostate-specific membrane antigen (PSMA) are used herein. They discovered that they could target PET agents to predetermined tissues using a PET-based antibody.

[0004] For example, vitamin receptors are expressed on many cancer cell types, activated macrophages, and activated monocytes. Folate receptors, in particular, are overexpressed in many cancers. It is overexpressed in the folate receptor, which binds the vitamin folate with high affinity (<1 nM). The 38KD GPI-tethered protein is expressed in the ovaries, breasts, bronchi, It is overexpressed in many malignant tissues, including cancers of the brain and of all ovarian carcinomas. It is estimated that 95% of all cancers overexpress folate receptors. Normal tissues other than the plexus and placenta express low or undetectable levels of folate receptors. Also, most cells obtain the folate they need using an unrelated reduced folate carrier. .

[0005] Folate receptors are also overexpressed in activated macrophages and activated monocytes. Furthermore, folate receptor β, the non-epithelial isoform of the folate receptor, is active but dormant. It has also been reported to be expressed in activated synovial macrophages. Macrophages act by nonspecifically engulfing and killing foreign pathogens within their macrophages. Furthermore, by presenting degraded peptides derived from foreign proteins on the surface of macrophages, (where they can be recognized by other immune cells) and also by T and B lymphocytes. secrete cytokines and other factors that regulate lymphocyte function, further stimulating the immune response However, activated macrophages can participate in immune responses. Page 11 of 20 may also sometimes contribute to the pathophysiology of disease. For example, activated macrophages It is also known to be associated with atherosclerosis, rheumatoid arthritis, autoimmune diseases, among other conditions. These may contribute to the pathology of the patient and graft-versus-host disease.

[0006] Receptor binding of vitamins to vitamin receptors, e.g., folic acid and analogs and derivatives of folic acid After receptor binding to the folate receptor in the body, rapid endocytosis transports the vitamin into the cell. The endosomal compartment is then delivered to the endothelial cell where it is unloaded at a lower pH in the endosomal compartment. The study explored the role of small molecules, proteins, and even liposomes in binding to vitamin and other vitamin receptors. Covalent binding to a conjugated ligand does not inhibit the ability of that ligand to bind to the receptor, and therefore Such ligand conjugates are readily delivered into cells and undergo receptor-mediated endocytosis. Thus, diagnostic, imaging, and therapeutic agents can be delivered to cells via the Targeting vitamin receptors, including acid receptors, and delivery into vitamin receptor-expressing cells. can be done.

[0007] The prostate gland is a male reproductive organ that produces and stores semen, which is then released into the vagina during reproduction. It provides nutrients and fluids for the survival of the introduced sperm. Like other tissues, the prostate It may cause malignant (cancerous) or benign (non-cancerous) tumors. According to the American Cancer Society, prostate cancer is one of the most common cancers in men in Western society. It is the second leading form of malignant tumor in men.

[0008] Prostate-specific membrane antigen (PSMA) is an overexpressed biomarker in prostate cancer PSMA is more abundant in the kidney, proximal small intestine, and salivary glands than in other organs of the human body. In cases of malignant prostate cancer, PSMA is overexpressed in malignant prostate tissue. PSMA is also expressed in lung, colon, breast, kidney, and liver. Also expressed in the neovasculature within many non-prostatic solid tumors, including prostate and pancreatic carcinomas However, PSMA is expressed in very small amounts in the brain. PSMA consists of an intracellular domain (amino acids 1-18), a transmembrane domain (amino acids 19), and Approximately 11 amino acids are involved, including the extracellular domain (44–750 amino acids) and the extracellular domain (43–750 amino acids). It is a type II cell surface membrane-associated glycoprotein with a molecular weight of ∼0 kD. The role of the intracellular portion and transmembrane domain of this protein has been reported to be insignificant. The ectodomain is involved in several distinct activities. For example, PSMA acts in the central nervous system. It metabolizes N-acetylaspartyl glutamate (NAAG) to produce glutamate and PSMA also plays a role in the conversion of N-acetylaspartate to N-acetylaspartic acid in the proximal small intestine. Poly-γ-glutamic acid folate is deprived of γ-linked glutamic acid, and the peptide and plays a role in removing α-linked glutamic acid from small molecules. Summary of the Invention [Problem to be solved by the invention]

[0009] Although the detailed role of PSMA in prostate cancer cells remains unresolved, PSMA is thought to be a Similar to the amine receptor, it exhibits rapid internalization into cells, resembling a cell surface-bound receptor. It is known that PSMA is internalized through clathrin-coated pits, They can then recycle to the cell surface or go to the lysosomes. targeting diagnostic, imaging, and therapeutic agents to PSMA and inhibiting PSMs, such as prostate cancer cells A can be delivered into A-expressing cells. [Means for solving the problem]

[0010] The compounds and compositions described herein are intended to combat the effects of pathogenic cell populations. Targeted radionuclides for diagnosing and / or monitoring various diseases and conditions It has been discovered herein that the use of the hydroxybenzoates described herein is useful for the delivery of The compounds and compositions also have utility in treating a variety of diseases and conditions caused by pathogenic cell populations. Helps target and deliver radionuclides to treat medical conditions with radiation therapy and discovered that.

[0011] In one exemplary, non-limiting embodiment of the invention described herein, The compounds and compositions described herein are useful in treating a variety of diseases and conditions caused by pathogenic cell populations. Use to diagnose and / or monitor or treat a condition. In exemplary embodiments, various diseases and conditions caused by pathogenic cell populations are diagnosed. and / or to monitor or treat the compounds described herein. In another embodiment, methods of administering the compounds and compositions to a patient affected by a pathogenic cell population are described. for diagnosing and / or monitoring various diseases and conditions caused by Methods of using the compounds and compositions to manufacture medicaments for treating In another embodiment, various diseases and conditions caused by pathogenic cell populations are diagnosed. The compounds described herein for diagnosing and / or monitoring or for treating Kits for preparing and / or using the products and compositions described herein are also provided. Bell. [Brief explanation of the drawings]

[0012] [Figure 1A] Figure 1 shows postmortem biodistribution study of 18F-AIF-QC07017 folate-NOTA-A1-18F conjugates and 18F-AIF-QC07043 folate-NOTA-A1-18F conjugates in various tissues 90 minutes after injection into nude mice bearing KB tumor xenografts. For each tissue, histograms are for four groups: 18F-AIF-QC07017, 18F-AIF-QC07017 + excess folate, 18F-AIF-QC07043, and 18F-AIF-QC07043 + excess folate. [Figure 1B]Figure 1 shows postmortem biodistribution study of the 18F-AIF-QC07017 folate-NOTA-A1-18F conjugate in various tissues 90 minutes after injection into nude mice bearing KB or A549 tumor xenografts. Note that the vertical axis is expanded and kidney data is truncated. For each tissue, histograms are for four groups, from left to right: 18F-AIF-QC07017 vs. A549 tumor xenografts, 18F-AIF-QC07017 + excess folate vs. A549 tumor xenografts, 18F-AIF-QC07017 vs. KB tumor xenografts, and 18F-AIF-QC07017 + excess folate vs. KB tumor xenografts. [Figure 1C] Figure 1 shows postmortem biodistribution study of the 18F-AIF-QC07043 folate-NOTA-A1-18F conjugate in various tissues 90 minutes after injection into nude mice bearing KB or A549 tumor xenografts. Note that the vertical axis is expanded and kidney data is truncated. For each tissue, histograms are for four groups, from left to right: 18F-AIF-QC07043 vs. A549 tumor xenografts, 18F-AIF-QC07043 + excess folate vs. A549 tumor xenografts, 18F-AIF-QC07043 vs. KB tumor xenografts, and 18F-AIF-QC07043 + excess folate vs. KB tumor xenografts. [Figure 2A]Figure 1 shows postmortem biodistribution study of 18F-AIF-QC07017 and 18F-AIF-QC07043 folate-NOTA-A1-18F conjugates compared to 99mTc-EC20 in KB tumor xenograft tissues in nude mice 90 minutes after injection. Histograms, from left to right, show: 99mTc-EC20 for KB tumor xenografts, 99mTc-EC20 + excess folate for KB tumor xenografts, 18F-AIF-QC07017 for KB tumor xenografts, 18F-AIF-QC07017 + excess folate for KB tumor xenografts, 18F-AIF-QC07043 for KB tumor xenografts, and 18F-AIF-QC07043 + excess folate for KB tumor xenografts. [Figure 2B] Figure 1 shows postmortem biodistribution study of 18F-AIF-QC07017 and 18F-AIF-QC07043 folate-NOTA-A1-18F conjugates compared to 99mTc-EC20 in A549 tumor xenograft tissues 90 min after injection in nude mice. Histograms, from left to right, show: 99mTc-EC20 on A549 tumor xenografts, 99mTc-EC20 + excess folate on A549 tumor xenografts, 18F-AIF-QC07017 on A549 tumor xenografts, 18F-AIF-QC07017 + excess folate on A549 tumor xenografts, 18F-AIF-QC07043 on A549 tumor xenografts, and 18F-AIF-QC07043 + excess folate on A549 tumor xenografts. DETAILED DESCRIPTION OF THE INVENTION

[0013] In each of the preceding embodiments, and in each of the following embodiments, the formula is , as well as including and representing all pharmaceutically acceptable salts of such compounds. It is understood that the term "compound" includes and represents any and all hydrates and / or solvates of any of the chemical formulas. It should be understood that some functional groups, such as hydroxy, amino, and similar groups, may react with water and and / or various physical forms of the compounds in combination with various solvents. It is understood that these compounds form structurally similar structures. Therefore, the chemical formulae set forth herein are not intended to be limiting. It is to be understood that the present invention includes and refers to various hydrates and / or solvates of the compounds. hydrates and / or solvates of the formula, as well as non-hydrates and solvates of the formula of the compound. It is understood that unsolvated and / or unsolvated forms are also described by such formulas.

[0014] As used herein, the term "composition" generally refers to a mixture of specified ingredients in specified amounts. and any product containing, directly or indirectly, a combination of the specified ingredients in the specified amounts. The compositions described herein refer to any product that is produced by the process described herein. from isolated compounds described herein or from salts, solutions, hydrates, solvates of the compounds described herein. It is understood that the compounds can be prepared from various functional groups, e.g. For example, hydroxy, amino, and similar groups can be easily reacted with water and / or various solvents. It is known that compounds form complexes and / or coordination compounds in various physical forms. These compositions also include various amorphous and non-amorphous forms of the compounds described herein. The compound may be prepared in a rufous, partially crystalline, crystalline, and / or morphological form. It should be understood that these compositions may also contain various hydrated forms of the compounds described herein. It is understood that compounds can be prepared from compounds and / or solvates. Such pharmaceutical compositions of the compounds described herein may be prepared by administering to a subject in need thereof various of the compounds described herein. and / or in the form of a hydrate or solvate, or any It is understood that these compositions include combinations. It is understood that various co-crystals of the compounds can be prepared.

[0015] Illustratively, these compounds may be combined with one or more carriers, excipients, and / or Pharmaceutical excipients may be included. The compositions may be administered in therapeutically effective amounts in any conventional dosage form suitable for the methods described herein. Such formulations may be used to prepare the compounds or compositions described herein. Compositions containing them can be prepared by a wide variety of conventional routes for the methods described herein, or The drug can be administered in a wide variety of dosage forms using known procedures (generally, Remi ngton:The Science and Practice of Pharma cy (21st ed., 2005).

[0016] In each of the above-described embodiments and in each of the following embodiments, The chemical formulas represent each possible isomer, e.g., stereoisomers and geometric isomers, individually and It is also understood to include and represent any and all possible mixtures. In each of the foregoing embodiments, and in each of the following embodiments, is intended to describe any and all crystalline, partially crystalline, and amorphous and / or partially crystalline forms of such compounds. It should also be understood to include and refer to amorphous forms.

[0017] Exemplary embodiments of the present invention are described in the following paragraphs. formula, BLP or a pharmaceutically acceptable salt thereof, wherein B is a vitamin receptor binding ligand, a radical of a targeted agent selected from a PSMA-binding ligand and a PSMA inhibitor, L is a bivalent linker and P is a linker of an imaging or radiotherapeutic agent, e.g., a radioactive Radicals of nuclides or radionuclide-containing groups, or precursors thereof, or radionuclides or A radical of a compound that can be bound to a radionuclide-containing group, e.g., a metal chelating group. do.

[0018] The compound described in the preceding paragraph, wherein the targeted agent is a radical of a folate receptor binding ligand. Merge. A conjugate as described in any one of the preceding clauses, wherein the targeted agent is a radical of folic acid. . The conjugate of any one of the preceding clauses, comprising folate-Asp. The conjugate of any one of the preceding clauses, comprising folate-Asp-Arg. The conjugate of any one of the preceding clauses, comprising folate-Arg. The conjugate of any one of the preceding clauses, wherein the linker comprises a polypeptide. The linker may contain lysine, arginine, or aspartic acid, or a combination thereof. The conjugate of any one of the preceding clauses, comprising a polypeptide comprising The conjugate of any one of the preceding clauses, wherein the linker comprises lysine. The conjugate of any one of the preceding clauses, wherein the linker comprises Lys. The conjugate of any one of the preceding clauses, wherein the linker comprises Arg-Lys. . Any one of the preceding clauses, wherein the linker comprises Arg-Arg-Lys. A zygote. any one of the preceding clauses, wherein the linker comprises Asp-Arg-Arg-Lys; The zygote being. The linker may be a polyamine radical, for example a polyamine of the formula NH—(CH 2 ) 2 —NH The conjugate of any one of the preceding clauses, which does not contain a diradical. P is the formula JPEG2025120291000002.jpg26166 or a derivative thereof containing a chelated metal. A zygote. formula JPEG2025120291000003.jpg26166 or a derivative thereof containing a chelated metal. A zygote. The conjugate of any one of the preceding clauses, comprising folate-PEG. The conjugate of any one of the preceding clauses, comprising folate-PEG2. The conjugate of any one of the preceding clauses, comprising folate-PEG6. Folic acid-PEG 12 The conjugate of any one of the preceding clauses, comprising:

[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) Any of the preceding clauses containing NH—(CH 2 ) 2 NH, where n is an integer from 1 to about 12. A conjugate described in any one of the above.

[0020] The linker is [(CH2)2O]2, [(CH2)2O]6, or [(CH2)2O ] 12 The conjugate of any one of the preceding clauses, comprising:

[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) A zygote.

[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 Any of the preceding clauses containing -(CH2)2-C(O)NH or a conjugate described in one.

[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, Merge.

[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 Any one of the preceding clauses containing -(CH2)2-C(O)NH-(CH2)2NH The described zygote.

[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 of 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 Any of the preceding clauses, including A zygote.

[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 Any of the preceding clauses containing -(CH2)2-C(O) or a conjugate described in one.

[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, A conjugate as described in any one of the preceding clauses.

[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 Any one of the preceding clauses containing -(CH2)2-C(O)NH-(CH2)2 The described zygote.

[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 The preceding clause, including -(CH2)2-C(O)NH-(CH2)2NH 1. A conjugate according to any one of the preceding claims.

[0031] The linker is NH[(CH2)2O] n -(CH2)2NH (wherein n is from 1 to about 12) The conjugate of any one of the preceding clauses, wherein

[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 Merge.

[0033] The linker is NH[(CH2)2O] n -(CH2)2NH-C(O)-(CH2)2 -C(O), where n is an integer from 1 to about 12. The described zygote.

[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 The conjugate of any one of the preceding clauses, including (O).

[0035] formula JPEG2025120291000004.jpg30166 or a derivative thereof containing a chelated metal. A zygote. P is the formula JPEG2025120291000005.jpg38166 or a derivative thereof containing a chelated metal. A zygote. formula JPEG2025120291000006.jpg49166 or a derivative thereof containing a chelated metal. A zygote.

[0036] The preceding clause, wherein the targeted agent is a radical of a PSMA-binding ligand or a PSMA inhibitor. 1. A conjugate according to any one of the preceding claims. Any of the preceding paragraphs in which the targeted agent is a radical of a PSMA inhibitor A zygote.

[0037] formula JPEG2025120291000007.jpg32166 (where n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). (or JPEG2025120291000008.jpg68166 (where n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). (or JPEG2025120291000009.jpg68166 (wherein W is O or S). Merge.

[0038] The conjugate of any one of the preceding clauses, wherein the linker comprises a polypeptide. the linker is phenylalanine, lysine, arginine, or aspartic acid, or Any of the preceding clauses, including polypeptides containing these combinations. zygote. The conjugate of any one of the preceding clauses, wherein the linker comprises lysine. The conjugate of any one of the preceding clauses, wherein the linker comprises Lys. The conjugate of any one of the preceding clauses, wherein the linker comprises Arg-Lys. . The linker may comprise Asp-Arg-Lys. A zygote. Any one of the preceding clauses, wherein the linker comprises Arg-Asp-Arg. A zygote. any one of the preceding clauses, wherein the linker comprises Arg-Asp-Arg-Lys; The zygote being. The linker may comprise Phe-Arg-Asp. A zygote. any one of the preceding clauses, wherein the linker comprises Phe-Arg-Asp-Arg; The zygote being. Any one of the preceding clauses, wherein the linker comprises Phe-Arg-Asp-Arg-Lys. The conjugate described in one. Any one of the preceding clauses, wherein the linker comprises Phe-Phe-Arg. A zygote. any one of the preceding clauses, wherein the linker comprises Phe-Phe-Arg-Asp; The zygote being. Any one of the preceding clauses, wherein the linker comprises Phe-Phe-Arg-Asp-Arg. The conjugate described in one. Any of the preceding clauses, wherein the linker comprises Phe-Phe-Arg-Asp-Arg-Lys. A conjugate described in any one of the above. A radical of a radionuclide or a radionuclide-containing group, or a precursor thereof, or a radionuclide The radical of the compound that can be bonded to a species or radionuclide-containing group is the radioactive species of NOTA. 2. A zygote as described in any one of the preceding clauses, wherein the zygote is a galactosidase.

[0039] P is the formula JPEG2025120291000010.jpg30166 or a derivative thereof containing a chelated metal. A zygote. formula JPEG2025120291000011.jpg28166 or a derivative thereof containing a chelated metal. A zygote. formula JPEG2025120291000012.jpg33166 (where n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). The conjugate of any one of the preceding clauses, comprising formula The conjugate of any one of the preceding clauses, including JPEG2025120291000013.jpg33166. The linker has the formula The conjugate of any one of the preceding clauses, including JPEG2025120291000014.jpg20166. The linker has the formula The conjugate of any one of the preceding clauses, including JPEG2025120291000015.jpg22166. The linker has the formula The conjugate of any one of the preceding clauses, including JPEG2025120291000016.jpg22166. The foregoing sentence, wherein one or more of the phenylalanines is L-phenylalanine. A conjugate as described in any one of the clauses. formula JPEG2025120291000017.jpg60166 or a derivative thereof containing a chelated metal. A zygote. P is the formula JPEG2025120291000018.jpg38166 or a derivative thereof containing a chelated metal. A zygote. formula JPEG2025120291000019.jpg122166 or a derivative thereof containing a chelated metal. A zygote.

[0040] A conjugate as described in any one of the preceding clauses, wherein the radionuclide is a positron-emitting nuclide. body. The conjugate of any one of the preceding clauses, wherein the radionuclide is a metal ion. The conjugate of any one of the preceding clauses, wherein the radionuclide is a metal salt. Aluminum halides, such as aluminum fluoride, aluminum chloride, and aluminum bromide iodide, or aluminum iodide, as described in any one of the preceding clauses. zygote. The conjugate of any one of the preceding clauses, comprising aluminum fluoride. 18 F - A joint as described in any one of the preceding clauses, containing aluminum fluoride body. The conjugate of any one of the preceding clauses, comprising aluminum iodide. 125 I - Aluminum iodide, containing the compounds listed in any one of the preceding clauses Merge. The conjugate of any one of the preceding clauses, comprising gallium ions. 66 The conjugate of any one of the preceding clauses, comprising Ga ions. 68 The conjugate of any one of the preceding clauses, comprising Ga ions. The conjugate of any one of the preceding clauses, comprising zirconium ions. 89 The conjugate of any one of the preceding clauses, comprising Zr ions. The conjugate of any one of the preceding clauses, comprising copper ions. 64 The conjugate of any one of the preceding clauses, comprising Cu ions. The radioactive nuclide 131 Iodine, including I 177 Lutetium, including Lu 90 Contains Y Yttrium, 89 Strontium, including Sr 153 Samarium, including Sm Any radiotherapeutic agent or radiotherapeutic agent-containing group as described in any one of the preceding clauses. The zygote being.

[0041] Lutetium ions, e.g. 177 containing Lu ions, as described in any one of the preceding clauses The zygote being. Yttrium ions, e.g. 90 Any of the preceding clauses containing Y ions A zygote that is being fertilized.

[0042] formula JPEG2025120291000020.jpg112166 conjugate or a pharmaceutically acceptable salt thereof. formula JPEG2025120291000021.jpg115166 conjugate or a pharmaceutically acceptable salt thereof. formula A conjugate of JPEG2025120291000022.jpg68166 or a pharmaceutically acceptable salt thereof. formula JPEG2025120291000023.jpg75166 conjugate or a pharmaceutically acceptable salt thereof. P is the formula JPEG2025120291000024.jpg27166(in the formula, - is the conjugate base of an acid such as trifluoromethanesulfonic acid) 1. A conjugate as described in any one of the preceding clauses. formula JPEG2025120291000025.jpg55166 (in the formula, - is the conjugate base of an acid such as trifluoromethanesulfonic acid) 1. A conjugate as described in any one of the preceding clauses. P is the formula The conjugate of any one of the preceding clauses, including JPEG2025120291000026.jpg26166. P is the formula The conjugate of any one of the preceding clauses, including JPEG2025120291000027.jpg29166. formula The conjugate of any one of the preceding clauses, including JPEG2025120291000028.jpg26166. formula The conjugate of any one of the preceding clauses, including JPEG2025120291000029.jpg26166.

[0043] P is the formula * NH-C(CH2OH)3, as set forth in any one of the preceding clauses. A zygote. The conjugate of any one of the preceding clauses, comprising boron fluoride. 18 The conjugate of any one of the preceding clauses, comprising F-boron fluoride. One or more of the conjugates described in any one of the preceding paragraphs or in combination with a carrier, filler, or excipient, or a combination thereof. A pharmaceutical composition comprising:

[0044] for diagnosing and / or monitoring pathogenic cell populations, e.g., cancer or infectious diseases , diagnosis of one or more of the zygotes described in any one of the preceding paragraphs A therapeutically effective amount, optionally with one or more carriers, fillers, or excipients. A composition in a unit dose or in unit dose form comprising the composition in combination with an additive, or a combination thereof.

[0045] Any of the preceding clauses for treating a pathogenic cell population, e.g., cancer or an infectious disease. A therapeutically effective amount of one or more of the conjugates described in one of and optionally one or more carriers, fillers, or excipients, or a combination thereof. A composition in a unit dose or in unit dose form comprising the combination.

[0046] A pathogenic cell population in a host animal, e.g., cancer or an infectious disease, at least in part the foregoing statements to diagnose and / or monitor diseases or conditions caused by Valid for diagnosing one or more of the zygosities listed in any one of the sections a composition comprising an amount of, or one of the conjugates described in any one of the preceding clauses. A diagnostically effective amount of one or more species, and optionally one or more species The pharmaceutical composition further comprises a filler, a bulking agent, or an excipient, or a combination thereof.

[0047] A pathogenic cell population in a host animal, e.g., cancer or an infectious disease, at least in part a method for treating a disease or condition caused by an agent selected from the group consisting of: a composition comprising a therapeutically effective amount of one or more of the conjugates described herein; Therapeutic use of one or more of the conjugates described in any one of the preceding paragraphs a therapeutically effective amount of the compound, optionally containing one or more carriers, fillers, or pharmaceuticals. a pharmaceutical composition further comprising a pharmaceutical additive, a pharmaceutical composition containing a pharmaceutical agent ...

[0048] A pathogenic cell population in a host animal, e.g., cancer or an infectious disease, at least in part to diagnose and / or monitor diseases or conditions caused by Valid for diagnosing one or more of the zygosities listed in any one of the sections or administering to the host animal an amount of a conjugate described in any one of the preceding paragraphs. and optionally one or more of the following: Pharmaceuticals further comprising multiple carriers, fillers, or excipients, or combinations thereof A method comprising administering the composition.

[0049] A pathogenic cell population in a host animal, e.g., cancer or an infectious disease, at least in part a drug described in any one of the preceding clauses to treat a disease or condition caused by an administering to the host animal a therapeutically effective amount of one or more of the conjugates or one of the conjugates described in any one of the preceding paragraphs, or Contains multiple therapeutically effective amounts, optionally with one or more carriers, fillers, or a pharmaceutical excipient, or a combination thereof. A method including:

[0050] A pathogenic cell population in a host animal, e.g., cancer or an infectious disease, at least in part Manufacture of pharmaceuticals for diagnosing and / or monitoring diseases or conditions caused by In one or more of the conjugates described in any one of the preceding clauses A species of zygote containing the species or one of the species described in any one of the preceding paragraphs or more, and optionally one or more carriers, fillers, or pharmaceuticals using a pharmaceutical composition further comprising a pharmaceutical excipient, or a combination thereof.

[0051] A pathogenic cell population in a host animal, e.g., cancer or an infectious disease, at least in part In the manufacture of a medicament for treating a disease or condition caused by an Containing one or more of the conjugates described in any one of the preceding comprising one or more of the conjugates set forth in any one of the preceding clauses, Optionally, one or more carriers, fillers, or excipients, or and using a pharmaceutical composition further comprising the combination of:

[0052] One or more of the conjugates described in any one of the preceding paragraphs, or or optionally one or more carriers, fillers, or excipients, or or the pharmaceutical composition further comprising these combinations, an optional solvent, and an optional reaction volume. and one or more radionuclides are prepared, and the one or more radionuclides are The nuclide may be combined with one or more of the conjugates to produce an imaging agent, a diagnostic agent, or and a set of instructions for preparing the therapeutic agent.

[0053] One or more of the conjugates described in any one of the preceding paragraphs, or or optionally one or more carriers, fillers, or excipients, or or the pharmaceutical composition further comprising these combinations, an optional solvent, and an optional reaction volume. a container and one or more radionuclides, and The nuclide may be combined with one or more of the conjugates to produce an imaging agent, a diagnostic agent, or and a set of instructions for preparing the therapeutic agent.

[0054] If the compound or chemical formula is ( * ) or contains an atom or locus that contains this mark In each case, ( * ) indicates that the compound or formula has a vacant atom or position. A radical with an open valence, the atom or site of which is It should be understood that the radicals in the formula (I) represent the attachment sites of the radicals.

[0055] In another exemplary embodiment, the conjugate, composition, or any other embodiment described herein may be used. The unit dose, method, use, or kit may be prepared according to the formula JPEG2025120291000030.jpg29166 (wherein each R independently represents a carboxylic acid or salt thereof, an ethylenediamine, R is selected to form an ester or amide. 1 , R 2 , and R 3 Is that each independently hydrogen and optionally substituted alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl) or a derivative thereof containing a chelated metal, or a radical of the foregoing.

[0056] In another exemplary embodiment, the conjugate, composition, or any other embodiment described herein may be used. The unit dose, method, use, or kit may comprise 1,4,7,10-tetraazacyclododeca thiadione-1,4,7,10-tetraacetic acid (DOTA) or its derivatives containing chelated metals or containing the aforementioned radicals.

[0057] In another exemplary embodiment, the conjugate, composition, or any other embodiment described herein may be used. The unit dose, method, use, or kit may be prepared according to the formula JPEG2025120291000031.jpg30166 (wherein each R independently represents a carboxylic acid or salt thereof, an ethylenediamine, R is selected to form an ester or amide. 1 , R 2 , and R 3 Is that each independently hydrogen and optionally substituted alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl) or derivatives thereof containing chelated metals, or the aforementioned radicals, e.g., And JPEG2025120291000032.jpg29166 compound (wherein JPEG2025120291000033.jpg177166), or its carboxylate or carboxamide derivatives (CONH2), or any of the foregoing radicals, or derivatives thereof containing a chelated metal.

[0058] In another exemplary embodiment, the conjugate, composition, or any other embodiment described herein may be used. The unit dose, method, use, or kit may be prepared according to the formula JPEG2025120291000034.jpg27166 (wherein R 4 and R 5 is a group consisting of hydrogen and optionally substituted alkyl, cyclo heteroalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkoxy or a derivative thereof containing a chelated metal, or the aforementioned radicals For example, the illustrative compound JPEG2025120291000035.jpg47166), or its carboxylate or carboxamide derivatives (CONH2), or any of the foregoing radicals, or derivatives thereof containing chelated metals.

[0059] In another exemplary embodiment, the conjugate, composition, or any other embodiment described herein may be used. The unit dose, method, use, or kit may be prepared according to the formula JPEG2025120291000036.jpg25166 compound (wherein JPEG2025120291000037.jpg47166JPEG2025120291000038.jpg231166JPEG2025120291000039.jpg153166), or its carboxylate or carboxamide derivatives (CONH2), or any of the foregoing radicals, or derivatives thereof containing a chelated metal.

[0060] In another exemplary embodiment, the conjugate, composition, or any other embodiment described herein may be used. The unit dose, method, use, or kit may be prepared according to the formula JPEG2025120291000040.jpg120166, where n is an integer selected from 1, 2, 3, 4, 5, or 6. compound, or its carboxylate or carboxamide derivative (CONH2), or includes any of the foregoing radicals, or derivatives thereof containing a chelated metal.

[0061] As used herein, the term "radical" refers to a radical that is generally a hydrogen atom or a carboxylic acid. refers to a compound or chemical fragment with an open valence resulting after removal of a hydroxyl group. For example, radicals JPEG2025120291000041.jpg41166(In the formula, each ( * ) atoms are available for attachment to the linker and / or targeting drug. The valence of the bond can be formed from L-NETA.

[0062] The aforementioned compounds and their radicals can be combined with linkers and / or targeting groups. Further functionalization to attach reactive groups for subsequent attachment of the ng group It is to be understood that the reactive intermediates are also useful. JPEG2025120291000042.jpg26166 is described. In the formula, n is 0 or 1, and NX is For example, JPEG2025120291000043.jpg21166.

[0063] compound JPEG2025120291000044.jpg128166 (wherein n is 1 or 3) and its metal chelate compounds are used in the conjugates of the present invention. Please understand that this is not the case.

[0064] The compounds described herein may contain one or more chiral centers, It may also exist as multiple stereoisomers. It is understood that the present invention is not limited to any particular stereochemical requirement and that these compounds and The compositions, methods, uses, and medicaments containing them may optionally be pure, Also, racemic mixtures and other mixtures of enantiomers, other mixtures of diastereomers, etc. It is to be understood that the compound may be any of a variety of stereoisomeric mixtures, including: Such mixtures of isomers may have a single stereochemical configuration at one or more chiral centers. , still containing a mixture of stereochemical configurations at one or more other chiral centers It should also be understood that the term "input" can be included in the following:

[0065] Similarly, the compounds described herein may be substituted with other compounds, such as cis, trans, E, and Z double bonds. In another embodiment, the invention described herein comprises: The present invention is not limited to the requirement of a particular geometric isomer, and these compounds, compositions, and methods The compounds, methods of use, and medicaments containing them may be pure or may contain various geometric isomers. It is understood that the isomers may be any of a mixture of geometric isomers. indicates a single configuration at one or more double bonds and one or more other double bonds. It is also understood that a mixture of geometries may be included at the bond. sea bream.

[0066] As used herein, the term "alkyl" refers to an optionally branched chain of carbon atoms. As used herein, the terms "alkenyl" and "alkynyl" are used interchangeably. each containing a branched chain of carbon atoms and each containing at least one double bond or contains a triple bond. Alkynyl can also contain one or more double bonds. It should be understood that in some embodiments, alkyl is advantageously C1-C 24 , C1~ C 12 , C1-C8, C1-C6, and C1-C4 are of limited length, including It should be further understood that, for example, C1-C8, C1-C6, and C1-C4 Such alkyl groups of particularly limited length, including: In some embodiments, alkenyl and / or alkynyl are each advantageously C C 24 , C2~C 12 , limited to C2-C8, C2-C6, and C2-C4 It should be further understood that the length of the conductor can be any length. Such specifically limited length alkenyls include C2 to C6, and C2 to C4, and and / or alkynyl groups may be referred to as lower alkenyl and / or alkynyl. The shorter the alkyl, alkenyl, and / or alkynyl group, the smaller the aliphatic parent of the compound. can result in different pharmacokinetic behaviors. In the embodiments of the invention described herein, The details of alkyl include alkyl as defined herein, and optionally It is understood that this refers to lower alkyl. In each case, the recitation of alkenyl refers to alkenyl as defined herein. and in some cases lower alkenyl. In an embodiment of the present invention, the reference to alkynyl in each case is It is understood to refer to alkynyl as defined herein, and optionally lower alkynyl. Illustrative examples of alkyl, alkenyl, and / or alkynyl groups include, but are not limited to: However, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, se c-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl , hexyl, heptyl, octyl, etc., and one or more double and / or triple corresponding groups containing double bonds, or combinations thereof.

[0067] As used herein, the term "alkylene" refers to an optionally branched di- and di-membered alkylene group of carbon atoms. As used herein, the terms "alkenylene" and "alkynylene" include , optionally branched divalent chains of carbon atoms, each containing at least one divalent Contains a double or triple bond. Alkynylene also contains one or more double bonds. It is to be understood that in some embodiments, alkylene can be advantageously C1- C 24 , C1~C 12, limited to C1-C8, C1-C6, and C1-C4 It should be further understood that the lengths are as follows. and C1-C4, including alkylene groups of such particularly limited length, are referred to as lower alkylene groups. In some embodiments, alkenylene and / or alkynylene are C2 to C are advantageous, respectively. 24 , C2~C 12 , C2~C8, C2~C6, and C2~ It should further be understood that the length may be limited to C4. Such specifically limited groups include C2 to C8, C2 to C6, and C2 to C4. The alkenylene and / or alkynylene groups of length may be lower alkenylene and / or alkenylene. Alkylene, alkenylene, and / or alkynylene can be used. A shorter amino group can give the compound less lipophilicity and therefore different drug It is understood herein that the invention described herein will have the same pharmacokinetic behavior. In certain embodiments, alkylene, alkenylene, and alkynylene are used in each case. References to ylene include alkylene, alkenylene, and alkynylene as defined herein. quinylene, and optionally lower alkylene, alkenylene, and alkynylene; Illustrative examples of alkyl groups include, but are not limited to, methylene, ethylene, and the like. ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene pentylene, 1,2-pentylene, 1,3-pentylene, hexylene, heptylene , octylene, etc.

[0068] As used herein, the term "linker" refers to a group of molecules that connect two or more functional moieties of a molecule. It includes a chain of atoms that forms a bond. Illustratively, the chain of atoms may be C, N, O, S, Si, and and P, or C, N, O, and S, and P, or C, N, O, and S. The chain of atoms provides various functional capabilities for the conjugate, such as targeting agents, drugs, diagnostic agents, and imaging agents. The linker is covalently bonded to the The linker can have a wide variety of lengths ranging from 100 to 100. The alkylenes may be bonded in any chemically appropriate manner, for example, alkylene, alkenylene, and alkylene. A chain of carbon atoms forming an olefin group, etc., and also forming an ether, polyoxyalkylene group or when bonded to a carbonyl group, forming esters and carbonates etc. A chain of carbon and oxygen atoms, also consisting of amines, imines, polyamines, hydrazines, and hydrazones. When they form or bond to a carbonyl group, they form amides, ureas, semicarbazides, carbazides, and A chain of carbon and nitrogen atoms forming a phosphate, etc., and also alkoxyamines, alkoxylamines, etc. When they form amines or when they bond to carbonyl groups, they form urethanes, amino acids, acyloxy groups, etc. A chain of carbon, nitrogen, and oxygen atoms forming silylamines, hydroxamic acids, etc., and many other In addition, in each of the exemplary embodiments described above, Thus, for example, alkanes, alkenes, alkynes, imines, etc. The linker may be a single bond, double bond, or triple bond, such as a radical contained in It is understood that the atoms forming the double bond may be saturated or unsaturated. In addition, the atoms forming the linker may also be cycloalkanes, cyclic ethers, cyclic amines, and other heterocyclic arylenes, heteroarylenes, etc. They may open together to form bivalent ring structures forming linked linkers, or they may be cyclic. It is understood that in this latter arrangement the length of the linker can be defined by any path through the ring structure or structures. It should be understood that, for example, the length of the linker is the shortest length that can penetrate each of the cyclic structures. The linker is optionally a linker that connects the free valences along the chain of atoms. At any one or more of these, for example, a carbon, nitrogen, silicon, or phosphorus atom It is understood that the linker can be substituted with any of the above optional substituents. Attaching two or more functional moieties of a molecule to form a conjugate at any available valence The two or more functional moieties of the molecule forming the conjugate can be connected to each other, and the ... It should also be understood that it need not be attached to the apparent edge.

[0069] As used herein, the term "cycloalkyl" refers to a group in which at least a portion of the chain is cyclic. In some cases, it includes a branched chain of carbon atoms. It is understood that cycloalkyl is a subset of cycloalkyl. Cycloalkyl can also be polycyclic. It should be understood that examples of cycloalkyl include, but are not limited to, cyclopropyl. , cyclopentyl, cyclohexyl, 2-methylcyclopropyl, cyclopentylethene -2-yl (cyclopentyleth-2-yl), adamantyl, etc. As used herein, the term "cycloalkenyl" refers to a group in which at least a portion of the chain is cyclic. , containing at least one double bond, optionally containing a branched chain of carbon atoms. Alternatively, the double bonds may be bonded to the cyclic portion of the cycloalkenyl and / or the cycloalkenyl. It is understood that cycloalkenyl alkyl groups may be present in the non-cyclic portion of the alkyl group. Cycloalkyl and cycloalkylalkenyl are each a subset of cycloalkenyl. It is understood that cycloalkyl can also be polycyclic. Illustrative examples of chloroalkenyl include, but are not limited to, cyclopentenyl, cyclohexyl, Examples of cycloalkyl and cycloalkyl-2-ethenyl include cycloheptenyl and cycloheptenylpropenyl. and / or the chain forming the cycloalkenyl is advantageously C3-C 24 , C3~C 12 , Limited lengths including C3-C8, C3-C6, and C5-C6 It should be further understood that the groups forming cycloalkyl and / or cycloalkenyl, respectively, The shorter the alkyl and / or alkenyl chains, the less lipophilic the compound. It is understood herein that these compounds may have different pharmacokinetic behaviors. You can see it in this example.

[0070] As used herein, the term "heteroalkyl" refers to a group consisting of carbon and at least one heteroatom. Examples of heteroatoms include nitrogen, oxygen, and sulfur. In some variations, examples of heteroatoms include phosphorus and selenide. As used herein, heterocyclyl and heterocycles are included. The term "cycloheteroalkyl" refers to a group containing both carbon and at least one heteroatom. A chain of atoms including, for example, heteroalkyl, optionally branched, Some are cyclic. Examples of heteroatoms include nitrogen, oxygen, and sulfur. In some variations, illustrative heteroatoms also include phosphorus and selenium. Illustrative examples of heteroalkyl include, but are not limited to, tetrahydrofuryl, pyrrolidinyl, and the like. tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl Examples include quinuclidinyl and quinuclidinyl.

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

[0072] As used herein, the term "optionally substituted" refers to a radical that is optionally substituted. This includes replacing hydrogen atoms on the alkyl with other functional groups. These include, but are not limited to, amino, hydroxyl, halo, thiol, alkyl, haloal alkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, hetero Aryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfone Examples include acids and their derivatives, carboxylic acids and their derivatives, etc. No, hydroxyl, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, Either heteroaryl, heteroalkyl, and / or sulfonic acid are optionally substituted. It will be exchanged.

[0073] As used herein, the terms "optionally substituted aryl" and "optionally substituted "Substituted heteroaryl" refers to an optionally substituted aryl or heteroaryl. This includes replacing hydrogen atoms with other functional groups. Such other functional groups are also included herein. These are also referred to as aryl substituents, illustratively including but not limited to amino, hydrochloride, and hydroxyl groups. oxy, halo, thio, alkyl, haloalkyl, heteroalkyl, aryl, arylar alkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylene Heteroalkyl, nitro, sulfonic acid and its derivatives, carboxylic acid and its derivatives, etc. Examples include amino, hydroxy, thio, alkyl, haloalkyl, heteroaromatic alkyl, and the like. alkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, hetero Heteroarylalkyl, heteroarylheteroalkyl, and / or sulfonic acid Either one is optionally replaced.

[0074] Illustrative examples of substituents include, but are not limited to, the radical -(CH2) x Z x The following are mentioned: In the formula, x is an integer of 0 to 6, and Z x is halogen, hydroxy, C1-C6 alkyl alkanoyloxy including aryloxy, optionally substituted aryloxy, C Alkyl including C6 alkyl, alkoxy including C1-C6 alkoxy, C3-C8 cyclo cycloalkyl including cycloalkyl, cycloalkoxy including C3-C8 cycloalkoxy , alkenyl including C2-C6 alkenyl, alkynyl including C2-C6 alkynyl, C Haloalkyl including 1-C6 haloalkyl, haloalkoxy including C1-C6 haloalkoxy oxy, halocycloalkyl including C3-C8 halocycloalkyl, C3-C8 halocyclo Halocycloalkoxy including alkoxy, amino, C1-C6 alkylamino, (C1- C6 alkyl)(C1-C6 alkyl)amino, alkylcarbonylamino, N-(C1 ~C6 alkyl) alkylcarbonylamino, aminoalkyl, C1~C6 alkylamino Noalkyl, (C1-C6 alkyl) (C1-C6 alkyl) aminoalkyl, alkyl Carbonylaminoalkyl, N-(C1-C6 alkyl) alkylcarbonylaminoalkenyl Choose from Kill, Cyano, and Nitro, or Z x -CO2R 4 and -C ONR 5 R 6 (where R 4 , R 5 , and R 6 are respectively in each case each independently represents hydrogen, C1-C6 alkyl, aryl-C1-C6 alkyl, and hetero- C1-C6 alkyl).

[0075] The recitation of integer ranges for any variable in any instance disclosed herein for the cited range, all individual members of the range, and the variable It should be understood that all possible subranges are expressed. For example, if n is an integer between 0 and 8, The statement "0, 1, 2, 3, 4, 5, 6, 7, and 8" refers to the range and the individual values 0, 1, 2, 3, 4, 5, 6, 7, and 8. and represents selectable values, e.g., n is 0, or n is 1, or n is 2, etc. In addition, the statement that n is an integer from 0 to 8 also applies to each and every part expresses a range of values, each of which may be used as a basis for further embodiments, e.g., n may range from 1 to Up to 8, 1 to 7, 1 to 6, 2 to 8, 2 to 7, 1 to It can be an integer up to 3, from 2 to 4, etc.

[0076] As used herein, the term "composition" generally refers to a mixture of specified ingredients in specified amounts. Any product containing the specified ingredients, whether directly or indirectly, from a combination of the specified ingredients in the specified amounts. The compositions described herein refer to products obtained indirectly from the isolated compounds described herein. from the compounds described herein or from salts, solutions, hydrates, solvates, and the like of the compounds described herein. It is understood that some functional groups, e.g., hydroxy groups, can be prepared from the above and other forms. The hydroxy, amino, and similar groups allow the compounds to be easily dissolved in water and / or various solvents. It is known that the compounds form complexes and / or coordination compounds of various physical forms. These compositions include various amorphous and non-amorphous forms of the compounds described herein. that the compound may be prepared from a crystalline, partially crystalline, crystalline, and / or morphological form. It is understood that these compositions may also include various hydrates and hydrates of the compounds described herein. It is to be understood that the compounds may be prepared from the solvates and / or solvates. Such pharmaceutical compositions of the compounds described herein include various of the compounds described herein. and / or in the form of a hydrate or solvate, or any It is understood that combinations are included.

[0077] Illustratively, the composition may comprise one or more carriers, fillers, and / or pharmaceutical agents. The compounds described herein or compositions containing them may contain additives. , any conventional agent suitable for the methods described herein, in a diagnostically or therapeutically effective amount. Such formulations include those of the compounds or Compositions containing them can be prepared by a wide variety of conventional routes for the methods described herein. and can be administered in a wide variety of dosage forms using known procedures (generally, Re minton:The Science and Practice of Phar Macy (21st ed., 2005).

[0078] As used herein, the term "diagnostically effective amount" refers to an amount that is effective to treat the symptoms of the disease or disorder being treated. Researchers, veterinarians, physicians, or other professionals, including those diagnosing and / or monitoring the condition, are sought. activity that elicits a biological or drug response in the tissue system, animal, or human being in which it is administered; Refers to the amount of a compound or pharmaceutical agent that is administered to an illustrative host animal and is diagnostically effective in the conjugate. Suitable amounts include about 1 pg / kg to about 10 mg / kg, 1 ng / kg to about 10 mg / kg, and about 10 μg / kg to about 1 mg / kg, or about 100 μg / kg to about 500 μg / kg Examples include:

[0079] As used herein, the term "therapeutically effective amount" refers to an amount effective to treat the symptoms of the disease or disorder being treated. tissue systems, animals, and tissues required by researchers, veterinarians, physicians, or other professionals, including the alleviation of symptoms. or the amount of an active compound or pharmaceutical agent that elicits a biological or drug response in humans. In one aspect, a therapeutically effective amount refers to a reasonable benefit / risk ratio applicable to any treatment. The ratio is an amount that can treat or alleviate a disease or a symptom of a disease. The total daily dosage of the compounds and compositions described herein should be determined based on sound medical judgment. It is understood that the range of possible treatment options available to the attending physician is within the scope of the discretion of the attending physician. The effective dosage level for a particular treatment will depend on the disorder being treated and the severity of the disorder. the activity of the particular compound used and the age of the patient; Body weight, general health, sex, and diet and the time of administration of that particular compound used The route of administration and excretion rate, the duration of treatment, and the specific compound and combination used will determine the efficacy and safety of the compound. Various factors, including drugs used in combination or simultaneously, and researchers, veterinarians, , physician, or other person of ordinary skill in the art. An exemplary therapeutically effective amount of the conjugate administered to a host animal would be about 1 pg / mL. kg to approximately 10 mg / kg, 1 ng / kg to approximately 10 mg / kg, or approximately 10 μg / kg Examples of the dose include about 1 mg / kg, or about 100 μg / kg to about 500 μg / kg.

[0080] As used herein, the term "administration" refers to the administration of the compounds and compositions described herein to a subject. Any means of introduction into the host animal, including but not limited to oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, oral, ocular, sublingual, vaginal, rectal, etc. The compounds and compositions described herein are generally non-toxic, pharmaceutically acceptable, and and / or It can be administered in the form of a formulation.

[0081] As used herein, the term "amino acid" refers generally to beta, gamma, and more Long chain amino acids, e.g., -N(R)-(CR'R") q -C(O)- where R is hydrogen, alkyl, acyl, or a suitable nitrogen protecting group. and R' and R" are each independently selected hydrogen or a substituent in each instance. and q is an integer such as 1, 2, 3, 4, or 5. Illustratively, R' and / or R" may independently be selected from the group consisting of, but not limited to, methyl, benzyl, hydroxymethyl, Thiomethyl, carboxyl, carboxymethyl, guanidinopropyl, etc., and the like and protected derivatives thereof. The above formula includes all stereoisomeric variants. For example, the amino acid , alanine, aspartic acid, asparagine, cysteine, glutamic acid, phenylalanine Nine, histidine, isoleucine, lysine, leucine, methionine, proline, glutamine arginine, serine, threonine, valine, tryptophan, tyrosine, and ol Nitin etc. can be selected.

[0082] The recitation of integer ranges for any variable in any instance disclosed herein for the cited range, all individual members in that range, and the variable For example, if n is an integer between 0 and 8, then The statement "there is" includes the range and the individual values 0, 1, 2, 3, 4, 5, 6, 7, and 8. represents various and selectable values, e.g., n is 0, or n is 1, or n is 2, etc. In addition, the statement that n is an integer from 0 to 8 also applies to each and every part. expresses a partial range, each of which may be used as a basis for further embodiments, e.g., n is 1 to From 1 to 8, from 1 to 7, from 1 to 6, from 2 to 8, from 2 to 7, from 1 to It can be an integer from 0 to 3, from 2 to 4, etc.

[0083] In another embodiment, the linkers described herein are polyethers, e.g., JPEG2025120291000045.jpg53166, wherein m is an integer independently selected in each instance from 1 to about 8. wherein p is an integer independently selected from 1 to about 10, and n, in each instance, is 1 to about 10. In one embodiment, m is an integer independently selected from about 3. In one embodiment, m is independently selected in each instance from 1 to In another embodiment, n is 1 in each instance. In another embodiment, p is about 3 in each instance. In each case, the ratio is independently about 4 to about 6. For example, the corresponding Polypropylene polyethers are shown and can be included in the conjugate as linkers. In addition, a mixture of polyethylene polyether and polypropylene polyether can be used. It is understood that the compound may also be included in the conjugate as a linker. In the present study, cyclic variants of the aforementioned polyether compounds, such as tetrahydrofuranyl, 1,3-diphenyl ether, Those including oxane, 1,4-dioxane, etc. are shown.

[0084] In another embodiment, the linkers described herein are monosaccharides, oligosaccharides, polysaccharides, etc. The polyhydroxyl The containing linker comprises a plurality of -(CROH)- groups, where R is hydrogen or alkyl. It should be understood that this includes:

[0085] In another embodiment, the linker is a diradical JPEG2025120291000046.jpg85166, where R is H, alkyl, cycloalkyl, or aryl. m is an integer from 1 to about 3, and n1 is an integer from 1 to about 5, or n1 is an integer of 2 to about 5, p is an integer of 1 to about 5, and r is an integer selected from 1 to about 3. In one embodiment, the integer n is 3 or 4. In another embodiment, the integer p is 3 or 4. In another embodiment, the integer r is 1.

[0086] In another embodiment, the linker is a diradical JPEG2025120291000047.jpg27166, where R is H, alkyl, cycloalkyl, or aryl. m is an integer of 1 to about 3, and n is an integer of 1 to about 5 or 2 to about 5. where p is an integer from 1 to about 5, and r is an integer selected from 1 to about 3. In another embodiment, the integer n is 3 or 4. In another embodiment, the integer p is 3 or 4. where the integer r is 1.

[0087] In another embodiment, the linker is a cyclic polyhydroxyl group. JPEG2025120291000048.jpg188166, wherein n is an integer of 2 to about 5, and p is an integer of 1 to about 5. and each r is an integer independently selected from 1 to about 4. In one embodiment, the integer n is 3 or 4. In another embodiment, integer p is 3 or 4. In another embodiment, each integer r is independently 2 or 3. All stereochemical forms of such portions of the linker are included herein. It is understood that the moiety is described in the text. For example, in the formula above, this moiety is ribose, It can be derived from xylose, glucose, mannose, galactose, or other sugars. The stereochemistry of the pendant hydroxyl and alkyl groups present on these molecules can be In addition, various deoxy compounds are also described in the above formula. It should be understood that, as an illustration, JPEG2025120291000049.jpg37166, where n is equal to or less than r, for example, when r is 2 or 3, n is 1 or 2, or 1, 2, or 3, respectively.

[0088] In another embodiment, the linker has the formula JPEG2025120291000050.jpg23166, wherein n and r are each selected from 1 to about 3. In one aspect, the linker has the formula JPEG2025120291000051.jpg18166. It is to be understood that all stereochemical forms of the moieties are described herein. For example, In the formula above, this part can be ribose, xylose, glucose, mannose, galactose The pendant hydrochlorides present on these molecules can be derived from sugars or other sugars. The stereochemical configuration of the xyl and alkyl groups is maintained.

[0089] In another configuration, the linker L described herein may be a poly(N-N-methyl ... In one embodiment, such carbohydrate or polyhydroxyl groups is attached to the backbone by a triazole group to form a triazole-linked linker. Such linkers have the formula JPEG2025120291000052.jpg49166 diradical, where n, m, and r are integers and each independently represent a In one exemplary embodiment, m is independently selected in each instance from 1 to about 5. In another embodiment, r is 1 in each instance. and n is 1 in each instance. In one variation, the polyhydroxyl group is attached to the backbone of the linker. The groups to be attached to include, but are not limited to, pyrrole, pyrazole, 1,2,4-triazole, azole, furan, oxazole, isoxazole, thienyl, thiazole, isothiazole and various heteroaryl groups, including aryl, oxadiazole, etc. Similarly, divalent hexavalent Also depicted are four-membered heteroaryl groups. Another variation of the foregoing exemplary linkers is JPEG2025120291000053.jpg59166, where n and r are integers and in each instance each independently selected from 1 to about 5, and p is an integer selected from 1 to about 4.

[0090] In another embodiment, such carbohydrate or polyhydroxyl groups are linked by amide groups. to the backbone to form an amide bond linker. Illustratively, such a linker has the formula JPEG2025120291000054.jpg37166 diradical, wherein each n is an independently selected integer from 1 to about 3, and m is independently In one exemplary embodiment, each n is independently 1. or 2. In another exemplary embodiment, m is selected from about 6 to about 10, illustratively 8. In one variation, the group attaching the polyhydroxyl group to the backbone of the linker is including but not limited to esters, ureas, carbamates, acylhydrazones, etc. Various functional groups are shown. Cyclic variants are also shown. Other variants of the aforementioned exemplary linkers The form is the formula JPEG2025120291000055.jpg44166, wherein n is independently selected in each instance from 1 to about 5. where p is an integer selected from 1 to about 4.

[0091] In another embodiment, the linker is a diradical JPEG2025120291000056.jpg140166JPEG2025120291000057.jpg94166 wherein R is H, alkyl, cycloalkyl, or is arylalkyl, each m is independently an integer selected from 1 to about 3, and each n is are integers independently selected from 1 to about 6, p is an integer from 1 to about 5, and r is an integer from 1 to about 3 In one variation, each n is independently 3 or 4. In a variation, the integer p is 3 or 4. In another variation, the integer r is 1.

[0092] In another embodiment, the linker is a diradical JPEG2025120291000058.jpg39166, where R is H, alkyl, cycloalkyl, or is arylalkyl, each m is an integer independently selected from 1 to about 3, and each n is p is an integer independently selected from 2 to about 6, p is an integer from 1 to about 5, and r is an integer from 1 to about 3. In one variation, each n is independently 3 or 4. In a variation, the integer p is 3 or 4. In another variation, the integer r is 1.

[0093] In another embodiment, the linker is a diradical JPEG2025120291000059.jpg128166, wherein each m is an integer independently selected from 1 to about 3. each n is an integer independently selected from 1 to about 6; and p is an integer from 1 to about 5. and r is an integer selected from 1 to about 3. In one variation, each n is independently 3 or In another variation, the integer p is 3 or 4. In another variation, the integer r is 1 is.

[0094] In another embodiment, the linker is a diradical JPEG2025120291000060.jpg42166 wherein each m is an integer independently selected from 1 to about 3. each n is an integer independently selected from 2 to about 6, and p is an integer from 1 to about 5. and r is an integer selected from 1 to about 3. In one variation, each n is independently 3 or In another variation, the integer p is 3 or 4. In another variation, the integer r is 1 is.

[0095] In another embodiment, the linker is a diradical JPEG2025120291000061.jpg136166, wherein each m is an integer independently selected from 1 to about 3. where p is an integer from 1 to about 5, and r is an integer selected from 1 to about 3. In one variation, the integer p is 3 or 4. In another variation, the integer r is 1.

[0096] In another embodiment, the linker has the formula exemplified by JPEG2025120291000062.jpg26166, where n in each instance is an integer independently selected from 0 to about 3. The above formula is a combination of the skeleton and branched side chain designs shown in the figure. , and even larger cyclic sugars. In addition, the above formula , modified to represent a deoxy sugar (one or more of the hydroxy groups present in the formula It is understood that some may be replaced by hydrogen, alkyl, or amino. In addition, the corresponding carbonyl compounds (one or more of the hydroxy groups) The above formula also describes the carbonyls (or carbonyls in which one or more carbonyls are oxidized to the corresponding carbonyls). Additionally, in this exemplary embodiment, the pyranose may be a carboxyl group. It contains both aryl and amino functional groups, which can be inserted into the backbone (a) and (b) variations of this embodiment can provide synthetic access to branched side chains. Any of these pendant hydroxyl groups can be used to attach other chemical groups, including additional sugars. The corresponding oligosaccharides can be prepared by attaching pyranose or other sugars. into the skeleton at only one carbon, i.e., spiro at a geminal pair of carbons. Other variations of this embodiment are also shown, including arrangements and similar arrangements. One or two ends of the anchor, or reagent P, or ligand B, are inserted into the backbone. The sugars can be 1,1, or 1,2, or 1,3, or 1,4, or 2,3, or other The bonds can be formed in the following arrangement:

[0097] In another embodiment, the linker has the formula JPEG2025120291000063.jpg136166, wherein each n is independently in each instance is an integer selected from 1 to about 3. In one embodiment, each n is independently in each instance 1 or is 2. In another embodiment, the integer n is 1 in each instance.

[0098] In another embodiment, the linker is a sulfate ester, for example, an alkyl ester of sulfate. For example, the linker may have the formula JPEG2025120291000064.jpg110166, wherein each n in each instance is an integer independently selected from 1 to about 3. Illustratively, each n is independently 1 or 2 in each instance.

[0099] In such polyhydroxyl, polyamino, carboxylic acid, sulfuric acid, etc., hetero Those linkers that contain free hydrogen atoms may be linked to one or more of those free hydrogen atoms. or more than one, each protected with an appropriate hydroxyl-protecting group, amino-protecting group, or acid-protecting group. or alternatively, can be protected as the corresponding prodrug. It should be understood that the latter may be used for specific applications, e.g., general or specific physiological conditions. The prodrugs are selected to release the parent drug.

[0100] The stereochemical configurations shown herein in each of the foregoing examples are merely illustrative. It should be understood that other stereochemical configurations are also envisioned. For example, in one variation: JPEG2025120291000065.jpg64166 (wherein, as above, each n is an integer independently selected from 2 to about 5, and p is an integer from 1 to about 5). and r is an integer from 1 to about 4. The configurations may also be included in the conjugates described herein.

[0101] In the above embodiment ( * Vacant positions such as atoms marked with ) are used for target drug B or reagent B. It is further understood that (P) is a site for attachment. In addition to this, B and Such attachment of either or both of A's may be direct or via an intervening linker. It should be understood that additional examples of linkers are described in U.S. Pat. No. 7,601,332. and US Pat. No. 6,229,999, the disclosure of which is incorporated herein by reference.

[0102] Illustrative examples of divalent radicals that form part of a linker. JPEG2025120291000066.jpg79166JPEG2025120291000067.jpg210166

[0103] The bivalent linker may be connected in any chemically relevant manner, either directly or through an intervening heteroatom. and linking to construct the linkers described herein. stomach.

[0104] In another embodiment, the polyvalent linkers described herein are selected from the group consisting of carbonyl, thionocarbonyl, and the like. alkylene, cycloalkylene, alkylenecycloalkyl, alkylenecarbonyl Cycloalkylenecarbonyl, carbonylalkylcarbonyl, 1-alkylenecarbonyl succinimide-3-yl, 1 (carbonylalkyl) succinimide-3-yl, alkyl Sulfonyl alkyl, alkylene sulfoxyl alkyl, alkylene Sulfonylalkyl, carbonyltetrahydro-2H-pyranyl, carbonyltetrahydro 1-(carbonyltetrahydro-2H-pyranyl)succinimide-3-yl and 1-(carbonyltetrahydrofuranyl)succinimide-3-yl The linker comprises a linker selected from the group:

[0105] In another embodiment, the compounds described herein contain one or more amino acids. nothing.

[0106] The compounds described herein may be used in both human clinical medicine and veterinary applications. Thus, a host harboring a pathogenic cell population and receiving the compounds described herein may The animal may be a human, or in the case of veterinary applications, a laboratory animal, an agricultural animal, a domestic animal, or The present invention is directed to, but not limited to, humans and Rodents (e.g., mice, rats, hamsters, etc.), rabbits, monkeys, chimpanzees, etc. laboratory animals, domestic animals such as dogs, cats, and rabbits, and cattle, horses, pigs, sheep, and yaks. Farm animals such as geese, bears, pandas, lions, tigers, leopards, elephants, zebras, and giraffes. Responding to host animals, including captive wild animals such as gorillas, dolphins, and whales It can be used.

[0107] The compounds, compositions, methods and uses described herein can be used to treat a variety of pathologies in host animals. and to diagnose and treat diseases caused at least in part by pathogenic cell populations that may result in As used herein, the term "pathogenic cell" or "Pathogenic cell populations" include cancer cells, infectious agents such as bacteria and viruses, and bacteria or Virus-infected cells, inflammatory cells, and activated macrophages that can cause pathology and selectively expressing the targeting agent binding site described herein in a specific manner. The term "pathogenic cell" generally refers to any other type of pathogenic cell that expresses or overexpresses a pathogenic gene.

[0108] By way of example, pathogenic cell populations are cancer-causing cancer cell populations, including benign and malignant tumors. Cancer cell populations can occur naturally or can be non-tumorigenic. and mutations present in the germline of the host animal, or processes such as somatic mutations. It can be caused by a virus or it can be chemically, virally, or radiation-induced. The present invention is directed to the treatment of cancers including carcinomas, sarcomas, lymphomas, Hodgkin's disease, melanomas, mesothelioma, Diagnosing and monitoring such cancers, including Burkitt's lymphoma, nasopharyngeal carcinoma, leukemia, and myeloma These can be used to monitor and / or treat cancer cell populations. Cancers include, but are not limited to, oral cancer, thyroid cancer, endocrine cancer, skin cancer, stomach cancer, esophageal cancer, pharyngeal cancer, and pancreatic cancer Cancer, colon cancer, bladder cancer, bone cancer, ovarian cancer, cervical cancer, uterine cancer, breast cancer, testicular cancer, prostate cancer, rectal cancer Cancer, kidney cancer, liver cancer, and lung cancer.

[0109] For example, cancer cell populations may also be involved in diseases such as fibromyalgia, rheumatoid arthritis, osteoarthritis, and ulcerative colitis. , Crohn's disease, psoriasis, osteomyelitis, multiple sclerosis, atherosclerosis, pulmonary fibrosis, monkeys Coidosis, systemic sclerosis, transplant organ rejection (GVHD), lupus erythematosus, Sjogren's disease syndrome, glomerulonephritis, skin inflammation such as psoriasis, chronic inflammation, trauma such as head or spinal cord injury 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. The analogs / derivatives, linkers, and imaging and radiotherapeutic agents can be formed. The conjugates described herein can be used to generate biotin that is accessible for binding on pathogenic cells. Selective expression of receptors for targeted drugs such as agonists allows selection of pathogenic cell populations in the host animal. The vitamin molecule portion that can be used as a targeted drug (B) can be selectively targeted. Examples of minerals include carnitine, inositol, lipoic acid, pyridoxal, ascorbic acid, Niacin, pantothenic acid, folic acid, riboflavin, thiamine, biotin, vitamin B 12 and fat-soluble vitamins A, D, E, and K. These vitamins and The receptor-binding analogs and derivatives are linked to the imaging agent or radioactive agent by a bivalent linker (L). Illustrative targeting entities that can be bound to therapeutic agents are constructed and described herein. Form conjugates of targeted drugs (B) or radiotherapeutic drugs. The term vitamin is used unless otherwise indicated. Unless otherwise specified, it is understood to include vitamin analogs and / or derivatives. In addition, pteroic acid, a derivative of folic acid, biocytin, biotin sulfoxide, and oxybiopeptide are Biotin and biotin analogues such as other biotin receptor binding compounds are vitamins Vitamins described herein are considered to be vitamin analogs and vitamin derivatives. A vitamin analog or derivative is a compound in which the vitamin analog or derivative is covalently bonded to a divalent ribonucleotide. It should be understood that this refers to a vitamin that incorporates a heteroatom attached to an anchor (L).

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

[0112] In one embodiment, the targeting group B is folic acid, an analog of folic acid, or a derivative of folic acid. The term folate is used throughout this document to refer to folic acid itself and / or to the folate receptor. The terms "folic acid" and "folic acid derivatives" are used individually and collectively to refer to such analogs and derivatives of folic acid that can be bound to It should be understood that the term "internal" is used interchangeably.

[0113] Exemplary embodiments of vitamin analogs and / or derivatives include folic acid and folinic acid. Which folic acid analogues and derivatives and pteropolyglutamic acid (pteropolyglu) tamic acid), tetrahydropterin, dihydrofolic acid, tetrahydrofolic acid, etc. Which folate receptor-binding pteridines and their deaza and dideaza analogs are listed? The terms "deaza" and "dideaza" analogs refer to naturally occurring folic acid structures, or or its analogs, or derivatives thereof, in which one or two nitrogen atoms are replaced by carbon atoms Deaza analogs refer to analogs recognized in the art. For example, deaza analogs include the folic acid analog of folinic acid. of pteropolyglutamic acid, tetrahydropterin, dihydrofolic acid, tetrahydrofolic acid Folate receptor binding pteridines such as 1-deaza, 3-deaza, 5-deaza, and 8-deaza folate -deaza and 10-deaza analogs. Dideaza analogs include, for example, the , folinic acid, pteropolyglutamic acid, tetrahydropterin, dihydrofolic acid Folate receptor binding pteridines such as 1,5-dideaza, 5,10-tetrahydrofolate Included are the dideaza, 8,10-dideaza, and 5,8-dideaza analogs of the present invention. Other folates useful as ligand-forming conjugates include folate receptor binding analogs, such as benzophenone-1, benzophenone-2, and benzophenone-3. Minopterin, amethopterin (also known as methotrexate), and N 10 -methylfolate, 2-deamino-hydroxyfolate, and 1-deazamethopterin or 3- Deaza analogues such as deazamethopterin and 3',5'-dichloro-4-amino-4-de Oxy-N 10 -methylpteroylglutamic acid (dichloromethotrexate). The aforementioned folate analogs and / or derivatives are typically labeled with a folate receptor binding capacity reflecting their binding ability to the folate receptor. These ligands are called "folates" and when conjugated to exogenous molecules, e.g. The folic acid-mediated endocytosis described herein promotes transmembrane transport. It is effective for.

[0114] Additional folate analogs that bind to the folate receptor 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. The radical of the acid analog has the general formula I have JPEG2025120291000068.jpg21166. wherein X and Y are each independently halo, R 2 , OR 2 , S.R. 3 , and N.R. 4 R 5 is 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 ) represents 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 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 group wherein Z is oxygen or sulfur; R 1 are hydrogen, halo, C1-C 12 Alkyl, and C1-C 12 consisting of alkoxy selected from the group 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 is 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 or R 6 and R 7 is a lumpy carbo forming a methyl group, R 6a and R 7a are each independently hydrogen, halo, C1-C 12 a Lukil, and C1~C 12 alkoxy or R 6a and R 7 a come together to form a carbonyl group, L is one or more, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, It is an acid, and n, p, r, s, and t are each independently either 0 or 1.

[0115] As used herein, the term folate refers to the individual folic acids used in the formation of the conjugate, or both folic acid or its folic acid analogs or derivatives capable of binding to the folate receptor Please understand that this refers to the following.

[0116] In another embodiment, the targeting group is a PSMA ligand or inhibitor, e.g., a compound of the formula JPEG2025120291000069.jpg22166, a derivative of pentanedioic acid, wherein X is RP(O)(OH)CH2- (U.S. Pat. No. 5,529,493). 5,968,915), RP(O)(OH)N(R 1 )-(U.S. Patent No. 5,866 No. 3,536), RP(O)(OH)O- (US Pat. No. 5,795,877) RN(OH)C(O)Y- or RC(O)NH(OH)Y- (where Y is -C R1R2-, -NR3-, or -O-) (U.S. Pat. No. 5,962,521); RS(O)Y, RSO2Y or RS(O)(NH)Y (where Y is -CR1R2-, -NR3-, or -O-) (U.S. Pat. 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 linear or branched alkyl, C2-C9 linear or branched alkenyl, C3- It is selected from C8 cycloalkyl, C5-C7 cycloalkenyl, and aryl. In addition, in each case, each of R, R1, R2, and R3 may optionally be , for example, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, halo, hydroxy, Nitro, trifluoromethyl, C1-C6 straight or branched alkyl, C2-C6 straight or branched alkyl or branched alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy substituted with one or more groups selected from hydroxy, benzyloxy, amino, and aryl; In one embodiment, aryl may be 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridine phenyl, 3-pyridyl, 4-pyridyl, benzyl, and phenyl; In each case, aryl is optionally selected from halo, hydroxy, nitro, trifluoromethyl, , C1 to C6 linear or branched alkyl, C2 to C6 linear or branched alkenyl, C1 ~C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and substituted with one or more groups selected from amino, for example, 1 to 3 groups In one variation of each of the above formulas, R is not hydrogen.

[0118] Examples of PSMA ligands (U.S. Pat. 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-[ethylhydroxyphosphinyl]glutamic acid N-[propylhydroxyphosphinyl]glutamic acid, N-[butylhydroxyphosphinyl]glutamic acid, 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 diacid Examples include:

[0121] Examples of PSMA ligands (U.S. Pat. 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 diacid, 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]penta dioic acid, 2-[[(N-hydroxy-N-4-pyridyl)carbamoyl]methyl]pentanedioic acid, 2-[[(N-hydroxy)carboxamido]methyl]pentanedioic acid, 2-[[N-hydroxy(methyl)carboxamido]methyl]pentanedioic acid, 2-[[N-hydroxy(benzyl)carboxamido]methyl]pentanedioic acid, 2-[[N-hydroxy(phenyl)carboxamido]methyl]pentanedioic acid, 2-[[N-hydroxy(2-phenylethyl)carboxamido]methyl]pentanedioic acid , 2-[[N-hydroxy(ethyl)carboxamido]methyl]pentanedioic acid, 2-[[N-hydroxy(propyl)carboxamido]methyl]pentanedioic acid, 2-[[N-hydroxy(3-phenylpropyl)carboxamido]methyl]pentane acid, and 2-[[N-hydroxy(4-pyridyl)carboxamido]methyl]pentanedioic acid Examples include:

[0122] Examples of PSMA ligands (U.S. Pat. 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-[(sulfoximinyl)methyl]pentanedioic acid, 2-[(methylsulfoximinyl)methyl]pentanedioic acid, 2-[(ethylsulfoximinyl)methyl]pentanedioic acid, 2-[(propylsulfoximinyl)methyl]pentanedioic acid, 2-[(butylsulfoximinyl)methyl]pentanedioic acid, 2-[(phenylsulfoximinyl)methyl]pentanedioic acid, 2-[[(2-phenylethyl)sulfoximinyl]methyl]pentanedioic acid, 2-[[(3-phenylpropyl)sulfoximinyl]methyl]pentanedioic acid, 2-[[(4-pyridyl)sulfoximinyl]methyl]pentanedioic acid, and 2-[(benzylsulfoximinyl)methyl]pentanedioic acid Examples include:

[0123] Examples of PSMA ligands include: An example is JPEG2025120291000070.jpg73166.

[0124] In another embodiment, the PSMA ligand is a urea of two amino acids. These amino acids may contain one or more additional carboxylic acids. These amino acids may be supplemented with one or more additional phosphates, phosphonates, phosphinates, sulfonates, or sulfonates. In another embodiment, the amino acids include sulfonic acids, sulfonic acids, or boronic acids. In another embodiment, the thiol groups include one or more thiol groups or derivatives thereof. The amino acid may be one or more bioisosteres of a carboxylic acid, such as tetrazole. Including etc.

[0125] In another embodiment, the PSMA ligand is of the formula JPEG2025120291000071.jpg25166. 1 teeth, JPEG2025120291000072.jpg82166.

[0126] In another exemplary embodiment, the binder is an aminocarboxylic acid such as aspartic acid or glutamic acid. ureas of carboxylic acids with other aminodicarboxylic acids or their analogues, for example of the formula JPEG2025120291000073.jpg21166, where Q is an aminodicarboxylic acid such as aspartic acid or glutamic acid. or an analog thereof, wherein n and m are each independently selected from an integer between 1 and about 6. And also ( * ) marks the attachment points of the linker L.

[0127] Illustratively, the PSMA ligand has the formula This is the compound JPEG2025120291000074.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-dicarboxyl) The compound is dimethylaminopropyl (dimethylaminopropyl)-pentanedioic acid (DUPA).

[0129] Other examples of PSMA ligands include quisqualic acid, aspartic acid glutamic acid (Asp -Glu), Glu-Glu, Gly-Glu, γ-Glu-Glu, beta-N-acetic acid Peptide analogs such as β-L-aspartic acid-L-glutamic acid (β-NAAG) Examples include:

[0130] In another embodiment, the PSMA ligand comprises a lysine and one or more amino acids or This includes, but is not limited to, urea or thiourea with several types of carboxylic acid derivatives. However, lysine and aspartic acid or glutamic acid or homoglutamic acid are not urea or or thiourea.

[0131] In another embodiment, the PSMA ligand is a urea or thiamin derivative of L-lysine and L-glutamic acid. Contains urea.

[0132] In another embodiment, the PSMA ligand is JPEG2025120291000075.jpg62166.

[0133] In another embodiment, the PSMA ligand is Contains JPEG2025120291000076.jpg25166.

[0134] The compounds, linkers, intermediates, and conjugates described herein are incorporated by reference in their entirety. / 002993 Brochure, International Publication No. 2004 / 069159 Brochure, Country International Publication No. 2007 / 022494 and International Publication No. 2006 / 0125 No. 27, and U.S. Patent Application No. 13 / 837539 (2013 (The disclosures of each of the above are incorporated herein by reference in their entirety.) These compounds can be prepared using conventional methods, including those described in the US Pat. No. 6,49 ... the disclosure of which is incorporated by reference. Cut.

[0135] Each publication cited herein is hereby incorporated by reference.

[0136] In another embodiment, a method for diagnosing and / or monitoring a disease or condition is described. The method comprises administering to a patient being evaluated for a medical condition an effective amount of a conjugate of the general formula BLP. The method includes the step of allowing sufficient time for the conjugate to bind to the target tissue. and diagnosing a disease or condition outside the body, for example by positron emission tomography; and / or This includes monitoring.

[0137] The radionuclide contains a positron-emitting isotope with an appropriate half-time and toxicity profile. In various embodiments, the radioisotope is administered for more than 30 minutes, 7 More than 0 minutes, More than 80 minutes, More than 90 minutes, More than 100 minutes, Less than 8 hours, 6 In other embodiments, the radiation has a half-life of less than 1 hour, less than 4 hours, or less than 3 hours. Sex isotopes are from about 30 minutes to about 4 hours, from about 70 minutes to about 4 hours, from about 80 minutes to about 4 hours, and 90 minutes to 4 hours, 100 minutes to 4 hours, 30 minutes to 6 hours, 70 minutes to 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 approximately 8 hours, approximately 70 minutes to approximately 8 hours, approximately 80 minutes to approximately 8 hours, approximately 90 minutes to approximately 8 hours or has a half-life of about 100 minutes to about 8 hours.

[0138] Radionuclides include one or more positron-emitting isotopes, such as but not limited to: However, 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 Select from F In another embodiment, the radionuclide is a halide, e.g., In another embodiment, the radionuclide is a metal ion, e.g., a positron-emitting halide. In another embodiment, the radionuclide is a gallium ion, e.g., a positron-emitting metal ion. In another embodiment, the radionuclide is a positron-emitting gallium ion. 89 Zr, 64 Cu , 68 Ga, 66 Ga, 124 I, and 18 In another exemplary embodiment, is a radioactive isotope 89 Zr, 64 Cu, 68 Ga, 124 I, and 18 Selected from F In another embodiment, the radioisotope is 68 Ga or 89 Zr or 18 It's F. In another embodiment, in each of the above and below embodiments described herein, radioactive The isotopes are 68In another embodiment, the above and below embodiments described herein are In each state, the radioisotope 18 In another embodiment, the hydroxybenzoates are as described herein. In each of the above and below embodiments, the radioisotope is 89 Zr. Another In embodiments, in each of the above and below embodiments described herein, a radioisotope The body, 64 Cu. The fluorine isotopes mentioned herein are: 18 F and 19 Various F It is also understood that a combination of isotopes may be selected. The agent may be administered to a patient in a pharmaceutically acceptable carrier prior to administration. The half-life of the positron-emitting isotope is sufficient to allow for the preparation of a composition suitable for PET scanning. and a residual half-life sufficient to produce sufficient activity to allow in vitro measurement by It should be understood that the preferred isotope may be selected to avoid exposing the patient to unnecessary radiation. In an exemplary embodiment, 110 has a half-life of minutes 18 F is a reasonable time and acceptable amount of time for the preparation of the diagnostic composition. It gives the rate of deterioration. 18 F is 18 Convert to O.

[0139] Examples of positron-decaying isotopes with suitable half-lives include: 34 Cl (half-life approximately 32 minutes) , 45 Ti (half-life approximately 3 hours), 51 Mn (half-life approximately 45 minutes), 61 Cu (half-life is Approximately 3.4 hours) 63 Zn (half-life approximately 38 minutes), 82 Rb (half-life approximately 2 minutes),68 G a (half-life is approximately 68 minutes), 66 Ga (half-life approximately 9.5 hours), 11 C (half-life is about 20 minutes), 15 O (half-life approximately 2 minutes), 13 N (half-life approximately 10 minutes), or 18 F(half-life (The maximum length is approximately 110 minutes.)

[0140] In another embodiment, the radionuclide is a radiotherapeutic agent. Illustrative Radionuclides for Radiotherapy for, 177 Isotopes of lutetium, such as Lu, 90 Isotopes of yttrium, such as Y, 67 Cu and 64 Examples include copper isotopes such as Cu.

[0141] The radionuclide may be incorporated into the conjugate, e.g., benzamidyl, benzyl, phenyl, pyridinyl, Pyrimidinyl, pyridazinyl, naphthyl, benzothiazolyl, benzimizolyl, benzo Covalently attached to an aryl or heteroaryl aromatic group, including groups such as oxazolyl In one exemplary embodiment, the radioisotope 18 F, and this radioactive The nuclide comprises an aryl group to which a radioisotope is covalently attached. The radionuclide can also be non-covalently attached to the conjugate, for example, in a chelate.

[0142] These methods also involve the use of other diagnostic agents already in development, and X-ray contrast agents. Computed tomography (CT), magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMR) I), ultrasound imaging, and single-photon emission computed tomography (SPECT). and in combination with any other method of cancer diagnosis already developed and known in the art, including methods It 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 method, either substantially complete fluorination or only partial fluorination is desired. It is recognized that this may be desirable. The method can be implemented in a variety of alternative embodiments. In those embodiments where oxidation is desired, the methods and syntheses described herein are based on stoichiometry. It is understood that the present invention can be carried out using less than the amount of fluorinating agent. Some of the methods described, i.e., each of the processes and synthetic methods described herein, In the examples, substantially complete radiofluorination or It is recognized that there are cases where either partial or only partial radiofluorination is desirable. Therefore, the methods and synthetic methods described herein can be practiced in a variety of alternative embodiments. Therefore, in those embodiments where only partial radiofluorination is desired, the present invention The methods and syntheses described herein involve the use of less than stoichiometric amounts of radiofluorinating agent (the remainder is optional). By choice 19 It can be seen that this can be implemented using F.

[0144] The following examples further illustrate certain embodiments of the present invention; however, the following illustrative examples are by no means limiting. and should not be construed as limiting the invention. [Example]

[0145] General: Water was distilled and then filtered using a Milli-Q water filtration system (Millipore Co. Deionized (18 MΩ / cm) by passage through a 1000 kJ / cm filter (RPM, Milford, MA). 2 )death Unless otherwise specified, all chemicals and solvents were purchased from Sigma (St. Louis, MO). Amino acids were purchased from Chem-Impex I (O) and used without further purification. nt (Chicago, IL). 2,2'-(7-(2-((2,5-dithiothiazolinone) 2-oxopyrrolidin-1-yloxy-2-oxoethyl-1,4,7-triazonane -1,4-diyl)diacetic acid (NOTA-NHS) was purchased from CheMatech (France). N10-TFA-pteroic acid was purchased from Endocyte, Inc. High-performance liquid chromatography (HPLC) analysis and DUPA-NOTA The purification of the precursor was carried out on an Agilent G6130B instrument. Radio-HPLC was performed using X Select CSH C18 (250 × 10 mm) column and MeCN and and 0.1% formic acid in a γ-counter. JPEG2025120291000077.jpg101166

[0146] Example: C-NETA tert-Butyl[2-hydroxy-1-(4-nitrobenzyl)ethyl]carbamate The commercially available methyl 2-amino-3-(4-nitrophenyl)propanol (QC04011) was used. Prepared from panoate by NaBH4 reduction and Boc protection. Dess-Martin oxidation and reductive amination of tris-Boc protected compounds QC04013 was obtained after Boc deprotection in 4M HCl in dioxane. This was later converted to QC04014 by tert-butyl bromoacetate. Treatment, followed by hydrogenolysis of the NO2 group, gave QC04016. Further reaction with citric anhydride affords the difunctional ester as the corresponding tert-butyl ester. The potential C-NETA (QC04018) was obtained. JPEG2025120291000078.jpg24166

[0147] Example: Di-tert-butyl [1,4,7]triazanonane-1,4-dicarboxylate ( QC04001) QC04001 was prepared according to a modified procedure of previously reported synthetic procedures [19–21]. 1,4,7-Triazonan trihydrochloride (TACN) dissolved in CHCl3 (25 mL) 3HCl, 1.85g, 7.7mmol, MW: 238.6), A(4.0mL, 3.0g, 23.1mmol, MW:129.24, d:0.74 2) and BOC-ON (3.77 g, 15.3 mmol, MW: 246.26) The resulting mixture was stirred for 5 days and the solvent was evaporated in vacuo. The mixture was partitioned between 0% NaOH solution (10 mL) and diethyl ether (30 mL). The product 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 in vacuo to give QC04001 (2.5%). 3 g, quantitative), which was used without further purification. 1 H NMR (400MH 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 8(m,2H),2.86~2.99(m,4H),1.48(s,18H); 13 C NMR(101MHz,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 derived from 53.20 to 47.6), 28.60 ( t- Bu). JPEG2025120291000079.jpg19166

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

[19] 2-amino-3-(4-nitrophenyl)-2-( ... ) The HCl salt of methyl propanoate was used directly without neutralization with Et3N and heated at 23 °C to obtain M This 2-amino-3-(4-nitrophenyl)propanoic acid was dissolved in eOH (70 mL). To a solution of methyl methyl hydrochloride (6.22 g, 23.9 mmol), NaBH4 (2.86 g, 7 1.4 mmol) was added in portions. The reaction was monitored by TLC and LC-MS. The mixture is heated to reflux (in a water bath at approximately 70°C) until most of the starting material has disappeared. Add NaBH4 in small increments as needed (approximately 6 grams of NaBH4 required in total). After evaporation of the solvent, the residue was treated with HO (70 mL) and diluted with DCM / IPA (3 / 1). The combined organic layers were dried, filtered, and concentrated in vacuo to give a white solid, QC04 010 (4.4 g, 94) was obtained, which was used without further purification.

[0149] Example: QC04010 (4.4 g, 22.7 mmol) was dissolved in CH3CN (30 mL) and to it BOC-ON (11.2 g, 27.2 mmol, 1.2 equiv.) To the above mixture was added DIPEA (5.24 mL, 3.76 g, 29.2 m mol, MW: 129.24, d: 0.742) was added, and the resulting mixture was stirred for 4 hours. The residue was dissolved in ethyl ether (50 mL) and 10% NaOH solution (20 mL). The ether layer was separated and washed with 10% NaOH solution (10 mL) and water (10 mL). The ether layer was dried, filtered, and concentrated in vacuo. The residue was washed with ether (20 mL) to give QC04011 (5.31 g, 75%). This was used without further purification. To prepare an analytical sample, this residue was diluted with hexane / acetic acid. Column chromatography on SiO2 eluting with ethyl acetate (3 / 1 to 1 / 1 with 1% MeOH) Purification by chromatography gives pure QC04011 as a white solid. 1 HNM R(400MHz, CDCl3)δ=8.15(d, J=8.8MHz,2H),7.4 0(d,J=8.8MHz,2H),4.84(d,J=6.8MHz,1H),3.9 0(s,1H),3.68(dd,J=3.1MHz,1H),3.57(dd,J=3 .1MHz,1H),2.98(d,J=6.0MHz,2H),1.39(s,9H) ; 13 C NMR(101MHz,CDCl3)δ=156.0,146.4,146. 2,130.1,123.5,79.8,63.3,53.1,37.3,28.0. JPEG2025120291000080.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). and cooled to 0°C, to which was added Dess-Martin periodinane (1.70 g, 5.16 mmol). 1, 1.2 equiv.) was added in one portion. After stirring at 0° C. for 15 min, the reaction was warmed to 23° C. The reaction was stirred for 45 minutes. The reaction was diluted with basic NaSO and The mixture was quenched by the addition of aqueous NaHCO (50 / 50 v / v) and the resulting mixture was After extraction with CH2Cl2 (3x), the organic phase was diluted with water and brine. Successively washed with HCl, dried over Na2SO4, filtered and concentrated in vacuo to give QC04012 This was used without further purification. JPEG2025120291000081.jpg23166

[0151] Example: QC04013, i.e., 7-(2-{[(tert-butoxy)carbonyl] Amino}3-(4-nitrophenyl)propyl)-1,4,7-triazonane-1,4- QC0 for preparing 1,4-di-tert-butyl dicarboxylate (QC04013) Reductive amination of 4012 and QC04001 4 Compound QC04012 (theoretical 4.3 mmol) was dissolved in DCE (100 mL) at 0 °C. The resulting solution was added to a solution of QC04001 (1.40 g, 4.3 mmol). Stir for 10 minutes and add sodium triacetoxyborohydride (1.28 g, 6. The mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was concentrated, treated with saturated aqueous NaHCO3 (50 mL), and acetic acid The combined organic layers were dried over Na2SO4 and filtered. The residue was purified by flash chromatography (SiO2, Hex / EA=3 Purification by HPLC (HPLC: 1.001 μg / 1) gave QC04013 (2.31 g based on theoretical 2.61 g, The compound was obtained in two steps (88.5%) as a pale yellow semi-solid. 1 H NMR (400 MHz, CDCl3)δ=8.11(2H,d,J=7.6Hz),7.35(2H,d,J=7 .6Hz)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 C NMR (101M 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 NO([M+H] + ) Calculated value: 608.4, measured value: 608.3. JPEG2025120291000082.jpg20166

[0152] Example: 1-(4-nitrophenyl)-3-(1,4,7-triazonan-1-yl)propanol propan-2-amine QC04013 (2.31 g, 3.8 mmol) was dissolved in 30 mL of 4 M HCl / dioxane. The resulting mixture was stirred at room temperature for 20 hours. Addition of 0 resulted in the precipitation of a white solid, which was collected and dried in air to give the pure product Q. C04014 (1.71 g quantitative yield) was obtained as a pale white solid. MS m / z:MS-API:C 15 H 26 NO2([M+H] + ) calculated value: 308. 2. Actual measured value: 308.2. JPEG2025120291000083.jpg34166

[0153] Example: Introduction of ethyl tri-tert-butyl acetate 1b QC04014 (78 mg, 0.19 mmol) and D dissolved in DMF (2 mL) IPEA (0.272mL, 202mg, 1.56mmol, 8.2eq, MW:1 29.24, d: 0.742) solution, NaI (233.8 mg, 1.56 mmol, 8.2 equivalents, MW: 149.89) and tert-butyl bromoacetate (0.126 mL, 168mg, 0.86mmol, 4.5eq, MW:195.05,d:1. 321) was slowly added at room temperature. The resulting mixture was heated to 60-70°C and stirred for 20 hours. After completion, monitored by TLC and LC-MS, the reaction was quenched with water and The combined organic solvents were washed successively with water and brine, and the resulting solution was extracted with Et2O. After filtration, the solvent was evaporated under vacuum and the resulting dark oily residue was purified by Si Flash chromatography on O2 (DCM / MeOH = 100 / 1 to 100 / 4) Purification by HPLC gave QC04015 (14 mg, 10%) and QC040 as a yellow oil. 15' (61 mg, 49.4%) was obtained. MS m / z: MS-API: C 39 H 66 N5O 10 ([M+H] + ) Calculated value: 764.5, measured value: 764.4. JPEG2025120291000084.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 atmosphere (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 NO([M+H] + ) Calculated value: 734.5, measured value :734.4.

[0155] Examples directed at folic acid JPEG2025120291000085.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-pteroic acid (560mg, 1.3 A solution of 1.2 mL of PEG-400 (7 mmol) and DIPEA (1.2 mL, 6.85 mmol) was placed under N2 After stirring at 23°C for 15 minutes, PyBOP (720 mg, 1.0 mm ol) was added and the reaction mixture was stirred at 23° C. for 24 h. The volatiles were removed under reduced pressure to give a crude The product was obtained as a semi-solid, which was further purified three times with Hex / EA (1 / 1) to give a solid. Purification by extraction gave QC02023 as a pale yellow solid in quantitative yield. Used without further purification. max = 280 nm; LC-MS (Agilent G6 130B Quadrupole LC / MS):Mobile phase: Buffer (pH7)-CH3C N; Column: analytical C18 column; Method: 0-100 CH3CN-15 min, t R =5. 62 min. MS m / z: MS-API: C 26 H 29 F3N7O7([M+H] + ) Calculated value: 608.2, measured value: 608.1. JPEG2025120291000086.jpg28166

[0156] Example: (S)-4-(4-(N-((2-amino-4-oxo-3,4-dihydropteran-2-yl)-4-oxo-3,4-dihydropteran-2-yl) Lysin-6-yl)methyl)-2,2,2-trifluoroacetamido)benzamide) -5-Methoxy-5-oxopentanoic acid (QC02024) 224 mg of QC02023 was dissolved in TFA / DCM (15 mL, 1 / 3) at 23 °C. The reaction was stirred at 23° C. and monitored by TLC. After 1.5 h, the starting material The volatiles were removed under reduced pressure to give a semi-solid residue. This was treated with cold Et2O to give a pale white precipitate which was collected by filtration and Dry in air to obtain (S)-4-(4-(N-((2-amino-4-oxo-3,4-dihydrochloride). Dropteridin-6-yl)methyl)-2,2,2-trifluoroacetamido)benzo Amido)-5-methoxy-5-oxopentanoic acid (QC02024) (169 mg, 2 s 83% for the step. max = 280 nm; LC-MS (Agilent G6130B Quadrupole LC / MS): Mobile phase: Buffer (pH7)-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 value: 552.1, measured value: 552.1. 1 H NMR (400 MHz, DM SO)δ=12.16(s,br,1H),8.88(d,J=7.2Hz,1H),8 .65(s,1H),7.92(d,J=8.0Hz,2H),7.64(d,J=8. 0Hz,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 C NMR (101M Hz,DMSO)δ=173.91,172.36,165.93,161.03,15 6.11,155.76(d,J=35.8HZ),154.19,149.40,14 4.45,141.80,134.30,128.89,128.62,128.29, 117.91(d,J=48.5Hz),53.90,52.23,52.06,30. 26,25.81; 19 F NMR(377MHz, CDCl3)δ=62.87. JPEG2025120291000087.jpg42166

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

[0158] [Table 1]

[0159] Place Fmoc-Lys-resin (1.0 mg, 0.5 mmol) in a peptide synthesis vessel. The first Fmoc deprotection was performed with DMF (3 x 10 mL). The reaction was carried out for 10 minutes per cycle using a 20% piperidine solution dissolved in DMF ( After washing with i-PrOH (3 × 10 mL), the Kaiser test was performed. After another DMF wash (3 x 10 mL), DMF, PyBO P (2.0 equivalents), and a solution of amino acids (2.0 equivalents) in DIPEA (3.0 equivalents) (amount) was added to the vessel and the solution was bubbled with argon for 1 hour. The coupling solution was filtered. The resin was washed with DMF (3 × 10 mL) and i-PrOH (3 × 10 mL) and the reaction The Kaiser test was performed to determine the completion of the above process. The resin was cleaved in 95% CF3CO2H, 2.5% H2O, and 2.5% triisopropylsilane. 10 mL) was poured onto the resin and bubbled with argon for 30 minutes, followed by filtration into a clean flask. Two further cleavage reactions were performed in succession with fresh cleavage cocktails, each lasting 10 minutes. The combined filtrates were poured onto cold diethyl ether and the precipitate formed was stirred at 4000 rpm for 5 minutes. The precipitate was collected by decanting and centrifuging under vacuum. The crude precipitate was dried and the resulting product was deprotected by distilling the crude precipitate in HO (15%). This was achieved by dissolving this in Na2CO3 (mL) and bubbling it with argon. Upon completion of the reaction as confirmed by LCMS, 2M HCl was used to basify the reaction to pH 9. The solution was acidified to pH 3 using HCl and the desired linker was isolated by preparative HPLC (mobile phase A = 10 mM acetic acid). Ammonium chloride (pH = 5), organic phase B = acetonitrile, method: 10% B in 30 min Purification by 100% B) gave EC1777 (112 mg, 39%). 1 H NMR (500MHz, DMSO-d6) Main signal: δ 8.60 (s, 1H), 7.58 (d ,2H),6.60(d,2H),4.45(s,2H). [M+H] + = Calculated value 570 .23, actual value 570.582. JPEG2025120291000089.jpg41166

[0160] Example: Pte-γGlu-Lys-NOTA In a dry flask, EC1777 (30.5 mg, 0.054 mmol, 1.0 equiv.), 1,1,3,3-tetramethylguanidine (13.45 μL, 0.107 mmol, 2. 0 equiv.), and DMSO (2.5 mL) were sonicated under argon for 1 hour. DIPEA (0.19 mL, 1.07 mmol, 20 equiv.) was added to the solution, followed by additional The clear solution was sonicated for 1 hour. g, 0.059 mmol, 1.1 equiv) was added and the reaction was monitored by LCMS until completion. , preparative HPLC (mobile phase A = 10 mM ammonium acetate (pH = 5), organic phase B = acetonitrile) Nitrile, Method: 10% B to 100% B in 30 min) and purified using EC1778 ( 16 mg, 29%) was obtained. 1 H NMR (500MHz, DMSO-d6) main signal :δ8.60(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 synthesized using published methods. 18 by reacting with F3·3H2O (one-step method) or with AlCl3·3H2O, Next is Na 18 Pte-γGlu-Lys-N by reacting with F (two-step method) OTA-Al- 18 Prepare F. JPEG2025120291000090.jpg46166

[0162] Example: N10-TFA-Pte-γGlu-OtBu-Arg(Pbf)-Arg(P bf)-Lys(Mtt)-Resin(3) A general procedure described for the synthesis of resin-bound folate-peptide resin (1) is shown below, using 2X Fmoc -L-Arg(pbf)-OH, Fmoc-Glu-OtBu, and N10-TFA- For coupling of Pte-OH with Fmoc-L-Lys(Mtt)-Wang resin This was followed by JPEG2025120291000091.jpg58166

[0163] Example: Pte-γGlu-Arg-Arg-Lys-Bn-NOTA (4) (EC22 17) Add N10-TFA-Pte-γGlu-OtBu-Arg(Pbf) to a peptide synthesis vessel. -Arg(Pbf)-Lys(Mtt)-resin (0.28 g, 0.07 mmol) The vessel was washed with DCM (3 x 10 mL). A 2% CF3CO2H / DCM solution was added. Selective Mtt deprotection was carried out by bubbling argon for 10 minutes. The oil was washed with dichloromethane followed by a fresh solution of 2% CF3CO2H / DCM. This process was repeated until no more yellow solution was produced, and the Kaiser test was performed. After washing with F (3 × 10 mL), p-SCN-Bn-NOTA.3H dissolved in DMF was added to the container. Cl (50 mg, 0.09 mmol, 1.2 equiv.) and DIPEA (80 μL, 0.4 5 mmol, 6.0 equiv.) was added and the solution was bubbled with argon for 2 hours. The rinsing solution was filtered and the resin was washed with DMF (3 × 10 mL) and i-PrOH (3 × 10 mL). The reaction was washed with 100 ml of HCl and the Kaiser test was performed to determine the completion of the reaction. rt-Butyl ester deprotection was carried out in 95% CF3CO2H, 2.5% H2O, and 2.5 The cleavage reaction mixture (10 mL) was Pour onto the resin and bubble with argon for 60 minutes, then filter into a clean flask. Two further cleavage reactions were performed sequentially with fresh cleavage cocktail for 0 minutes each. The filtrate was poured onto cold diethyl ether and the precipitate formed was stirred at 4000 rpm for 5 min ( The precipitate was collected by centrifugation (3x). The precipitate was decanted and the solids were collected under vacuum. After drying, the trifluoroacetyl group was removed by diluting the crude precipitate with HO (15 mL). ), which is then bubbled with argon and diluted with Na2CO3 to pH Upon completion of the reaction as confirmed by LCMS, 2M HCl was used to basify to 9. The solution was acidified to pH 5 using HCl and the desired linker was analyzed by preparative HPLC (mobile phase A = 10 mM acetic acid). ammonium (pH = 5), organic phase B = acetonitrile, method: 10% B to 10% in 30 min Purification by HPLC (0% B) gave EC2217 (35 mg, 35%). 1 H NMR (50 0 MHz, DMSO-d6) Main signal: δ 8.61 (s, 1H), 7.54 (d, J = 8.4Hz,2H),7.17~7.03(m,2H),6.99(d,J=8.0Hz ,2H),6.66(d,J=8.5Hz,2H),4.52~4.45(m,1H), 4.17(dt,J=8.9,4.6Hz,2H),4.12(s,1H)4.07~3 .97(m,1H). [M+H] + = Calculated value 1332.59, measured value 1332.87. JPEG2025120291000092.jpg45166

[0164] Example: N10-TFA-Pte-γGlu-OtBu-Asp(OtBu)-Arg( Pbf)-Arg(Pbf)-Lys(Mtt)-Resin(5) A general procedure described for the synthesis of resin-bound folate-peptide resin (1) is shown. -L-Arg(pbf)-OH, Fmoc-L-Asp(OtBu)-OH, Fmoc- Glu-OtBu, and N10-TFA-Pte-OH, Fmoc-L-Lys(M tt)-This was followed for coupling with Wang resin. JPEG2025120291000093.jpg61166

[0165] Example: Pte-γGlu-Asp-Arg-Arg-Lys-Bn-NOTA (6) ( EC2218) Folate-peptide-NOTA (4) was synthesized by the method described in (4). rg-Arg-Lys-Bn-NOTA (EC2218) was prepared in 18% yield. H NMR (500 MHz, DMSO-d6) main signal: δ 8.58 (s, 1H), 7 .52(d,J=9.0Hz,2H),7.14~7.08(m,4H),6.61(d ,J=9.0Hz,2H),4.16~4.09(m,2H),4.06(dd,J=1 0.0,4.3Hz,1H),3.90(dd,J=7.8,4.7Hz,1H). [M +H] + = Calculated value 1449.64, measured value 1449.76. JPEG2025120291000094.jpg38166

[0166] Example: N10-TFA-Pte-γGlu-OtBu-Arg(Pbf)-Lys(M tt)-Resin(7) A general procedure described for the synthesis of resin-bound folate-peptide resin (1) is Arg(Pbf)-OH, Fmoc-Glu-OtBu, and N10-TFA-Pte -OH was used for coupling with Fmoc-L-Lys(Mtt)-Wang resin. I was attacked. JPEG2025120291000095.jpg50166

[0167] Example: Pte-γGlu-Arg-Lys-Bn-NOTA (8) (EC2219) Folate-peptide-NOTA (4) was synthesized by the method described in (4) and (4) using Pte-γGlu-Arg-L. ys-Bn-NOTA (EC2219) was prepared in 20% yield. 1H NMR (50 0 MHz, DMSO-d6) Main signal: δ 8.68 (s, 1H), 7.60 (d, J = 8.4Hz, 3H), 7.27~6.97(m, 4H), 6.77~6.69(m, 2H) ),4.28~f4.19(m,2H),4.08(dd,J=9.0,5.4Hz,1 H),4.01(dd,J=8.5,5.4Hz,1H). [M+H] + = Calculated value 117 8.51, actual value 1178.7. JPEG2025120291000096.jpg66166

[0168] Example: Pte-γGlu-Arg-Arg-Lys-NOTA (9) (EC2222) Add N10-TFA-Pte-γGlu-OtBu-Arg(Pbf) to a peptide synthesis vessel. -Arg(Pbf)-Lys(Mtt)-resin (0.5 g, 0.12 mmol) was added. Wash with DCM (3 x 10 mL). Add 2% CF3CO2H / DCM solution to the vessel. Selective Mtt deprotection was performed by bubbling argon through the resin for 10 min. The residue was washed with dichloromethane followed by fresh 2% CF3CO2H / DCM solution. This process was repeated until no yellow solution was produced, and the Kaiser test was performed. After washing (3 × 10 mL), the vessel was filled with NOTA-bis(tBu) ester (0 .10g, 0.24mmol, 2.0eq), PyBOP (0.14g, 0.26mmol 1, 2.2 equiv.), and DIPEA (64 μL, 0.36 mmol, 3.0 equiv.) were added. The solution was then bubbled with argon for 2 hours. The coupling solution was filtered and the resin was then added to DMSO. Wash with F (3 × 10 mL) and i-PrOH (3 × 10 mL), and then test with Kaiser The reaction was judged complete by carrying out the resin cleavage / global tert-butyl ester deprotection. , from 95% CF3CO2H, 2.5% H2O, and 2.5% triisopropylsilane The cleavage reaction mixture (10 mL) was poured onto the resin and purged with argon for 1 hour. The mixture was then bubbled for 10 minutes, followed by filtering into a clean flask. The cleavage was carried out twice consecutively with fresh cleavage mixture. The combined filtrates were washed with cold diethyl ether. and the precipitate formed was removed by centrifugation at 4000 rpm for 5 minutes (3x). The precipitate was obtained after decanting and drying the solid under vacuum. Deprotection of the -acetyl group was achieved by dissolving the crude precipitate in HO (15 mL). This was basified to pH 9 with Na2CO3 while bubbling with argon. Upon completion of the reaction, as determined by HCl, the solution was acidified to pH 5 using 2M HCl to obtain the desired The linker was separated by preparative HPLC (mobile phase A = 10 mM ammonium acetate (pH = 5), organic phase B = 10 mM ammonium acetate (pH = 5) B = acetonitrile, Method: 10% B to 100% B in 30 minutes) 22 (28 mg, 20%) was obtained. 1H NMR (500 MHz, DMSO-d6) showed the main Gunal: δ 8.60 (s, 1H), 7.51 (d, J = 8.1 Hz, 2H), 6.64 ( d,J=8.4Hz,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. JPEG2025120291000097.jpg43166

[0169] Example: 18-4-(N-((2-amino-4-oxo-3,4-dihydropteridine- 6-yl)methyl)-2,2,2-trifluoroacetamido)benzamido)-2,2 -Dimethyl-4,15-dioxo-3,8,11-trioxa-5,14-diazanonade (S)-methyl methyl 19-canthate (QC07010) QC02024 (100 mg, 0.181 mmol) was dissolved in DMSO under N2 at 23 °C. Mono-Boc-PEG-NH2 (45 mg, 0.181 m) dissolved in SO (2 mL) mol) and DIPEA (0.158 mL, 0.905 mmol). After stirring at 3°C for 15 minutes, PyBOP (94.2 mg, 0.181 mmol) was added. The reaction mixture was stirred for 24 h at 23° C. The volatiles were removed under reduced pressure and the crude material was further purified by S Purified by PE purification and diluted with ACN (2x), EA (1x), and Et2O (1x). Subsequent extraction gave the pure product QC07010 (127 mg, 90%). max =2 80nm;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: 782.3, Measured value: 78 2.2.1H NMR(400MHz,DMSO)δ=11.59(s,br,1H), 8.92(d,J=7.2Hz,1H),8.64(s,1H),7.85~8.02( m,3H),7.64(d,J=8.0Hz,2H),6.75(t,J=5.2Hz, 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(101MHz,DMSO)δ=172.43,171.46,165. 73,160.87,156.80,155.70(d,J=35.5Hz),155. 67,154.17,149.49,144.20,141.73,134.30,12 8.82,128.55,128.23,116.20(d,J=290.0Hz),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 (377MHz, CDCl3)δ=-62.87. JPEG2025120291000098.jpg45166

[0170] Example: 2-(4-(N-((2-amino-4-oxo-3,4-dihydropteridine- 6-yl)methyl)-2,2,2-trifluoroacetamido)benzamido)-5-( (2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-5-oxopentane (S)-methyl ester (QC07011) QC07010 (274 mg, 0.35 mmol) was dissolved in TFA / DCM (4 mL, 1 / 3 ) at 23° C. The reaction was stirred at 23° C. and monitored by LC-MS. After 1.5 hours, TLC showed that all starting material had disappeared. The mixture was then diluted with 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, measured value: 682.2. JPEG2025120291000099.jpg45166

[0171] Example: (S)-2,2'-(7-(4-(4-(N-((2-amino-4-oxo-3 ,4-Dihydropteridin-6-yl)methyl)-2,2,2-trifluoroacetami Benzamido)-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) with NOTA-NHS (18.2 mg, 0.028 mmol), followed by DIPEA ( 5 μL, 0.084 mmol) was added. 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 =280nm;LC-MS(Agilent G6130B Quadr upole LC / MS): Mobile phase: Buffer (pH7)-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: 967.4, Measured value: 967.2; HPLC (Agilent Preparative C18 Column): Mobile phase :Buffer (pH7)-CH3CN; Method: 0~100 CH3CN-30 min, t R =10 .75 minutes. JPEG2025120291000100.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-PEG-1- NOTA, QC07017) QC07013 (20.8 mg, 0.022 mmol) was dissolved in 1.2 mL of 1 M NaO H (aq) at 23°C and the reaction was monitored by LC-MS. All starting materials were converted to products and the crude materials were purified by RP-C18 HPLC to Q C07017 (11.3 mg, 60%) was obtained. max = 280 nm; HPLC (Ag ilent Preparative C18 Column): Mobile phase: Buffer solution (pH 7) -CH3CN; Method: 0 to 30% CH3CN for 30 minutes, tR = 11.49 minutes. LC- MS (Agilent G6130B Quadrupole LC / MS): Mobile phase: Buffer (pH 7) -CH3CN; Method: 0 to 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 (1 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。 JPEG2025120291000101.jpg102166

[0173] Example: Solid Phase Synthesis (SPS) of FA-PEG-EDA-NH2 Precursor (QC03019) ) 1,2-Diaminoethane trityl resin (1.2 mmol / g, 100 mg, 0.12 m mol) in dichloromethane (DCM, 3 mL), followed by dimethylformamide (DMF, After swelling the resin in DMF, fluorenyl methyl acrylate was added to the resin. Fmoc-PEG-OH (1.5 equivalents), HATU (1.5 equivalents) A solution of 1.0 eq. of HCl, 2.0 eq. of DIPEA, and 2.0 eq. of DIPEA was added. Argon was bubbled for 2 hours to dissolve the resin. Wash with DMF (3 × 3 mL) and i-PrOH (3 × 3 mL). -(OtBu)-OH and N 10 The above procedure for conjugating -TFA-Ptc-OH is The coupling steps were repeated two more times. Trifluoroacetic acid (TFA):H2 The final product was prepared using a reaction mixture of O:triisopropylsilane (95:2.5:2.5). The product was cleaved from the resin and concentrated under vacuum. The concentrated product was precipitated in diethyl ether. It was then incubated in saturated Na2CO3 and subjected to LC-M After 1 h, the mixture was neutralized to pH=7 with 2M HCl (aq.) and RP-C 18 HPLC (solvent gradient: 0% B to 50% B in 30 min; A = 10 mM NH OAc (pH=7, B=CH3CN). The acetonitrile was removed under vacuum. The residue was lyophilized to give QC03019 as a yellow solid (59 mg, 60%). 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 (pH7)-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. JPEG2025120291000102.jpg43166

[0174] Example: FA-PEG6-NOTA QC03019 (9.5 mL) dissolved in DMSO (0.40 mL at a concentration of 0.0029 M) mg, 0.011 mmol) to NOTA-NHS (8.6 mg, 0.013 mmol), DIPEA (7.0 μL, 0.039 mmol) was then added. The reaction was stirred at 23° C. The reaction mixture was monitored by LC-MS. Most of the starting material was converted to the corresponding product within 5 hours. The raw material was 18 Purification by HPLC gave the pure product QC07029 (5.5 m g, 45%). 18 HPLC:t R =3.91min(A=10mM NHOAc (pH = 7.0); B = CHCN, solvent gradient: 0% B to 50% B in 15 min );Preparative RP-C 18 HPLC:t R =10.51 min(A=10mM NH4OAc(p H = 7.0), B = CH3CN, solvent gradient: 0% B to 50% B in 30 min); λ max =2 80nm;HPLC(Agilent Preparative C18 Column ):Mobile phase: Buffer (pH7)-CH3CN; Method: 0~30 CH3CN-30 min, t R =10.51 minutes. LC-MS(Agilent G6130B Quadrupole LC / MS): Mobile phase: Buffer (pH7)-ACN; Method: 0~50 ACN-15 minutes , t R = 3.91 min; MS m / z: MS-API: C 48 H 74 N 13 O 17 ([M+ H] + ) Calculated value: 1104.5, measured value: 1104.4. JPEG2025120291000103.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 for the chelation reaction with F-Al are varied, including pH value, concentration of the substance, and temperature. FA-NOTA-Al- 18 A general method for F is given below.

[0176] Method a): FA-NOTA precursor was dissolved in 2 mM NaOAc (pH 4.5) and 0.5 mM Al was dissolved in ethanol at 25°C and freshly prepared before application. 18 F3·3H2O(1 The pH was adjusted to 4.5-5.0 and maintained at 4.5-5.0. The reaction mixture was refluxed for 15-30 minutes under the same conditions. After cooling to room temperature, the crude material was transferred to the cartridge. The radioactive tracer was then eluted into a bottle. After dilution to a specific activity (>1 Ci / µmol), the radiotracer - is now ready for in vivo PET imaging.

[0177] Method b): FA-NOTA precursor was dissolved in 2 mM NaOAc (pH 4.5) and This was treated with AlCl3·3H2O (1.5 equivalents), the pH was adjusted to 4.5-5.0, and The reaction mixture was refluxed for 15-30 minutes while maintaining the pH at 4.5-5.0. Purified by RP-HPLC 18 FA-NOTA-Al- ready for F-labeling The appropriate amount of FA-NOTA-Al-OH was added to NaOH. 18 F Saline and Et Treat with ethanol (1 / 1, v / v) and heat the whole mixture at 100-110°C for 15 min. After cooling to room temperature, the crude material was loaded into cartridges and the radioactive tracer was placed in a bottle. The eluate was sterile filtered and purified to obtain the appropriate radioactivity (5-10 mCi) and specific activity (>1 Ci / μL). After dilution to 1000 uM, the radiotracer is ready for in vivo PET imaging. Everything is ready. JPEG2025120291000104.jpg60166

[0178] Example: Folic Acid - NOTA-Al 18 Standard Protocol for the Formation of F Radiotracer this 18 The resin containing F was first washed with 1.5 mL of ultrapure water, then with 1.0 mL of By using a 0.4M KHCO3 solution 18 F was eluted from the resin. 18 F 100 μL of elution solution containing 10 μL of acetic acid, 25 μL of AlCl (0.1 M 2 mM in NaOAc (pH 4) buffer), and 125 μL of 0.1 M NaO The mixture was added to a stem vial filled with Ac (pH 4) buffer. The whole was incubated for 2 minutes, and then 125 μL of 0.1 M NaOAc (pH 4) buffer was added. 0.25 mg of folate-NOTA precursor (1) dissolved in buffer was transferred to the same base vial. The reaction was immediately heated to 100° C. for 15 min.

[0179] After cooling to room temperature, the crude material was mixed with 0.7 mL of 0.1% folic acid and eluted with MeOH as the mobile phase. Xselect CSH C18 (250 x 10 mm) with CN and 0.1% folic acid The product was purified by radio-HPLC on a 11.5 min column. The fraction at 11.5 min was collected to give approximately A pure radioactive tracer with 98% radiochemical purity (RCP) is prepared at approximately 40-50% The radiochemical yield (RCY) was 70±18.4 GBq / μmol specific activity (SA). Folic acid with NOTA-Al 18 F((2), Al 18 F-QC07017) Radiochemical synthesis was achieved in approximately 37 minutes. Sterile filtration and dissolution in isotonic saline to the desired radioactivity was performed. After appropriate dilution by folic acid-NOTA-Al 18 The F(2) radiotracer was The image inspection is ready.

[0180] Using the same strategy, F with a specific activity (SA) of 49 ± 17.1 GBq / μmol was obtained. A-PEG 12 -NOTA-Al 18 Radiochemistry of F radiotracer (QC07043) The synthesis was accomplished in approximately 35 minutes. Radiochemical purity was excellent and after radio-HPLC purification Although the radiochemical yield is approximately 100%, the overall radiochemical yield (RCY) is relatively low, at approximately 25-30%. After sterile filtration and appropriate dilution with isotonic saline to the desired radioactivity, this FA-P EG 12 -NOTA-Al 18 The F radiotracer is now ready for PET imaging. JPEG2025120291000105.jpg101166

[0181] Example: FA-PEG 12 Solid-phase synthesis of -EDA-NH2 (QC07042)

[11] (S PS) 1,2-Diaminoethanetrityl resin (1.2 mmol / g, 50 mg, 0.06 mm ol) in dichloromethane (DCM, 3 mL), followed by dimethylformamide (DMF, 3 After swelling the resin in DMF, fluorenylmethacrylate dissolved in DMF was added. Fmoc-PEG 12-OH (1.5 equivalents), HATU (1.5 equivalents) A solution of 1.0 eq. of HCl, 2.0 eq. of DIPEA, and 2.0 eq. of DIPEA was added. Argon was bubbled for 2 hours to dissolve the resin. Wash with DMF (3 × 3 mL) and i-PrOH (3 × 3 mL). -(OtBu)-OH and N 10 The above procedure for conjugating -TFA-Ptc-OH is The coupling steps were repeated two more times. Trifluoroacetic acid (TFA):H2 The final product was prepared using a reaction mixture of O:triisopropylsilane (95:2.5:2.5). The product was cleaved from the resin and concentrated under vacuum. The concentrated product was precipitated in diethyl ether. It was then incubated in saturated Na2CO3 and subjected to LC-M After 1 h, the mixture was neutralized to pH=7 with 2M HCl (aq.) and RP-C 18 HPLC (solvent gradient: 0% B to 50% B in 30 min; A = 10 mM NH The mixture was purified by HCl (pH = 7, B = CH3CN). Acetonitrile was removed under vacuum. The residue was lyophilized to give pure QC07042 as a yellow solid (32.5 mg, 50%). Analytical RP-C 18 HPLC:t R =4.76min(A=10mM NH4OAc (pH = 7.0); B = CH3CN, solvent gradient: 0% B to 50% B in 15 min); preparative RP -C 18 HPLC:t R =13.75 min (A=10mM NH4OAc(pH=7.0) , B = CH3CN, solvent gradient: 0% B to 50% B in 30 min); UV-Vis: λ max = 280nm; preparative RP-C 18 HPLC: HPLC (Agilent Preparative ive C18 Column): Mobile phase: Buffer (pH7)-CH3CN; Method: 0~ 50 CH3CN, 30 min, t R = 13.75 min. LC-MS (Agil ent G6130B Quadrupole LC / MS):Buffer (pH7)-CH 3CN; Method: 0~50 CH3CN, 15 min, t R =4.76 minutes. MS m / z:MS -API:C 48 H 79 N 10 O 18 ([M+H] + ) calculated value: 1083.6, Actual value: 1083.4. JPEG2025120291000106.jpg43166

[0182] Example: FA-PEG-EDA-NH-NOTA (QC07043) FA-PEG12- dissolved in DMSO (0.25 mL with a concentration of 0.025 M) EDA-NH2(QC07042, 4.78mg, 0.004mmol, MW:10 82.5), followed by NOTA-NHS (3.5 mg, 0.005 mmol, 1.2 equiv.). Then DIPEA (2.7 μL, 0.039 mmol) was added. The whole mixture was stirred at 23°C. The mixture was stirred and monitored by LC-MS. After 4 hours, LC-MS showed that almost all of the starting material had been removed. The crude material was then purified by preparative RP-HPLC to give the pure HCl. FA-PEG12-EDA-NH2-NOTA (QC07043, 4.09 mg, 68 % was obtained. 18 HPLC:t R =6.21 min (A=10mM NH4O Ac (pH = 7.0); B = CH3CN, solvent gradient: 0% B to 30% B in 15 min); preparative RP-C 18HPLC:t R =15.60 min (A=10mM NH4OAc(pH=7. 0), B = CH3CN, solvent gradient: 0% B to 30% B in 30 min); UV-Vis: λ ma x =280nm; LC-MS: LC-MS of product mobile phase (Agilent G6130 B Quadrupole LC / MS): Buffer (pH7)-CH3CN; Method: 0~ 8.00(m,1H),7.55(d,J=6.4Hz,1H),7.54(s,br, 2H),6.81~6.93(m,1H),6.62(d,J=8.0Hz,2H),4 .45(d,J=4.4Hz,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 (overlapping with the peak of MSO residue), 2.27-2.34 (m, 2H), 2.02-2. 12(m,2H), 1.99~2.01(m,2H). JPEG2025120291000107.jpg63166

[0183] Example: C-NETA and Folate-C-NETA PyBOP-promoted coupling between QC04018 and compound (6), followed by T Deprotection of the tert-butyl ester with FA gave folate-C-NETA. This folate-C-NETA is used to 18 F and 68 The labeling efficiency of Ga was evaluated, and To evaluate in vivo PET imaging. JPEG2025120291000108.jpg28166

[0184] Example: Methyl 3-cyano-4-(dimethylamino)benzoate (QC07002) [1] Methyl 3-cyano-4-fluorobenzoate (5 g, 27 mL) dissolved in DMSO (6 mL) To a stirred solution of 1.0g (0.0 ... Then potassium carbonate (8.1 g, 58.6 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The residue was dissolved in dichloromethane (50 mL) and added to water (2×25 mL). L) and brine, dried over Na2SO4, and concentrated in vacuo to give 3-cyano- Methyl 4-(dimethylamino)benzoate (QC07002) was obtained in quantitative yield and further Used without further purification. JPEG2025120291000109.jpg31166

[0185] Example: 2-cyano-4-(methoxycarbonyl)-N, trifluoromethanesulfonate N,N-trimethylbenzeneaminium (QC07003) 3-Cyano-4-(dimethylamino)benzoate dissolved in anhydrous dichloromethane (17 mL) To a stirred solution of methyl benzoate (3.4 g, 16.7 mmol) was added trifluoromethanesulfone Methyl acetate (10 g, 60.9 mmol, MW 164.1) was added dropwise. was stirred at room temperature for 16 hours, and another portion of methyl trifluoromethanesulfonate (10 g, 6 0.9 mmol, MW 164.1) was added. The reaction was stirred again for 16 hours. Then, tert-butyl methyl ether (20 mL) was slowly added. The suspension was filtered. The collected solid was washed with tert-butyl methyl ether. 18 Purification by HPLC (acetonitrile / water gradient 1:99 to 80:20) gave product Q C07003 (3.69 g) was obtained in 60% yield. 18 HPLC:t R =0.49 min (A=10mM NH4OAc (pH=7.0); B=CH3CN, solvent gradient Distribution: 0%B to 100%B in 15 minutes); max = 275 nm; LC-MS (Agilent t G6130B Quadrupole LC / MS): Mobile phase: Buffer (pH7)- CH3CN; Column: analytical C 18 Column; Method: 0-100 CH3CN-15 min, t R =0.49 min. MS m / z: MS-API: C 12 H 15 N2O2([M] + ) Calculated: 219.1, Found: 219.0. 1H NMR (400 MHz, DO) δ=8.67(d,J=2.1Hz,1H),8.44(dd,J=9.1,2.1Hz ,1H),8.15(d,J=9.1Hz,1H),3.93(s,3H),3.87( s,9H) ppm. JPEG2025120291000110.jpg28166

[0186] Example: 4-carboxy-2-cyano-N,N,N-trifluoromethanesulfonic acid Methylbenzeneaminium (QC07004) QC07003 (3.6 g, 9.5 mL) dissolved in water (83 mL) and TFA (83 mL) A solution of 100 mg of 1,000 sachets ... The pale green oil was treated with diethyl ether to give a suspension, and the solid was collected by filtration. , washed with diethyl ether, and dried in vacuo to obtain 4-calcium trifluoromethanesulfonate. Box-2-cyano-N,N,N-trimethylbenzeneaminium QC07004(2. 8g, 82%). 18 HPLC:t R =0.61min(A=10mM NHOAc (pH = 7.0); B = CHCN, solvent gradient: 0% B to 100% B in 15 min %B);λ max =240nm;LC-MS(Agilent G6130B Quad rupole LC / MS): Mobile phase: Buffer solution (pH7)-CH3CN; Column: For analysis C 18 Column; Method: 0-100 CH3CN, 15 min, t R =0.61 minutes. MS m / z:MS-API:C 11 H 13 N2O2([M] + Calculated value for: 205.1, actual Measured value: 205.1.1H NMR(400MHz,DMSO)δ=8.58(d,J=2 .07Hz,1H),8.39~8.49(m,1H),8.23~8.35(m,1H) ),3.85(s,9H). JPEG2025120291000111.jpg51166

[0187] Example: FA-PEG1-TMA Precursor (QC07005) QC07004 (62 mg, 0.17 mmol) was dissolved in DMSO under N at 23 °C. QC07011 (0.14 mmol) and DIPEA (87 After stirring at 23°C for 15 minutes, PyBOP ( 91 mg, 0.17 mmol) was added and the reaction mixture was stirred at 23° C. for 24 hours. The reactants were removed under reduced pressure to give the crude product, which was further purified by RP-HPLC (C 18 ) by and purified to give pure compound QC07005 as a pale yellow solid (125.1 mg, 72%). Analytical RP-C 18 HPLC:t R =4.17min(A=10mM NH4OAc( pH = 7.0); B = CH3CN, solvent gradient: 0% B to 100% B in 15 min); λ max =280nm;LC-MS(Agilent G6130B Quadrupole L C / MS): Mobile phase: Buffer (pH7)-CH3CN; Column: Analytical C 18 column; Method: 0~100 CH3CN-15 min, t R = 4.17 min. MS m / z: MS-API :C 28 H 35 F3N9O8([M] + ) Calculated value: 868.3, Measured value: 868 .2. JPEG2025120291000112.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 The (0.144M) solution was dried azeotropically with CH3CN at 90-100°C. 1.2 mg (0.0012 mmol, 1.0 equivalent) of the solution was added to 50 μL of anhydrous DMSO. QC07005 dissolved in 7 ml of HCl was added to a precursor concentration of 0.024 M. The sample was immediately immersed in an oil bath preheated to 0-75°C and kept at 70-75°C for 10 minutes. After cooling, add 200 μL of 1 M NaOH (aq) to a concentration of 0.8 M NaOH (aq). The reaction was monitored by LC-MS and found to be complete after 5 minutes. It was neutralized with 1M HCl (aqueous) and analyzed by LC-MS (QC07006). The overall labeling efficiency was approximately 30% based on LC-MS analysis. 18 HP LC: A = 10 mM NH4OAc (pH = 7.0); B = CH3CN, solvent gradient: 15 (0%B to 100%B in minutes); max =280nm;LC-MS:Method:0~100C 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. JPEG2025120291000113.jpg94166

[0189] Example: Folic acid 18 F-boronic acid PET imaging agents Examples directed at PSMA JPEG2025120291000114.jpg95166

[0190] Example: EC1380(10) Add H-Glu(O) to a dry flask. 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 The resulting solution was dissolved in CH2Cl2 (30 mL) under an argon atmosphere. The solution was cooled to 0°C, and then DIPEA (4.50 mL, 25.2 mmol, 3 equiv.) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. , H-Lys-(Z)-O t Bu (4.39 g, 11.8 mmol, 1.4 equiv) and DIPEA (4.50 mL, 25.2 mmol, 3 eq) was added and stirred for 1 hour. Once complete, the reaction was quenched with saturated NaHCO3 and extracted three times with CH2Cl2. The extracts were combined, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The product was purified using silica gel chromatography with ethyl acetate. The bz-protected amine was transferred to a round-bottom flask with 10% Pd / C (10 wt. % equiv.). The mixture was dissolved in MeOH (30 mL) under a hydrogen atmosphere (1 atm) and stirred for 3 h. After this time, the reaction mixture was filtered through Celite and the solvent was removed under reduced pressure to give the crude amine. The amine was dissolved in CH2Cl2 (30 mL) under an argon atmosphere and cooled to 0 °C. To the cooled solution was added 4-nitrophenyl chloroformate (2.2 g, 10.9 mmol). l, 1.3 equiv.) and DIPEA (6.0 mL, 33.6 mmol, 4 equiv.) were added successively. The reaction mixture was quenched with saturated NH4Cl and diluted with ethyl acetate for 3 h. The organic extracts were combined, dried over Na2SO4, filtered, and the solvent was removed in vacuo. The product was purified using silica gel chromatography to obtain the desired activated amine EC. Yield 1380 (2.54 g, 46%). JPEG2025120291000115.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) A general procedure described for the synthesis of resin-bound folate peptide resin (1) is 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 This was followed for coupling with s(Mtt)-Wang resin. The peptide was subjected to standard Fmoc deprotection, washing, and Kaiser test. After washing with DMF once more (3 x 10 mL), EC1380 solution (2.0 mL) dissolved in DMF was added. (3.0 equiv.) and DIPEA (3.0 equiv.) 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 a Kaiser test was performed to determine reaction completion. JPEG2025120291000116.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 following the method described for folate-peptide-NOTA (4). Made. 1 H NMR (500 MHz, DMSO-d6) main signal: δ 7.25-7. 18(m,2H),7.14(d,J=8.1Hz,1H),7.12~7.06(m, 5H),4.47(ddd,J=17.8,7.5,5.6Hz,2H),4.11~4 .08(m,3H),4.08~4.02(m,2H),3.98(dd,J=8.2, 5.1Hz, 1H). [M+H] + = Calculated value 1319.50, measured value 1319.70. JPEG2025120291000117.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) A general procedure described for the synthesis of resin-bound folate peptide resin (1) is rg(Pbf)-OH, Fmoc-L-Asp(O t Bu)-OH, Fmoc-L-Ar g(Pbf)-OH, 2X Fmoc-Phe-OH, Fmoc-Aoc-OH, Fmo cL-Lys(Z)-O t Bu, Fmoc-(L)-Glu(O t Bu), and EC 1380 for coupling with Fmoc-L-Lys(Mtt)-Wang resin It was followed. JPEG2025120291000118.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 synthesized by the method described for folate-peptide-NOTA (4) for 3 min. It was prepared in 7% yield. 1 H NMR (500 MHz, DMSO-d) main signal: δ 7.25~7.14(m, 6H), 7.16~7.08(m, 3H), 4.47(dd, J=9.0,4.7Hz,1H),4.42(t,J=5.9Hz,1H),4.36( dd,J=10.4,4.4Hz,1H),4.27(t,J=6.9Hz,1H),4 .16(t,J=5.6Hz,1H),3.97~3.88(m,2H). [M+H] + = Calculated value 1639.84, measured value 1640.22. JPEG2025120291000119.jpg32166

[0195] Example: DUPA-EAOA-Phe-Arg-Lys-NH2(2-[3-(3-benzo[ Dimethyloxycarbonyl-1-tert-butoxycarbonyl-propyl)ureido]pen Tanedioic acid di-tert-butyl ester (2)) [1,2] Di-tert-butyl L-glutamate dissolved in DCM (25.0 mL) at -78 °C Ester hydrochloride (1) (1.0 g, 3.39 mmol) and triphosgene (329.8 mg, 1.12 mmol) of triethylamine (TEA, 1.0 mL, 8.19 After stirring under argon at -78°C for 2 hours, DCM (5.0 mmol) was added. L-Glu(OBn)-OtBu (1.2 g, 3.72 mmol) dissolved in 1 mL of A solution of 1000 μL of ethanol and TEA (600 μL, 4.91 mmol) was added. The reaction mixture was allowed to stand. The reaction was allowed to warm to room temperature (rt) over 1 h and stirred at ambient temperature overnight. After quenching, the organic layer was washed with brine and dried over Na2SO4. The crude product was purified using filtration (hexane: EtOAc = 1:1) to give intermediate (2) ( 1.76 g, 90.2%) was obtained as a colorless oil, which was concentrated using hexane:DCM. Crystallized: Rf=0.67 (hexane: EtOAc=1:1). 1 H NMR (CDC l3):δ1.43(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, RH); 5.10 (s, 2H, CH2-Ar); 5.22 (s (broad), 2H, urine 7.34(m,5H,Ar-H). EI-HRMS(m / z):C 30 H 47 (M+H) for N2O9 + Calculated value: 579.3282, measured value: 579.3289.

[0196] Example: 2-[3-(1,3-bis-tert-butoxycarbonyl-propyl)-urea Ido]pentanedioic acid 1-tert-butyl ester, DUPA_1 A solution of 2 (250 mg, 432 mmol) in DCM was added to 10% Pd / C. The reaction mixture was hydrogenated at room temperature and 1 atm for 24 hours. The HCl was filtered and washed with DCM. Flash chromatography (hexane: EtOAc The crude product was purified using a mixture of 1000 and 1000 kJ / kg of DUPA_1 (169 mg, 80.2%). was obtained as a colorless oil, which was crystallized using hexane:DCM. f =0.5 8 (hexane: EtOAc = 40:60). 1 H NMR (CDCl): 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,RH);5.05(t,2H,urea-H);EI- HRMS(m / z):C 23 H 41 (M+H) for N2O9 + Calculated value: 489.28 12. Actual value: 489.2808. JPEG2025120291000120.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 min, (ii) Fmoc-8-amino-octanoic acid (EAO), HB TU, HOBt, DMF / DIPEA, 2 hours, (d)(i) 20% piperidine / DMF , room temperature, 10 min, (ii)(tBuO)3-DUPA-OH, HBTU, HOBt, DI PEA, 2 h, (e) TFA / H2O / TIPS (95:2.5:2.5), 1 h.

[0198] Example: DUPA-EAOA-Phe-Arg-Lys-NH2 Fmoc-Lys(Boc)-Wang resin (0.43 mM) was dissolved in DCM (3 mL), followed by The resin was swollen in dimethylformamide (DMF, 3 mL). A solution of 20% piperidine in 10 mL of HCl was added and argon was bubbled through for 5 minutes. Wash with DMF (3 × 3 mL) and isopropyl alcohol (i-PrOH, 3 × 3 mL). The formation of free amines was determined by the Kaiser test. The resin was swelled in DMF. After hydration, Fmoc-Arg(Boc)2-OH (2.5 equivalents) dissolved in DMF, H A solution of BTU (2.5 equiv.), HOBt (2.5 equiv.), and DIPEA (4 equiv.) Argon was bubbled for 2 h and the resin was dissolved in DMF (3 × 3 mL) and i-PrOH (3 The coupling efficiency was evaluated by the Kaiser test. Nilanarin (Phe), 8-amino-octanoic acid (EAO), and DUPA were sequentially The above procedure was repeated three more coupling steps to introduce the Fluoroacetic acid (TFA):H2O:triisopropylsilane cocktail (95:2.5:2 The final compound was cleaved from the resin using HCl (5) and concentrated under vacuum. Precipitation in cold diethyl ether and drying under vacuum was performed. Preparative RP-HPLC ((λ) 21 0 nm, solvent gradient: 0% B to 50% B in a 30 min run, mobile phase: A) 0.1% TFA (p The crude product was purified using H=2, B) acetonitrile (ACN). The pure fraction was lyophilized to give DUPA-EAOA-Phe-Arg-Lys- NH2 was obtained as a white solid. UV / vis: λ max =205nm. Analysis RP-H PLC:t R = 6.2 min (A = 0.1% TFA; B = CH3CN, solvent gradient: 0 at 15 min %B~50%B); ESI-MS (m / z): C 40 H 65 N 10 O 13 for (M+ H) +Calculated value: 893.5, measured value: 893.4. JPEG2025120291000121.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, 5.0mg, 0.0056mmol, M. Wt.:893.0) and NOTA-NHS (5.5 mg, 0.0084 mmol, 1.5 equiv.), followed by DIPEA (2.9 μL, 0.017 mmol). The mixture was stirred at 5°C and monitored by LC-MS. Most of the starting material was converted to the corresponding product within 5 hours. The raw material was 18 The ACN was removed under vacuum and the pure fraction was purified by HPLC. The resulting solution was lyophilized to obtain pure DUPA-EAOA-Phe-Arg-Lys-NH2-NO TA (QC08002, 3.3 mg, 50%) was obtained. 18 HPLC:t R = 5.98 min (A = 0.1% TFA; B = CH3CN, solvent gradient: 0% B to 5% B in 15 min) 0%B);Preparative RP-C 18 HPLC:t R = 16.16 min (A = 0.1% TFA; B = CH3CN, solvent gradient: 0% B to 50% B in 30 min); UV-vis: λ max =201 nm;HPLC(Agilent Preparative C18 Column); Mobile phase: A=0.1%TFA, B=CH3CN; Method: 0~50 CH3CN-30 min, t R =16.16 min;LC-MS(Agilent G6130B Quadrupol 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: 1178.6, measured value: 1178.4. JPEG2025120291000122.jpg41166

[0200] Example: DUPA-EAOA-Phe-Arg-Lys-NH2-NOTA-Al 18 F Method a) 2mM DUPA-EAOA-Phe-Arg-Lys-NH2-NOTA Dissolved in NaOAc (pH 4.5) and 0.5 mL of ethanol, it was freshly prepared before application. Newly prepared Al 18 Treat with F3·3H2O (1.5 equivalents) to adjust the pH to 4.5-5.0. The reaction mixture was refluxed for 15 to 30 minutes while maintaining the pH at 4.5 to 5.0. After cooling to room temperature, the crude material is loaded into cartridges and the radioactive tracer is dissolved in a bottle. After sterile filtration, the appropriate radioactivity (5-10 mCi) and specific activity (>1 Ci / μm After dilution to 100µL, the radiotracer is ready for in vivo PET imaging. will be in order.

[0201] Method b) 2mM DUPA-EAOA-Phe-Arg-Lys-NH2-NOTA Dissolved in NaOAc (pH 4.5) and treated with AlCl3·3H2O (1.5 equiv.). Adjust the pH to 4.5-5.0 and perform the reaction mixture while maintaining the pH at 4.5-5.0. The mixture was refluxed for 15-30 min. The crude material was purified by RP-HPLC to give 18 F-label Synthesis-ready DUPA-EAOA-Phe-Arg-Lys-NH2-NOTA-A Obtain the l-OH intermediate by adding an appropriate amount of DUPA-EAOA-Phe-Arg-Lys-NH 2-NOTA-Al-OH, Na 18 F salt solution and ethanol (1 / 1, v / v) The mixture is then heated to 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 bottle. After sterile filtration, After dilution to the appropriate radioactivity (5-10 mCi) and specific activity (>1 Ci / µmol), The radiotracer is then ready to be used for in vivo PET imaging. JPEG2025120291000123.jpg37166

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

[0203] Example: Solid-phase peptide synthesis of DUPA-EAOA-Phe-Phe-EDA-NH2 (S PPS) [2,3] DUPA-EAOA-Phe-Arg-Lys-NH2 (QC08001) DUPA-EAOA-Phe-Phe-EDA-NH2 was prepared as described in the specification. Commercially available Trt-EDA resin was prepared by dissolving in DCM (3 mL) followed by dimethylformamide ( DMF, 3 mL) and added Fmoc-Phe-OH (2.5 equivalents) dissolved in DMF. amount), HBTU (2.5 equiv.), HOBt (2.5 equiv.), and DIPEA (4 equiv.) A solution of DMF (3 × 3 mL) and i-Pr was added. Argon was bubbled for 2 h and the resin was then washed with DMF (3 × 3 mL) and i-Pr The coupling efficiency was evaluated by the Kaiser test. A solution of 20% piperidine in DMF (3 x 3 mL) was added to the resin and argon was added. The resin was then dissolved in DMF (3 × 3 mL) and isopropyl alcohol (i- The formation of free amines was determined by the Kaiser test. The second phenylanaline (Phe), 8-amino-octanoic acid (EAO), and The above procedure requires three more coupling steps to introduce DICH and DUPA successively. Repeated. Trifluoroacetic acid (TFA):H2O:triisopropylsilane cocktail The final compound was cleaved from the resin using (95:2.5:2.5) and concentrated under vacuum. The concentrated product was precipitated in cold diethyl ether and dried under vacuum. PLC ((λ) 210 nm, solvent gradient: 0% B to 100% B in a 30 min run, mobile phase: A 1) 10 mM NH4OAc (pH = 7, buffer solution), B) acetonitrile (ACN) The crude product was purified using HCl. The ACN was removed under vacuum and the pure fractions were lyophilized to give DUPA. -EAOA-Phe-Phe-EDA-NH2 was obtained as a white solid. 18 HPLC:t R=3.99 min(A=10mM NH4OAc(pH=7.0);B= CH3CN, solvent gradient: 0% B to 100% B in 15 min); preparative RP-C 18 HPLC:t R =16.05 min (A=10mM NH4OAc (pH=7.0); B=CH3CN, Medium gradient: 0%B~100%B in 30 minutes); UV-vis:λ max = 209 nm; LC- MS: LC-MS (Agilent G6130B Quadrupol) of the product mobile phase e LC / MS): Buffer (pH7)-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: 798.4, Measured value: 798.3; C 39 H 55 N7O 11 K( [M+H] + ) calculated value: 836.4, observed value: 836.3. ent Preparative C18 Column); Mobile phase: Buffer solution (pH7) -CH3CN;Method: 0~100 ACN-30min, t R =16.05 minutes. JPEG2025120291000124.jpg78166

[0204] Example: DUPA-EAOA dissolved in DMSO (0.25 ml at a concentration of 0.025 M) -Phe-Phe-EDA-NH2(QC08008, 5.9mg, 0.0074mmo l, MW: 797.4) with NOTA-NHS (7.3 mg, 0.011 mmol, 1.5 equiv.), followed by 4 drops of DIPEA. The mixture was stirred at 23°C and analyzed by LC-MS. After 4 hours, LC-MS showed that almost all of the starting material had been converted to product. The crude material was then purified by preparative RP-HPLC to give pure DUPA-EA. OA-Phe-Phe-NOTA (QC08009, purity by HPLC at 210 nm) 4.50 mg (56%) was obtained compared to the theoretical 8.02 mg (97%). -C 18 HPLC:t R =3.45 min(A=10mM NH4OAc(pH=7.0); B = CH3CN, solvent gradient: 0% B to 100% B in 15 min); preparative RP-C 18 HPLC :t R =10.09min(A=10mM 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 (Agilent G6130B Quadruple) ole LC / MS): Buffer (pH7)-CH3CN; Method: 0~100 ACN-1 5 minutes, t R = 3.45 min, MS m / z: MS-API: C 51 H 75 N 10 O 16 ([ M+H] + ) calculated value: 1083.5, observed value: 1083.3. lent Preparative C18 Column); Mobile phase: Buffer solution (pH7 )-CH3CN; Method: 0~100 ACN-30 min, t R =10.09 minutes. 1 HNM R(400MHz,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). JPEG2025120291000125.jpg73166

[0205] Example: DUPA-EAOA-Phe-Arg-Lys-NOTA- 64 Cu radioactive Radiochemical synthesis of the laser NOTA for Nuclear Medicine / Radiotherapy 64 / 67 In Cu formulations, NOTA-based chelates The corresponding DUPA-NOTA- 6 4 Cu can be used for dual purposes of diagnostic imaging and therapy (theranostics) DUPA-EAOA-Phe-Arg-Lys-NOT A- 64 Cu was prepared according to standard protocols with minor modifications [4, 14~ 16]. 0.1M ammonium acetate (pH 5.5) was used in situ. 64 Prepared from CuCl2 Made 64 Cu(OAc) was added to the reaction tube containing the DUPA-NOTA precursor. The resulting mixture was then heated at 95°C for 15 minutes. After cooling to room temperature, Radio-HPLC on a C18 column using MeCN and 0.1% TFA as the phase The crude material is then purified to obtain the target radiotracer with a radiochemical purity of approximately 90% (R Sterile filtration and dilution with isotonic saline to the desired radioactivity was performed for PET imaging. This resulted in radioactive tracer ready for histology. JPEG2025120291000126.jpg66166

[0206] Example: DUPA-EAOA-Phe-Phe-NOTA- 64 Cu / Al- 18 F release Shooting chemical synthesis JPEG2025120291000127.jpg70166

[0207] Example: DUPA-EAOA-Phe-Phe-NOTA- 68 Radiochemical synthesis of Ga

[0208] Working Example: 68 General procedure for Ga labeling 68 Ga with 0.1N HCl 68 Ge / 68 Ga was dissolved from the generator. 0.1N A given amount of HCl dissolved 68 Ga was dissolved in acetate buffer (pH 4.8) The labeling mixture was incubated at room temperature and the labeling efficiency was determined by radioactivity The radiolabeled product was purified by radio-HPLC and analyzed by HPLC. UPA-NOTA- 68 The Ga peak samples were collected, sterile filtered, and analyzed for the appropriate radioactivity (5–1 After dilution to a specific activity (>1 Ci / µmol), the radiotracer - is now ready for in vivo PET imaging. JPEG2025120291000128.jpg77166

[0209] Example: Radiochemical synthesis of DUPA-C-NETA-based theranostics JPEG2025120291000129.jpg70166

[0210] Example: Preparation of NOTA Derivatives Bifunctional conjugates (also referred to herein as theranotics) The compounds described herein are useful for PET imaging. 18 F and Beauty 68 Radionuclides such as Ga, and radionuclides for radiation therapy 177 Lu and 90 Y C-NETA, a derivative of NOTA, can tightly chelate both achieves Al with approximately twice the efficiency (87%) of NOTA. 18 It has been reported to chelate F

[17] Furthermore, C-NETA also 177 Lu and 90 Commonly used It has been reported that it can chelate various radiotherapeutic nuclides with high labeling efficiency

[18] . Therefore, C-NETA can be used for both PET imaging and radiotherapy. Bifunctional chelating agents capable of chelating radionuclides (the radionuclides are metal or metal halides, e.g. BaAl 18 F, 68 Ga, 177 Lu, or 90 Y) is useful as You can find out by reading the book.

[0211] Example: PyBOP-promoted coupling between QC04018 and QC08008 Subsequent deprotection of the tert-butyl ester with TFA afforded DUPA-C-NETA DUPA-C-NETA is used to obtain Al 18 F, 68 Ga, 177 Lu, Call 90 The labeling efficiency of Y was evaluated and the results were used for in vivo PET imaging and radiology. Evaluate treatment.

[0212] Example of the method Example: The specificity of binding of radionuclide-containing conjugates to FR was determined using KB xenograft homogenates. and Ca151 xenograft homogenates. 18 F-AIF-QC07 017 and 18 Concentration-dependent binding of F-AIF-QC07043 was evaluated, and specific No significant nonspecific binding was observed in the KB homogenate. A small amount of nonspecific binding was observed in the Ca151 homogenate. 18 F-AIF -For QC07017, specific / nonspecific ratio was >3:1 at all concentrations up to approximately 30 nM The bond ratio, 18 F-AIF-QC07043 was used for all concentrations up to approximately 20 nM. The specific / nonspecific binding ratio was >2:1 at high concentrations. A549 homogenate showed a small amount of nonspecific binding. Heterogeneous binding is observed, 18 For F-AIF-QC07043, all concentrations up to approximately 10 nM Specific / nonspecific binding ratios of >2:1 at all concentrations were obtained. Scatchard analysis was also performed. In human tumor xenografts (KB and Ca151) by self-competition 18 FA Displacement and saturation binding of IF-QC07017 was observed. 18 F-AIF-QC07 017 and 18Both F-AIF-QC07043 and F-AIF-QC07043 were effective in all cell xenografts. The high Bmax / Kd ratio indicates that the antibody binds to a single site with high affinity in KB xenografts. It showed high specific binding affinity to Ca151 xenografts. The lowest binding affinity was observed for A549 xenografts, and the lowest binding affinity was observed for A549 xenografts. Although not bound, moderate expression of FR in Ca151 xenografts resulted in lower binding affinity This specification considers this to be the main cause of the above.

[0213] [Table 2]

[0214] [Table 3]

[0215] Example: Nude mice bearing KB tumor xenografts under standard and competitive conditions μPET imaging was performed to assess FR 18 F-AIF-QC07017(2) Binding specificity was assessed in vivo by injecting 0.01% β-glucan into nude mice bearing KB tumor xenografts on the left shoulder. 0.30–0.40 mCi of (2) were injected. Ten minutes before the intravenous injection of (2), competitor groups were added. The loops received 100 μg of folic acid, and the treatment groups were injected with the corresponding amount of phosphate buffer. Time course observation of PET images obtained at various time points was performed 60–90 min after tracer injection. Subsequent data revealed that PET imaging provides the best visual diagnosis. 2) uptake was completely inhibited by competition with folic acid, whereas K B tumors became clearly visible. This is in vivo in response to FR (2). Without being bound by theory, the high radioactivity found in the kidneys is Radioactive uptake via FR expressed in the proximal tubule cells in the kidney and radioactive transpiration via renal excretion This is further believed to be due to the potential accumulation of hydroxylase in the blood. This is evidenced by the biodistribution studies described below. There is no significant uptake in other organs except the liver. Under competitive conditions, a significant blocking effect on hepatic uptake was observed.

[0216] Example: Baseline and competition conditions in nude mice bearing KB tumor xenografts on the left shoulder Ex vivo biodistribution studies of the compounds described herein under both conditions demonstrated FR( +) Demonstrates high and specific uptake in tumors. Whole blood, plasma, heart, kidney, liver, in lung, muscle, spleen, KB xenograft tumor tissue, and A549 xenograft tumor tissue 18 F-AIF-QC07017 and 18 Radiotracer F-AIF-QC07043 The amount of IgG was determined (Figure 1A, Figure 1B, and Figure 1C). The highest signal was observed in the kidney. Accumulation was observed in the liver to a much lesser extent. Without being bound by theory, it is possible that accumulation in the kidney The highest accumulation of radioactivity observed was in the hepatobiliary system, i.e., the liver, bile, and intestine / feces. Together with the relatively low uptake of the tracer, this demonstrates that renal excretion is the predominant route of excretion. Except for the kidney, accumulation in KB xenograft tumor tissue was the highest. Accumulation in A549 xenograft tumor tissue was significantly higher than that in the liver. In both KB and A549 xenograft tumor tissues, Accumulation in the nucleosomes is blocked under competitive conditions with folate (Figures 2A and 2B). 18 F-AIF -QC07017 and 18 FR specificity of F-AIF-QC07043 was confirmed in KB xenografts Both the single tumor tissue and the A549 xenograft tumor tissue were treated with the clinical trial compound, eta. The efficacy was comparable to that of rfolatide (EC20).

[0217] [Table 4]

[0218] [Table 5]

[0219] Example: DUPA-EAOA-Phe-Phe-NOTA- 68 Ga radioactive tracer ( 68 In vitro evaluation of Ga-QC08009 67 Ga 68 It has a longer half-life than Ga (approximately 3.3 days vs. approximately 68 minutes, respectively). Therefore 67 Ga for in vitro evaluation of Kd values and tissue imaging 68 G Used as a substitute for a. 67 Observed Kd values for Ga and tissue imaging In vitro evaluation 68 Please understand that this is a prophetic version of Ga. -EAOA-Phe-Phe-NOTA- 67 Ga( 67 Ga-NOTA-LC-PSM A(2)) was prepared in nearly quantitative radiochemical yield. In vivo analysis of both PSMA(+) and PSMA(+) cell lines (LnCaP and PIP-PC3) In vitro studies revealed high and specific PSMA-mediated uptake, with a Kd of 8.4. The values were 5±2.16 nM. PC3 is a PSMA-negative cell line, and LnCaP is a PSM A(+) cell line, and PIP-PC3 has higher PSMA expression. PIP-PC3 cells are transfected with 68 The uptake of Ga-QC08009 The amount of LnCaP and PIP-PC3 was small and did not change when competed. R 68 The uptake of Ga-QC08009 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 competitive ligand. Imaging during 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 Ga-NOTA-LC- In vivo micro-PET / CT scanning with PSMA(2) radiotracer The tumor showed uptake of 4.29% of the PSMA(+) tumors. The majority of the sex tracer was found in the bladder. Without being bound by theory, the data suggest that the primary excretory This is believed herein to be evidence that the route of administration is urinary. A small amount of radiotracer accumulation was observed in the kidney compared with the control group. The relatively high expression of PSMA in mouse kidneys compared with other tissues suggests that the 68 Ga -NOTA-LC-PSMA(2) This may be at least one of the reasons for the small amount of radiotracer accumulation. The present specification is considered to describe the part.

Claims

1. formula B-L-P zygote wherein B is a vitamin receptor binding ligand, a PSMA binding ligand, and a PSMA inhibitor. L is a bivalent linker; and P is a radical of a targeting agent selected from the group consisting of radioactive a radical of an imaging or radiotherapeutic agent, such as a nuclide or radionuclide-containing group; its precursor, or a compound that binds to a radionuclide or radionuclide-containing group, such as a metal chelating group or a pharmaceutically acceptable salt thereof.

2. 2. The conjugate of claim 1, comprising folate-Asp.

3. 2. The conjugate of claim 1, comprising folate-Arg.

4. The linker is lysine, arginine, or aspartic acid, or a combination thereof.

2. The conjugate of claim 1, comprising a polypeptide comprising:

5. The linker is of the formula NH—(CH ２ ) ２ 2. The method of claim 1, wherein the diradical of —NH is not included. The zygote.

6. formula or a derivative thereof containing a chelated metal.

7. The conjugate of claim 1 comprising folic acid-PEG.

8. formula or a derivative thereof containing a chelated metal.

9. formula or a derivative thereof containing a chelated metal.

10. 4. The method of claim 1, wherein the targeting agent is a radical of a PSMA-binding ligand or a PSMA inhibitor.

2. The conjugate according to claim 1.

11. formula wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. (or wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. (or 11. The conjugate of claim 10, comprising: wherein W is O or S.

12. The linker may be phenylalanine, lysine, arginine, or aspartic acid, or 11. The conjugate of claim 10, comprising a polypeptide comprising:

13. formula or a derivative thereof containing a chelated metal.

14. formula wherein n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. The conjugate of claim 10, comprising:

15. The linker is represented by the formula The conjugate of claim 10 comprising:

16. The linker is represented by the formula The conjugate of claim 10 comprising:

17. formula or a derivative thereof containing a chelated metal.

18. 18. The method according to claim 1, wherein the radionuclide is a positron-emitting radionuclide. The zygote.

19. The conjugate of any one of claims 1 to 17, wherein the radionuclide is a radiotherapeutic agent. body.

Images