Prostate-specific membrane antigen as an imaging biomarker in inflammatory bowel disease

Abstract

A method for imaging inflammation associated with inflammatory bowel disease (IBD) has been disclosed, which involves administering an imaging agent targeting prostate-specific membrane antigen (PSMA) to a subject and acquiring images.

Description

[Background technology]

[0001] (Cross-reference of related applications) This application claims the benefit of U.S. Provisional Application No. 63 / 533,081, filed on 16 August 2023, and the entire disclosure of that application is incorporated herein by reference.

[0002] (Background technology) Inflammatory bowel disease (IBD) is an idiopathic, chronic, and often dysfunctional inflammatory bowel disorder. It comprises two subtypes, Crohn's disease (CD) and ulcerative colitis (UC), each accounting for approximately 50% of IBD cases. IBD is a widespread gastrointestinal disorder, with a prevalence of approximately 0.2% in the Western population. In the United States alone, 1.4 million people are diagnosed with IBD, resulting in significant suffering and healthcare costs. The ability to accurately and non-invasively detect and monitor gastrointestinal inflammation in IBD patients will have far-reaching clinical implications by contributing to treatment decisions, avoiding unnecessary treatments, and enhancing monitoring during both treatment and remission periods. [Overview of the project]

[0003] In some aspects of the subject matter of this disclosure, a method is provided for imaging inflammation associated with inflammatory bowel disease (IBD), the method comprising administering an imaging agent targeting prostate-specific membrane antigen (PSMA) to a subject and acquiring an image.

[0004] In some embodiments, inflammation associated with IBD includes mucosal inflammation. In more embodiments, imaging assesses one or more of the location, extent, and disease activity of IBD. In specific embodiments, the extent of IBD includes the proportion of inflammation in the IBD stenosis.

[0005] In one embodiment, inflammatory bowel disease is selected from Crohn's disease (CD), ulcerative colitis (UC), and combinations thereof.

[0006] In one aspect, the image comprises a positron emission tomography (PET) image. In certain aspects, the image comprises a positron emission tomography / computed tomography (PET / CT) image.

[0007] In some aspects, the imaging agent targeting PSMA comprises a compound having the following formula.

Chemical formula

[0008] In one aspect, V is -NH-C(=O)-, and the imaging agent targeting PSMA comprises the following compound.

Chemical formula

[0009] In certain aspects, the reporting moiety Rpt comprises a radiolabeled prosthetic group. In one aspect, the radiolabeled prosthetic group is 11 C or 18 F. In certain aspects, the imaging agent targeting PSMA comprises a radiolabeled prosthetic group, and the imaging agent is 125 I-DClBzL, 18 F]JK-PSMA-7, 18 F-YC88, 125 I]DCIT, 18 F]DCFBC, 11 C]DCMC, MIP-1072, MIP-1095, 18 F]-PSMA-1007, 18 F]-flutamine, and 18 selected from F]FPy-DUPA-Pep. In a further aspect, the imaging agent targeting PSMA comprises 18 F]DCFPyL.

[0010] In other embodiments, the reporting portion Rpt comprises a chelate portion. In one embodiment, the chelate portion further 68 Ga, 64 Cu, 99m Tc, and [ 18 The imaging agent comprises a radiometallic material selected from [F]AlF. In certain embodiments, the imaging agent targeting PSMA comprises a chelate moiety, the imaging agent being selected from PSMA-11, PSMA-617, PSMA-I&T, PSMA I&S, PSMA-R2, PSMA-SR6, P16-093, PSMA-BCH, Bi-PSMA, MIP-1555, MIP-1519, MIP-1545, MIP-1558, MIP-1379, MIP-1427, MIP-1428, MIP-1404, and MIP-1405, and the chelate moiety further comprises a radiometallic material suitable for PET imaging.

[0011] In other embodiments, the method further includes administering to the subject one or more additional therapeutic agents to prevent or reduce the accumulation of the PSMA-targeting imaging agent in off-target non-cancerous tissues, such as the kidney or lacrimal gland, in combination with the PSMA-targeting imaging agent. In some embodiments, the one or more additional therapeutic agents are administered to the subject before the administration of the PSMA-targeting imaging agent. In other embodiments, the one or more additional therapeutic agents are administered to the subject simultaneously with the PSMA-targeting imaging agent. In certain embodiments, the off-target tissues are located in organs selected from the kidney, lacrimal gland, and salivary gland.

[0012] Certain aspects of the subject matter of this disclosure are described above, and these are resolved in whole or in part by the subject matter of this disclosure, but other aspects will become apparent as the description progresses in relation to the embodiments and drawings which are most appropriately described below.

[0013] This patent or patent application file includes at least one drawing created in color. A copy of this patent or patent application publication with the color drawing will be provided by the Office upon payment of the prescribed fee and request.

[0014] Having outlined the subject matter of this disclosure, we will now refer to the attached drawings, however, these drawings are not necessarily drawn to scale. [Brief explanation of the drawing]

[0015] [Figure 1] Figure 1A shows the accumulation of abnormally increased long segments of [18F]DCFPyL in the terminal ileum (indicated by black and white arrows in the subfigure). This is the [18F]DCFPyL PET / CT accumulation in the terminal ileum in the coronal section. Figure 1B shows the accumulation of abnormally increased long segments of [18F]DCFPyL in the terminal ileum (indicated by black and white arrows in the subfigure). This is an axial CT image. Figure 1C shows the accumulation of abnormally increased long segments of [18F]DCFPyL in the terminal ileum (indicated by black and white arrows in the subfigure). This is an axial PET image. Figure 1D shows the accumulation of abnormally increased long segments of [18F]DCFPyL in the terminal ileum (indicated by black and white arrows in the subfigure). This is an axial [18F]DCFPyL PET / CT fusion image. [Figure 2] Figure 2A is an ileocoscopic image showing inflammation and pseudopolyposis up to 20 cm from the anal margin and terminal ileal stenosis. Figure 2B is an ileocoscopic image showing inflammation and pseudopolyposis up to 20 cm from the anal margin and requiring balloon dilation. Figure 2C is an ileocoscopic image showing inflammation and pseudopolyposis up to 20 cm from the anal margin and successful dilation. [Figure 3]Figure 3A shows PSMA immunohistochemical staining (IHC) in a full-thickness distal colon section. Arrows and arrowheads indicate PSMA staining sites in the colon and ileum sections. Figure 3B shows PSMA immunohistochemical staining (IHC) in a full-thickness distal colon section. Arrows and arrowheads indicate PSMA staining sites in the colon and ileum sections. Figure 3C shows PSMA immunohistochemical staining (IHC) in a full-thickness distal colon section. Arrows and arrowheads indicate PSMA staining sites in the colon and ileum sections. Figure 3D shows PSMA immunohistochemical staining (IHC) in a full-thickness distal colon section. Arrows and arrowheads indicate PSMA staining sites in the colon and ileum sections. [Figure 4] Figure 4A shows redness, fragility, and deep ulcers in the rectum and sigmoid colon during colonoscopy. Figure 4B also shows redness, fragility, and deep ulcers in the rectum and sigmoid colon during colonoscopy. [Figure 5] Figure 5A shows abnormally increased [18F]DCFPyL uptake in the sigmoid colon and rectum on PET / CT. It shows abnormally increased [18F]DCFPyL uptake in the sigmoid colon and rectum on PET / CT. This is the [18F]DCFPyL PET / CT uptake of the sigmoid colon in the coronal view (indicated by arrows and arrowheads). Figure 5B shows abnormally increased [18F]DCFPyL uptake in the sigmoid colon and rectum on PET / CT. This is an axial CT image with arrows showing active inflammation in the sigmoid colon and rectum. Figure 5C shows abnormally increased [18F]DCFPyL uptake in the sigmoid colon and rectum on PET / CT. This is an axial PET image with arrows showing active inflammation in the sigmoid colon and rectum. Figure 5D shows abnormally increased [18F]DCFPyL uptake in the sigmoid colon and rectum on PET / CT. This is an axial [18F]DCFPyL PET / CT fusion image with arrows indicating active inflammation of the sigmoid colon and rectum. [Figure 6] Figure 6A shows a flexible sigmoidoscope image indicating a Mayo endoscopic subscore of 3. Figure 6B shows a flexible sigmoidoscope image indicating a Mayo endoscopic subscore of 3. Figure 6C shows a flexible sigmoidoscope image indicating a Mayo endoscopic subscore of 3. [Figure 7] Figure 7A is a [18F]DCFPyL PET / CT image showing abnormally increased uptake in the descending colon (indicated by the red arrow), sigmoid colon, and rectum, corresponding to endoscopic findings. It is a [18F]DCFPyL PET / CT uptake of the descending colon in the coronal view. Figure 7B is a [18F]DCFPyL PET / CT image showing abnormally increased uptake in the descending colon (indicated by the red arrow), sigmoid colon, and rectum, corresponding to endoscopic findings. It is an axial CT image with arrows showing active inflammation of the descending colon. Figure 7C is a [18F]DCFPyL PET / CT image showing abnormally increased uptake in the descending colon (indicated by the red arrow), sigmoid colon, and rectum, corresponding to endoscopic findings. It is an axial PET image with arrows showing active inflammation of the descending colon. Figure 7D is a [18F]DCFPyL PET / CT image showing abnormally increased uptake in the descending colon (indicated by the red arrow), sigmoid colon, and rectum, corresponding to the endoscopic findings. It is an axial [18F]DCFPyL PET / CT fusion image showing active inflammation in the descending colon. [Figure 8] Figure 8A shows a histological image of chronic active inflammation and PSMA IHC showing the absence of PSMA-positive cells in non-inflammatory sites (black arrows). Figure 8B shows a histological image of chronic active inflammation and PSMA IHC showing an increase in PSMA-positive cells in a colon section of the inflammatory site. [Figure 9] Figure 9A shows the absence of PSMA expression in IHC in non-inflammatory tissue. Figure 9B shows IHC in the inflammatory colon with transient increase in PSMA expression in the apical epithelial membrane (black arrowheads) and numerous PSMA-positive cells throughout the mucosa (black arrows). [Modes for carrying out the invention]

[0016] The subject matter of this disclosure will be described in more detail below with reference to the accompanying drawings, although not all embodiments of the invention are shown here. The same numbers refer to the same elements throughout. The subject matter of this disclosure can be implemented in a variety of forms and should not be construed as being limited to the embodiments described herein. Rather, these embodiments are provided to satisfy the legal requirements to which this disclosure applies. In fact, many modifications and other embodiments can be readily conceived from the subject matter of this disclosure by the benefit of being taught herein and in the accompanying drawings. Therefore, the subject matter of this disclosure is not limited to the specific embodiments disclosed, and modifications and other embodiments are understood to be included in the scope of the accompanying claims. I. Prostate-specific membrane antigen as an imaging biomarker in inflammatory bowel disease

[0017] Prostate-specific membrane antigen (PSMA) is highly and specifically elevated in the active inflamed mucosa of patients with inflammatory bowel disease (IBD). The subject of this disclosure is to show that this elevation can be detected using positron emission tomography / computed tomography (PET / CT) imaging agents that target PSMA, thereby enabling non-invasive visualization of inflammation.

[0018] More specifically, in some embodiments, the subject matter of the present disclosure provides a method for imaging inflammation associated with inflammatory bowel disease (IBD), the method comprising administering an imaging agent targeting prostate-specific membrane antigen (PSMA) to a subject and acquiring an image.

[0019] In certain embodiments, inflammation associated with IBD includes mucosal inflammation. In even more specific embodiments, imaging assesses one or more of the location, extent, and disease activity of the IBD. In certain embodiments, the extent of the IBD includes the percentage of inflammation in the IBD stenosis. In certain embodiments, inflammatory bowel disease is selected from Crohn's disease (CD), ulcerative colitis (UC), and combinations thereof. In certain embodiments, imaging includes positron emission tomography (PET) images. In even more specific embodiments, imaging includes positron emission tomography / computed tomography (PET / CT) images. A. Representative PSMA-targeted imaging agents

[0020] In some embodiments, low molecular weight (or small molecule) ligands having affinity for PSMA can be combined with chelate moieties that bind to radiolabeled prosthetic groups or radiometallic metals to image inflammation in IBD. The main classes of PSMA low molecular weight ligands include phosphorinate compounds and thiols, glutamate-phospholamidates, glutamate-ureid derivatives, so-called PSMA-targeted carbamates and reverse carbamate derivatives. See, for example, WO2016065145 and WO2017027870, which are incorporated herein by reference in their entirety.

[0021] Examples of low molecular weight PSMA-binding motifs include, but are not limited to, the following: [ka]

[0022] Among these motifs, urea-based glutamate derivatives have attracted the most attention. Therefore, in some embodiments, the PSMA-targeted imaging agents disclosed herein include the glutamine-urea-lysine PSMA-binding motif or its modifications and derivatives. [ka] Here, V is selected from -NH-C(=O)-, -C(=O)-NH-, and -NH-. L is a linker, Rpt is the reporting section.

[0023] In certain embodiments, V is -NH-C(=O)-, and the PSMA-targeted imaging agent includes: [ka]

[0024] Linker "L" may be any suitable linker known to the industry. Typical linkers include, but are not limited to, those selected from (a), (b), (c), or (d). [ka] (a) Here, p1, p2, p3, and p4 can be arranged in any order. t1 and t2 are integers selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8, respectively. p1, p3, and p4 are each independently either 0 or 1. p2 is an integer selected from the group consisting of 0, 1, 2, and 3, and if p2 is 2 or 3, each R1 can be the same or different. m1 and m2 are integers independently selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8. W1 is selected from the group consisting of bond, -S-, -C(=O)-, -C(=O)-NR-, and -NR-C(=O)-. W2 is a bond, -S-, -CH2-C(=O)-NR-, -C(=O)-, -NRC(=O)-, -NR'C(=O)NR-, -NRC(=S)NR'2-, - NRC(=O)O-, -OC(=O)NR-, -OC(=O)-, -C(=O)NR-, -NR-C(=O)-, -C(=O)O-, -(O-CH2-CH2)q -and-(CH2-CH2-O) q A group consisting of is selected, where q is selected from 1, 2, 3, 4, 5, 6, 7, and 8. Each R or R' is independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and -OR4, where R4 is selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl, and q is as defined previously. Tz is a triazole group, and may or may not be present; if present, it is selected from the following options. [ka] Each R1 is independently H, C1-C6 alkyl, and C3-C 12 Ariel, -(CH2) q -C3-C 12 Ariel, -C4-C 16 Alkylaryl, or -(CH2) q -C4-C 16 The alkylaryls R2 and R3 are independently H and -CO2R5, respectively, where R5 is H, C1-C6 alkyl, and C3-C 12 Aryl, and C4-C 16 Selected from the group consisting of alkylaryls, if one of R2 or R3 is -CO2R5, the other is H. V is selected from the group consisting of -C(O)-, -C(S)-, -NRC(O)-, -NRC(S)-, and -OC(O)-. [ka] (b) Here, p1, p2, p3, m1, m2, Tz, W2, R, R1, R2, R3, and V are as defined above. (c) -L1-, -L2-L3-, or -L1-L2-L3-, where: L1 is -NR-(CH2) q -[O-CH2-CH2-O] q -(CH2) q -C(=O)-, L2 is -NR-(CH2) q -C(COOR5)-NR-, L3 is -(O=)C-(CH2) q -C(=O)-, Here, each q is independently selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8, and R and R5 are as defined above. (d)-(CR6H) q -(CH2) q -C(=O)-NR-(CH2) q -O- or -NR-(CH2) q -O-, where each q and R are as defined above, and R6 is H or -COOR5.

[0025] Furthermore, in certain embodiments, linker "L" is selected from the following: [ka] Here, u is an integer selected from 1, 2, 3, 4, 5, 6, 7, and 8, and R and R5 are as defined above.

[0026] In certain embodiments, the reporting portion "Rpt" is, 18 F, 124 I, 125 I, 131 I, and 211 It comprises a radiolabeled prosthetic group containing a radioactive isotope selected from the group consisting of At.

[0027] Furthermore, in certain embodiments, the radiolabeled prosthetic group is selected from the group consisting of the following: [ka]

[0028] Here, each X is 18 F, 124 I, 125 I, 131 I, and 211 A radioactive isotope selected from the group consisting of At, where each R and R' is as defined above, and each n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0029] Furthermore, in certain embodiments, the radiolabeled prosthetic group is selected from the group consisting of the following: [ka]

[0030] In one embodiment, the reporting portion "Rpt" comprises a chelating agent. In a more specific embodiment, the chelating agent is DOTAGA(1,4,7,10-tetraazacyclododecane, 1-(glutaric acid)-4,7,10-triacetic acid), DOTA(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTASA(1,4,7,10-tetraazacyclododecane-1-(2-succinic acid)-4,7,10-triacetic acid), CB-DO2A(10-bis(ca (Ruboxymethyl)-1,4,7,10-Tetraazabicyclo[5.5.2]tetradecane), DEPA(7-[2-(bis-carboxymethylamino)-ethyl]-4,10-bis-carboxymethyl-1,4,7,10-tetraaza-cyclododeca-1-yl-acetic acid), 3p-C-DEPA(2-[(carboxymethyl)][5-(4-nitrophenyl-1-[4,7,10-tris(carboxymethyl)-1,4,7,1 0-Tetraazacyclododecane-1-yl]pentan-2-yl)amino]acetic acid), TCMC(2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamonylmethyl)-cyclododecane), oxo-DO3A(1-oxa-4,7,10-triazacyclododecane-5-S-(4-isothiocyanatobenzyl)-4,7,10-triacetic acid), p-NH2 -Bn-Oxo-DO3A(1-oxa-4,7,10-tetraazacyclododecane-5-S-(4-aminobenzyl)-4,7,10-triacetic acid), TE2A((1,8-N,N'-bis-(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane), MM-TE2A, DM-TE2A, CB-TE2A(4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2)Hexadecane), CB-TE1A1P(4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8-(methanecarboxylic acid)), CB-TE2P(1,4,8,11-tetraazacyclotetradecane-1,8-bis(methanephosphonic acid)), TETA(1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), NOTA(1,4,7-triaz (NOTAGA)1,4,7-triazacid-1,4-diyl(triazonanane-1,4-diacetate), NODA(1,4,7-triazacid-1,4-diyl(triazonanane [Ethyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl}-acetic acid), TACN-TM (N,N',N'', Tris(2-mercaptoethyl)-1,4,7-triazazcyclononane), Diamsar(1,8-diamino-3,6,10,13,16,19-hexazabicyclo(6,6,6)eicosane, 3,6,10,13,16,19-hexazabicyclo[6.6.6]eicosane) Selected from the group consisting of cosane-1,8-diamine, Sarar (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane-1,8-diamine), AmBaSar (4-((8-amino-3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane-1-ylamino)methyl)benzoic acid), and BaBaSar.

[0031] Furthermore, in certain embodiments, the chelating agent is selected from the group consisting of the following: [ka] [ka] [ka] [ka]

[0032] In one embodiment, the chelating agent further comprises a radioactive metal. In a particular embodiment, the radioactive metal is 60 Cu, 62 Cu, 64 Cu, 67 Cu, 203 Pb, 212 Pb, 225 Ac, 177 Lu, 99m Tc, 68 Ga, 149 Tb, 86 Y, 90 Y, 111 In, 186 Re, 188 Re, 153 Sm, 89 Zr, 213 Bi, 212 Bi, 212 Pb, 67 Ga, 47 Sc, 166 Ho, and [ 18 Selected from F]AlF.

[0033] Furthermore, in certain embodiments, the imaging agent targeting PSMA comprises the following: [ka] Here, R is the reporting portion selected from the following. [ka] n is an integer selected from 1, 2, 3, and 4, and X is a radioactive isotope of iodine, chlorine, bromine, or astatine. In one embodiment, the radioactive isotopes of iodine, chlorine, bromine, or astatine are: 18 F, 123 I, 124 I, 125 I, 126 I, 131 I, 75 Br, 76Br, 77 Br, 80 Br, 80 mBr, 82 Br, 83 Br, and 211 Selected from At. For example, if international PCT patent application publication number 2010 / 014933 is referenced, the entire application is included here as a reference.

[0034] Furthermore, in certain embodiments, the imaging agent that targets PSMA is [ 18 F]DCFPyL. [ka] [ 18 F]DCFPyL and related compounds, as well as methods for producing them, are disclosed in U.S. Patent Nos. 8,487,129, 8,778,305, 9,226,981, 9,861,713, 10,500,292, and 10,947,197, each of which is incorporated herein by reference in whole.

[0035] Those skilled in the art will understand that other PSMA-targeting imaging agents are also applicable to the methods disclosed herein. Such PSMA-targeting imaging agents include, but are not limited to, the following: [ka]

[0036] Other imaging agents targeting PSMAs that have prosthetic groups substituted with radiolabeled halogens include: [ka]

[0037] Representative glutamine-urea-lysine PSMA targeting imaging agents with chelating groups include novel chemical entities (NCEs) approved by the FDA, using HBED-CC chelating agents, and also 18 able to coordinate with 68 Ga PSMA-11 ( 68 including the case where Ga is 18 substituted with 68 Ga]PSMA-617 (including 68 Ga]PSMA-I&T), 99 mTc]PSMA I&S, 68 Ga]PSMA-R2, PSMA-SR6, 68 Ga]P16-093, 18 F]-PSMA-BCH, 18 F]-Bi-PSMA, but not limited to these.

Chemical Structure

Chemical Structure

Chemical Structure

[0038] Other glutamine-urea-lysine-based PSMA ligands include those described in U.S. Patent Nos. 8,211,401, 8,211,402, 8,465,725, 8,487,129, 8,562,945, and PCT / US2014 / 011047, and the entire contents of each of these are incorporated herein by reference. Representative Glu-Urea-based PSMA ligands linked to the chelating moiety include, but are not limited to, MIP-1555, MIP-1519, MIP-1545, MIP-1427, MIP-1428, MIP-1379, MIP-1558, MIP-1405, MIP-1404.

Chemical Structure

Chemical Structure

[0039] In other embodiments, the imaging agent that targets PSMA 18 Contains 1F-labeled phospholamide. [ka]

[0040] In yet another embodiment, the imaging agent targeting PSMA is as follows: [ka]

[0041] The “subjects” treated by the methods disclosed herein, including many embodiments, are preferably human subjects, but it should be understood that the methods described herein are effective for all vertebrate species and the term “subjects” includes these. Thus, “subjects” include human subjects for medical purposes such as treatment of an existing condition or disease, or prophylactic treatment to prevent the onset of a condition or disease, or animal subjects for medical, veterinary, or embryological purposes. Suitable animal subjects include, but are not limited to, primates (humans, monkeys, apes, etc.), cattle (cattle, bulls, etc.), sheep (sheep, etc.), goats (goats, etc.), pigs (pigs, hogs, etc.), equine (horses, donkeys, zebras, etc.), felines (wild and domestic cats), canines (dogs), rabbits (rabbits, hares, etc.), and rodents (mice, rats, etc.). The animals may be transgenic animals. In some embodiments, the subject is a human being, including but not limited to fetuses, newborns, infants, toddlers, and adults. Furthermore, “subject” also includes patients who are suffering from or suspected to be suffering from a condition or disease. Thus, the terms “subject” and “patient” are used synonymously herein. The term “subject” also refers to an organism, tissue, cell, or group of cells derived from the subject.

[0042] B. Pharmaceutical compositions and administration In other words, this disclosure provides pharmaceutical compositions in which an imaging agent targeting one type of PSMA is mixed with pharmaceutically acceptable excipients, either alone or in combination with one or more additional therapeutic agents. Those skilled in the art will recognize that the pharmaceutical compositions include pharmaceutically acceptable salts of the compounds. Pharmaceutically acceptable salts include salts of the active compound that are well known to those skilled in the art and prepared with relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein. Where the disclosed compounds contain relatively acidic functional groups, base addition salts can be obtained by exchanging one basic counterion (base) in an ionic complex with another, either in a solvent-free or suitable inert solvent, or by ion exchange, by contacting a sufficient amount of the neutral form of such compound with the desired base. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts.

[0043] If the compounds of this disclosure contain relatively basic functional groups, an acid addition salt can be obtained by contacting the neutral form of the compound with a desired acid in sufficient quantity, either without a solvent or in a suitable inert solvent, or by ion exchange, where one acidic counterion (acid) in the ionic complex is replaced by another. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, and phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and trifluoroacetic acid (TFA). Furthermore, salts of amino acids such as arginine, and salts of organic acids such as glucuronic acid and galacturonic acid are also included (see, for example, Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of this disclosure contain both basic and acidic functional groups and can be converted into either a base or an acid addition salt.

[0044] Accordingly, pharmaceutically acceptable salts available for use in the subject matter of this disclosure include, but are not limited to, acetates, benzenesulfons, benzoates, bicarbonates, hydrogen tartrates, bromides, calcium edetate, cansylates, carbonates, citrates, edetates, edisylates, estrates, esylates, fumarates, guceptates, glucons, glutamates, glycolyl arsanilates, hexylresorcinate, hydravamin, hydrobromide, hydrochlorides, hydroxynaphthalates, iodides, isethionates, lactates, lactobionates, malates, maleates, mandelates, mesylates, mucates, napsylates, nitrates, pamoates (embonates), pantothenates, phosphates / diphosphates, polygalacturonates, salicylates, stearates, acetate trioxides, succinates, sulfates, tannates, tartrates, theocrates, and the like. Other pharmaceutically acceptable salts are described, for example, in Remington: The Science and Practice of Pharmacy (20th edition), Lippincott, Williams & Wilkins (2000). For therapeutic and / or diagnostic use, the compounds disclosed herein can be prepared in various dosage forms, including systemic and topical administration. Techniques for preparation and administration are generally described in Remington: The Science and Practice of Pharmacy (20th edition), Lippincott, Williams & Wilkins (2000), etc.

[0045] Depending on the specific condition being treated, such agents may be prepared in liquid or solid dosage forms and administered systemically or topically. For example, as is known to those skilled in the art, they may also be administered in time-release or sustained-release forms. Techniques for preparation and administration are described in Remington: The Science and Practice of Pharmacy (20th edition), Lippincott, Williams & Wilkins (2000), etc. Appropriate routes of administration include oral, buccal, inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration, as well as intramuscular, subcutaneous, intramedullary injection, and further, intrathecal, intraventricular, intravenous, intra-articular, intrasternal, synovial, intrahepatic, intralesional, intracranial, intraperitoneal, intranasal, intraocular injection, and other methods of administration.

[0046] For injection, the agents of this disclosure can be prepared and diluted in physiologically suitable buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. In the case of such transmucosal administration, an absorption enhancer suitable for the barrier to be traversed is used in the formulation. Such absorption enhancers are widely known in the industry.

[0047] The scope of this disclosure also includes formulation using pharmaceutically acceptable inert carriers to prepare the compounds of this disclosure into doses suitable for systemic administration. With appropriate carrier selection and appropriate manufacturing methods, the compositions of this disclosure, particularly those formulated as solutions, can be administered parenterally, such as by intravenous injection. The compounds can be readily formulated into doses suitable for oral administration using pharmaceutically acceptable carriers widely known to those skilled in the art. With such carriers, the compounds of this disclosure can be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions, etc., which can be taken orally by subjects (e.g., patients) under treatment.

[0048] For nasal or inhalation administration, the agents of this disclosure can be formulated in ways known to those skilled in the art, and may include, but are not limited to, dissolving, diluting, or dispersing agents (such as physiological saline), preservatives (such as benzyl alcohol), absorption enhancers, fluorocarbons, and the like.

[0049] In certain embodiments, the imaging agent targeting PSMA is administered intranasally in a form selected from the group consisting of nasal spray, nasal solution, powder, granules, cachet, tablet, aerosol, paste, cream, gel, ointment, salve, foam, paste, lotion, cream, oily suspension, emulsion, solution, patch, and stick. In this specification, “administration via nasal route” means administration through the nasal cavity structure.

[0050] The pharmaceutical compositions available in this disclosure include compositions containing an active ingredient in an amount effective to achieve its purpose. Determining the effective dose is within the capabilities of those skilled in the art, particularly considering the detailed disclosure herein. In general, the compounds of this disclosure are effective in a wide range of doses. For example, in the treatment of adult humans, doses of 0.01–1000 mg, 0.5–100 mg, 1–50 mg, and 5–40 mg per day are examples of use. Examples of doses that are not limited to 10–30 mg per day are also included. The exact dose depends on the route of administration, the form of administration of the compound, the subject being treated, the subject's body weight, the bioavailability of the compound, the absorption, distribution, metabolism, and excretion (ADME) toxicity of the compound, as well as the preference and experience of the attending physician.

[0051] In addition to the active ingredient, these pharmaceutical compositions may include a suitable pharmaceutically acceptable carrier containing excipients and adjuvants that facilitate the formulation of the active ingredient. Formulations prepared for oral administration may be in the form of tablets, sugar-coated tablets, capsules, or solutions.

[0052] Oral pharmaceutical preparations can be manufactured by mixing an active ingredient with a solid excipient, optionally grinding the resulting mixture, and further granulating it with appropriate adjuvants to obtain tablets or sugar-coated tablet cores. Suitable excipients include sugars such as lactose, sucrose, mannitol, and sorbitol, as well as cellulose preparations (e.g., corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose (CMC), and / or polyvinylpyrrolidone (PVP: povidone)). Optionally, disintegrants such as cross-linked polyvinylpyrrolidone, agar, alginic acid or its salts (e.g., sodium alginate) may also be added.

[0053] The sugar-coated tablet core is subjected to an appropriate coating. This may include concentrated sugar solutions containing gum arabic, talc, polyvinylpyrrolidone, carbopole gel, polyethylene glycol (PEG), and / or titanium dioxide, lacquer solutions, or suitable organic solvents or solvent mixtures. Colorants or pigments may be added to the tablets or sugar coatings to characterize them for identification or to distinguish between different combinations of active ingredient dosages.

[0054] Orally administered pharmaceutical formulations may include gelatin push-fit capsules or flexible seal capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). Push-fit capsules may contain the active ingredient mixed with excipients such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally, stabilizers. Within the flexible capsule, the active ingredient can be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol (PEG). Further stabilizers may also be added.

[0055] Generally, "effective dose" refers to the amount of active agent or drug delivery device required to elicit the desired biological response. As those skilled in the art will understand, the effective dose of an active agent or device can vary depending on factors such as the desired biological endpoint, the agent being delivered, the composition of the pharmaceutical composition, and the target tissue.

[0056] The term “combination” is used in its broadest sense to mean that a subject is administered at least two agents, more specifically the compounds described herein and at least one other therapeutic agent. More specifically, the term “in combination” refers to the simultaneous administration of two (or more) active ingredients, for example, for the treatment of a single disease condition. The active ingredients used herein may be administered mixed in a single dosage form, simultaneously in separate dosage forms, or alternately or consecutively in separate dosage forms on the same day or on different days. In one embodiment of this disclosure, the active ingredients are mixed and administered in a single dosage form. In other embodiments, the active ingredients are administered in separate dosage forms (for example, when it is desirable to change only the amount of one). The single dosage form may contain additional active ingredients for the treatment of a disease condition.

[0057] Furthermore, the compounds described herein can be administered alone or in combination with adjuvants that enhance the stability of the compounds, or in combination with one or more therapeutic agents, which in certain embodiments can facilitate the administration of pharmaceutical compositions containing them, enabling increased solubility or dispersion, enhanced inhibitory activity, provision of adjunctive therapy, or inclusion of other active ingredients. Such combination therapies have the advantage of reducing the dose of conventional therapeutic agents, thereby avoiding toxicity and adverse side effects that may occur when these agents are used as monotherapies.

[0058] The timing of administration of the compounds and at least one additional therapeutic agent described herein may be modified as long as a beneficial effect from the combination of these agents is obtained. Therefore, the expression “in combination” refers to the administration of the compounds and at least one additional therapeutic agent described herein simultaneously, sequentially, or in combination thereof. Accordingly, a subject administered with a combination of the compounds and at least one additional therapeutic agent described herein may receive the compounds and at least one additional therapeutic agent simultaneously (i.e., simultaneously) or at different times (i.e., sequentially, in any order, on the same day or on different days), as long as a combined effect of the two agents is obtained in the subject.

[0059] When administered consecutively, each agent may be administered at intervals of 1, 5, 10, 30, 60, 120, 180, 240 minutes or longer from each other. In other embodiments, agents administered consecutively may be administered at intervals of 1, 5, 10, 15, 20 days or longer from each other. When the compounds described herein and at least one additional therapeutic agent are administered simultaneously, each may be administered to the subject as a separate pharmaceutical composition comprising the compound or at least one additional therapeutic agent, or as a single pharmaceutical composition comprising both agents.

[0060] When administered in combination, the effective concentration of each agent required to elicit a specific biological response may be lower than the effective concentration when each agent is administered alone. Therefore, the dose of one or more agents can be reduced compared to the dose required when administered individually. The effects of multiple agents may be additive or synergistic, or not. Each agent may be administered multiple times.

[0061] In some embodiments, two or more agents can have a synergistic effect when administered in combination. In this specification, the terms “synergistic,” “synergistic,” and “synergistically,” and their derivatives, such as “synergistic effect,” “synergistic combination,” or “synergistic composition,” refer to a situation where the biological activity of a combination of the compounds described herein and at least one additional therapeutic agent is greater than the sum of the biological activities of each agent when administered individually.

[0062] The synergistic effect can be expressed as a "synergistic index (SI)," which can generally be calculated from the following ratios using the method described by FCKull et al., Applied Microbiology 9, 538 (1961). Q a / Q A +Q b / Q B =Geometric Index (SI) Here, Q A This is the concentration at which the endpoint was produced with respect to component A alone. Q a This is the concentration at which component A in the mixture produced the endpoint. Q B This is the concentration at which the endpoint was produced with respect to component B alone. Q b This is the concentration at which component B in the mixture produced the endpoint.

[0063] Generally, Q a / Q A and Q b / Q B If the sum is greater than 1, an antagonistic effect is observed. If the sum is 1, an additive effect is observed. If the sum is less than 1, a synergistic effect is observed. A smaller SI indicates a greater synergistic effect from the mixture. Therefore, a "synergistic combination" has higher activity than would be expected based on the observed activity of the components when used individually. Furthermore, "synergistic effective amount" refers to the amount of a component needed to exert a synergistic effect, for example, with other therapeutic agents present in the composition.

[0064] In some embodiments, the PSMA-targeted imaging agents of this disclosure may be administered in combination with one or more additional therapeutic agents to prevent or reduce the accumulation of prostate-specific membrane antigen (PSMA) imaging agents in off-target non-cancerous tissues such as the kidneys, lacrimal glands, and salivary glands. See, for example, WO2018191376 (A prodrug of 2-PMPA for the protection of healthy tissue during PSMA-targeted cancer imaging or radiotherapy, Slusher et al., published October 18, 2018). See also U.S. Patents 11,167,049, 10,668,174, and 9,956,305, each of which is incorporated herein by reference in whole.

[0065] C.Definition Certain terms are used in this specification, but these are used in a general and descriptive sense and not for limiting purposes. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art.

[0066] The following terms relating to the PSMA-targeting imaging agents of this disclosure are expected to be well understood by those skilled in the art, but the following definitions are provided to facilitate the explanation of this disclosure. These definitions are not intended to preclude any definitions that would become apparent to those skilled in the art when reviewing this specification, but are intended to supplement and illustrate them.

[0067] In this specification, the terms “substitution” or “substituent” refer to the substitution of one functional group on a molecule with another, as understood by those skilled in the art, including whether or not they are modified by the word “optionally,” as long as the valence of all atoms is maintained. Where multiple positions in a particular structure can be substituted by multiple substituents from a specified group, the substituents at each position may be identical or different. Furthermore, substituents may be further substituted (for example, when a substituent of an aryl group has further substituents, such as other aryl groups, and those aryl groups are further substituted at one or more positions).

[0068] When substituents or linking groups are written from left to right in a conventional chemical formula, substituents that would be chemically identical when the structure is written from right to left are also included. For example, -CH2O- is equivalent to -OCH2-, -C(=O)O- is equivalent to -OC(=O)-, -OC(=O)NR- is equivalent to -NRC(=O)O-, and so on.

[0069] When the term "independently selected" is used, the referenced substituents (e.g., groups such as the R group, R1, R2, etc., or variables such as "m" or "n") may be the same but different. For example, both R1 and R2 may be substituted alkyl groups, or R1 may be hydrogen and R2 may be a substituted alkyl group, etc.

[0070] In this specification, when the terms "a," "an," or "a(n)" refer to a group of substituents, they mean at least one. For example, when a compound is substituted with an "an" alkyl or aryl, it means that the compound is optionally substituted with at least one alkyl and / or at least one aryl. Furthermore, when a substructure is substituted with an R substituent, the group may be referred to as "R-substituted." When a substructure is R-substituted, it is substituted with at least one R substituent, and each R substituent can be optionally different.

[0071] A named "R" or group has a structure that a person skilled in the art would recognize as corresponding to its name, unless otherwise defined herein. For illustrative purposes, some of the representative "R" groups shown above are defined below.

[0072] The description of compounds in this disclosure is limited by the principles of chemical bonding known to those skilled in the art. Therefore, where a group can be substituted with one or more substituents, the substitutions are selected in accordance with the principles of chemical bonding and in such a way that the resulting compound is not inherently unstable, or is not a compound that those skilled in the art would recognize as unstable under room temperature conditions, such as aqueous, neutral, or other known physiological conditions. For example, heterocycloalkyl or heteroaryl compounds avoid inherent instability by being bonded to the remainder of the molecule via ring heteroatoms, in accordance with the principles of chemical bonding known to those skilled in the art.

[0073] Unless otherwise explicitly defined, “substituents” as used herein includes substructures selected from one or more functional groups as defined below.

[0074] As used herein, “hydrocarbon” refers to any chemical group containing hydrogen and carbon. Hydrocarbons may be substituted or unsubstituted. As those skilled in the art will know, in any substitution, all valencies must be satisfied. Hydrocarbons may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic. Exemplary hydrocarbons are further defined below and include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, allyl, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl, and the like.

[0075] When used alone or as part of another substituent, "alkyl" refers to a monovalent group obtained by removing a hydrogen atom from any carbon atom of an alkane, unless otherwise specified. n H 2n+1 This means that the group obtained by removing a hydrogen atom from the terminal carbon atom of a straight-chain alkane is a n-alkyl (n-alkyl) group H(CH2). n It forms a subclass of RCH2, R2CH(R≠H), and R3C(R≠H). The groups RCH2, R2CH(R≠H), and R3C(R≠H) are primary, secondary, and tertiary alkyl groups, respectively. Alkyls are linear (i.e., unbranched) or branched acyclic hydrocarbons having a specified number of carbon atoms (i.e., C 1-10(contains 1 to 10 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms). In certain embodiments, "alkyl" is C 1-20 This refers to a structure containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms.

[0076] Typical alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, and dodecyl.

[0077] "Branched" refers to an alkyl group in which a lower alkyl group such as methyl, ethyl, or propyl is bonded to a linear alkyl group. "Lower alkyl" refers to an alkyl group having 1 to approximately 8 carbon atoms (i.e., C 1-8 Alkyl) refers to alkyl groups having, for example, 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. "Higher alkyl" refers to alkyl groups having approximately 10 to approximately 20 carbon atoms, for example, alkyl groups having 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. In certain embodiments, "alkyl" specifically refers to C 1-8 This refers to a linear alkyl group. In other embodiments, "alkyl" specifically refers to C 1-8 This refers to branched-chain alkyl groups.

[0078] Alkyl chains can be optionally substituted with one or more alkyl substituents ("substituted alkyls"), and these substituents may be the same or different. "Alkyl substituents" include, but are not limited to, alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxy, alkoxy, alkylthio, arylthio, aralkyloxy, aralkylthio, carboxyl, alkoxycarbonyl, oxo, cycloalkyl, etc. The alkyl chain can be optionally inserted or substituted with one or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms, and the nitrogen substituents may be hydrogen, lower alkyl (also referred to herein as "alkylaminoalkyl"), or aryl.

[0079] Therefore, in this specification, "substituted alkyl" includes alkyl groups in which one or more atoms or functional groups of an alkyl group are substituted with other atoms or functional groups, such as alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxy, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, cyano, mercapto, etc.

[0080] When used alone or in combination with other terms, "heteroalkyl" means, unless otherwise specified, a linear or branched chain having 1 to 20 carbon atoms or heteroatoms, or a cyclic hydrocarbon group having 3 to 10 carbon atoms or heteroatoms, or a combination thereof, comprising at least one carbon atom and at least one heteroatom (selected from O, N, P, Si, S), wherein the nitrogen, phosphorus, and sulfur atoms may be optionally oxidatively substituted, and the nitrogen heteroatom may be optionally quaternized. The heteroatom (O, N, P, S, Si) may be located either internally within the heteroalkyl group or at a position where the alkyl group is bonded to the remainder of the molecule. Examples include -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, O-CH3, -O-CH2-CH3, -CN, etc. Two or up to three heteroatoms may be consecutive, for example, -CH2-NH-OCH3, -CH2-O-Si(CH3)3, etc.

[0081] As stated above, heteroalkyl groups as used herein include groups bonded to the remainder of the molecule via a heteroatom, such as -C(O)NR', ​​-NR'R'', -OR', -SR, -S(O)R, and -S(O2)R'. When the term "heteroalkyl" is used and a specific heteroalkyl group, such as -NR'R, is described, it should be understood that the terms heteroalkyl and NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is listed for clarification. Therefore, "heteroalkyl" as used herein should not be interpreted as excluding specific heteroalkyl groups such as -NR'R''.

[0082] "Cyclic" and "cycloalkyl" refer to monovalent groups obtained by removing hydrogen atoms from the ring carbon atoms of cycloalkanes. Cycloalkanes are saturated monocyclic hydrocarbons, with or without side chains, such as cyclobutane. Unsaturated monocyclic hydrocarbons having one intraring double or triple bond are called cycloalkenes and cycloalkynes, respectively. Those having multiple such multiple bonds are called cycloalkadienes, cycloalkatrienes, etc. A comprehensive term for cyclic hydrocarbons having any number of such multiple bonds is cyclic olefin or cyclic acetylene. In this specification, cycloalkyl can be a non-aromatic monocyclic or polycyclic ring system consisting of about 3 to about 10 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, 10 carbon atoms. Cycloalkyl groups may optionally be partially unsaturated. Cycloalkyl groups may optionally be substituted with alkyl substituents (as defined herein), oxos, and / or alkylenes. A cyclic alkyl chain may be optionally inserted or substituted with one or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms, where the nitrogen substituent can be hydrogen, an unsubstituted alkyl, a substituted alkyl, an aryl, or a substituted aryl. This results in a heterocyclic group. Typical monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Polycyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphan, noadamantyl, and condensed ring systems such as dihydronaphthalene and tetrahydronaphthalene.

[0083] As used herein, "cycloalkylalkyl" means a cycloalkyl group as defined above that also contains an alkylene group (e.g., C) as defined above. 1-20 This refers to molecules that are bonded to the parent molecule via an alkylene group. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.

[0084] A "cycloheteroalkyl" or "heterocycloalkyl" is a non-aromatic, unsaturated, or partially unsaturated cycloalkyl ring system having 3 to 10 members, which is a substituted or unsubstituted cycloalkyl ring system containing one or more heteroatoms (which may be the same or different), the heteroatoms being selected from the group consisting of nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), and silicon (Si), and which may optionally contain one or more double bonds.

[0085] Cycloheteralkyl rings may optionally be bonded to other cycloheteralkyl rings and / or non-aromatic hydrocarbon rings by condensation or other means. Heterocyclic rings include those having 1 to 3 heteroatoms (independently selected from oxygen, sulfur, and nitrogen), where the nitrogen and sulfur heteroatoms may optionally be oxidatively substituted, and the nitrogen heteroatom may optionally be quaternized. In certain embodiments, “heterocyclic” means a non-aromatic five-membered, six-membered, or seven-membered ring or polycyclic group (e.g., a bicyclic or tricyclic group) in which at least one ring atom is a heteroatom selected from O, S, and N (where the nitrogen and sulfur heteroatoms may be optionally oxidized), comprising a condensed six-membered ring having 1 to 3 heteroatoms (independently selected from oxygen, sulfur, and nitrogen), wherein (i) each five-membered ring has 0 to 2 double bonds, each six-membered ring has 0 to 2 double bonds, and each seven-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally oxidatively substituted, and (iii) the nitrogen heteroatom may be optionally quaternatively substituted, and (iv) any of the heterocyclic rings may be condensed with an aromatic ring or a heteroaromatic ring. Representative cycloheteralkyl ring systems include, but are not limited to, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiadinyl, and tetrahydrofuranyl.

[0086] In this specification, the terms "cycloalkyl" and "heterocycloalkyl" refer to the cyclic versions of "alkyl" and "heteroalkyl," respectively, unless otherwise specified. Furthermore, in the case of heterocycloalkyls, the heteroatom can occupy a position where it is bonded to the remainder of the molecule. Examples of cycloalkyls include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, and cycloheptyl. Examples of heterocycloalkyls include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, and 2-piperazinyl. The terms "cycloalkylene" and "heterocycloalkylene" refer to divalent derivatives of cycloalkyl and heterocycloalkyl, respectively.

[0087] In this specification, the terms “bicycloalkyl” and “bicycloheteroalkyl” refer to two cycloalkyl or cycloheteroalkyl compounds bonded together. Non-limiting examples include bicyclohexane and bipiperidine.

[0088] Unsaturated hydrocarbons have one or more double or triple bonds. Examples of unsaturated alkyl groups include vinyl, 2-propenyl, clotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and their higher homologs and isomers. Alkyl groups limited to hydrocarbon groups are called "homoalkyls."

[0089] More specifically, in this specification, “alkenyl” means a linear or branched C2 molecule having at least one carbon-carbon double bond. 2-20This refers to a monovalent group obtained by removing one hydrogen molecule from a hydrocarbon moiety. Examples of alkenyl groups include ethenyl (i.e., vinyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, pentenyl, hexenyl, octenyl, allenyl, and butadienyl.

[0090] In this specification, "cycloalkenyl" refers to a cyclic hydrocarbon containing at least one carbon-carbon double bond. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.

[0091] In this specification, "alkynyl" means a linear or branched chain having a predetermined number of carbon atoms and containing at least one carbon-carbon triple bond. 2-20 This refers to a monovalent group derived from hydrocarbons. Examples of "alkynyl" groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, pentynyl, hexynyl, and heptynyl groups.

[0092] The term "alkylene" refers to a linear or branched divalent aliphatic hydrocarbon group (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms) derived from an alkyl group having 1 to about 20 carbon atoms, either by itself or as part of other substituents. Alkylene groups can be linear, branched, or cyclic. Alkylene groups can optionally be unsaturated and can be substituted with one or more "alkyl group substituents." One or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms (also referred to herein as "alkylaminoalkyl") can be inserted into the alkylene group, where the nitrogen substituent is alkyl as described above. Typical alkylene groups include methylene (-CH2-), ethylene (-CH2-CH2-), propylene (-(CH2)3-), and cyclohexylene (-C6H 10-), -CH=CH-CH=CH-, -CH=CH-CH2-, -CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2C≡CCH2-, -CH2CH2CH(CH2CH2CH3)CH2-, -(CH2) q -N(R)-(CH2) r Examples include -(where q and r are integers from 0 to about 20, i.e., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, and R is hydrogen or a lower alkyl group), methylenedioxyl (-O-CH2-O-), ethylenedioxyl (-O(CH2)2-O-), etc. Alkylene groups may have about 2 to about 3 carbon atoms, and may further have 6 to 20 carbon atoms. Typically, alkyl (or alkylene) groups have 1 to 24 carbon atoms, and groups having 10 or fewer carbon atoms are some embodiments of this disclosure. "Lower alkyl" or "lower alkylene" generally refers to short-chain alkyl or alkylene groups having 8 or fewer carbon atoms.

[0093] The term "heteroalkylene" refers to a divalent group derived from a heteroalkyl group, either by itself or as part of another substituent, including, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, the heteroatom may occupy either or both ends of the chain (e.g., alkylene oxo, alkylenedioxo, alkyleneamino, alkylenediamino, etc.). Furthermore, for linking groups of alkylenes and heteroalkylenes, the orientation of the linking group is not indicated by the direction in which the formula of the linking group is written. For example, the formula -C(O)OR' represents both -C(O)OR'- and -R'OC(O)-.

[0094] Unless otherwise specified, "aryl" refers to a substituent obtained by removing a hydrogen atom from a ring carbon atom of an arene, i.e., a monocyclic or polycyclic aromatic hydrocarbon. Aryl groups can consist of a single ring or multiple rings (e.g., 1 to 3 rings) and may include aromatic hydrocarbon substituents that can be linked by condensation or covalent bonds. "Heteroaryl" refers to an aryl group (or ring) containing 1 to 4 heteroatoms selected from N, O, and S (one for each ring in the case of multiple rings), where the nitrogen and sulfur atoms can optionally be oxidatively substituted, and the nitrogen atom can optionally be quaternized. Heteroaryl groups can be bonded to the remainder of the molecule via carbon or heteroatoms. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl. Examples include 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, 6-quinolyl, etc. Each substituent in the above aryl and heteroaryl ring systems is selected from the group of permissible substituents described below. The terms "arylene" and "heteroarylene" refer to the divalent forms of aryl and heteroaryl, respectively.

[0095] For simplicity, when "aryl" is used in combination with other terms (e.g., aryloxy, arylthiooxy, arylalkyl), it shall include both the aryl and heteroaryl rings as defined above. Therefore, the terms "arylalkyl" and "heteroarylalkyl" include groups in which an aryl or heteroaryl group is bonded to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, furylmethyl, etc.), and also include alkyl groups in which a carbon atom (e.g., a methylene group) is substituted with an oxygen atom or the like (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, etc.). However, the term "haloaryl" as used herein refers only to aryls substituted with one or more halogens.

[0096] When a heteroalkyl, heterocycloalkyl, or heteroaryl has a specific number of members (e.g., "3-7 members"), "member" refers to a carbon atom or heteroatom.

[0097] Also, general formula [ka] The structure represented by refers to a cyclic structure, such as a 3-carbon, 4-carbon, 5-carbon, 6-carbon, or 7-carbon structure, i.e., an aliphatic and / or aromatic cyclic compound, which includes saturated, partially saturated, and unsaturated cyclic structures and has a substituent R group. The R group may or may not be present, and if present, one or more R groups may each substitute for one or more of the available carbon atoms in the cyclic structure. The presence or absence and number of R groups are determined by the value of the variable "n", which generally takes an integer value from 0 to the number of available carbon atoms in the ring. If multiple R groups are present, each R group substitutes for one of the available carbon atoms in the cyclic structure, rather than for another R group. For example, in the above structure, when n is between 0 and 2, the following group of compounds (but not limited to these) is included. [ka] etc.

[0098] In a cyclic ring structure, dotted lines indicate that the bond may or may not exist within the ring. In other words, dotted lines in a cyclic ring structure indicate that the ring structure is selected from a saturated ring structure, a partially saturated ring structure, or an unsaturated ring structure.

[0099] symbol [ka] This indicates the position where the substructure binds to the rest of the molecule.

[0100] If a named atom in an aromatic ring or heteroaromatic ring is defined as "absent," the named atom is replaced by a direct bond.

[0101] The terms listed above (e.g., "alkyl," "heteroalkyl," "cycloalkyl," "heterocycloalkyl," "aryl," "heteroaryl," "phosphonate," "sulfonate," and their divalent derivatives) include both substituted and unsubstituted forms of the indicated group. Any substituents of each group are described below.

[0102] Substituents of alkyl, heteroalkyl, cycloalkyl, and monovalent and divalent derivative groups of heterocycloalkyl (including those often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) include -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -C(O)NR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)OR', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -CN, CF3, and fluorinated C 1-4The R groups are selected from alkyl, -NO2, etc., and their number ranges from 0 to (2m'+1), where m' is the total number of carbon atoms in the group. R', R'', R'''', R'''' each independently refers to hydrogen, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group (e.g., an aryl group substituted with 1 to 3 halogens), a substituted or unsubstituted alkyl group, an alkoxy or thioalkoxy group, or an arylalkyl group. In this specification, an "alkoxy" group refers to an alkyl group bonded to the remainder of the molecule via a divalent oxygen. If the compounds of this disclosure contain multiple R groups, for example, each R group is selected independently, and if there are multiple R', R'', R'''', R'''' groups, each is also selected independently. If R' and R'' are bonded to the same nitrogen atom, they can form a 4-membered, 5-membered, 6-membered or 7-membered ring with the nitrogen atom. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above description of substituents, those skilled in the art will understand that the term "alkyl" also includes groups containing carbon atoms to which groups other than hydrogen are bonded, such as haloalkyls (e.g., -CF3 and -CH2CF3) and acyls (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, etc.).

[0103] Similar to the substituents on alkyl groups mentioned above, the typical substituents on aryl and heteroaryl groups (and their divalent derivatives) are also diverse, for example, halogens, -OR', -NR'R'', -SR', -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -C(O)NR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)OR', -NR-C(NR'R''R''')=NR'''', NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -CN, -NO2, R', -N3, -CH(Ph)2, fluoro(C 1-4 )alkoxy, fluoro(C 1-4) are selected from alkyl groups, etc., and the number of R groups is limited to the total number of open valence atoms in the aromatic ring system. R', R'', R'''', R'''' are each independently selected from hydrogen, substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups, substituted or unsubstituted aryl groups, and substituted or unsubstituted heteroaryl groups. If the compound of this disclosure contains multiple R groups, for example, each R group is independently selected, and if there are multiple R', R'', R'''', R'''' groups, each is also independently selected.

[0104] Two substituents on adjacent atoms of an aryl or heteroaryl ring are optionally -TC(O)-(CRR') q -U-, T, and U can form a ring of the formula -NR-, -O-, -CRR'- or a single bond, where q is an integer from 0 to 3. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring can optionally form -A-(CH2) r -B-, where A and B can be substituted with substituents of the formula -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, where r is an integer from 1 to 4.

[0105] One of the single bonds in the newly formed ring may optionally be replaced by a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be (CRR') s X'(C''R''') d The substituents of the formula can be substituted, where s and d are each independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R'' and R''' are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0106] As used herein, "acyl" refers to an organic acid group in which the OH group of a carboxyl group is substituted with another substituent, having the general formula RC(=O), where R is an alkyl, alkenyl, alkynyl, aryl, carbosicle, heterocycline, or aromatic heterocycline group as defined herein. Therefore, the term "acyl" includes arylacyl groups in particular, such as 2-(furan-2-yl)acetyl and 2-phenylacetyl. Specific examples of acyl groups include acetyl and benzoyl. Acyl groups also include amide-RC(=O)NR', ​​ester-RC(=O)OR', ketone-RC(=O)R', and aldehyde-RC(=O)H.

[0107] In this specification, "alkoxyl" and "alkoxy" are used synonymously and refer to saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O- and alkynyl-O-) groups bonded to the parent molecule via an oxygen atom. Here, "alkyl," "alkenyl," and "alkynyl" are as described above, C 1-20 This includes linear, branched, or cyclic, saturated, or unsaturated oxohydrocarbon chains, such as methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl, sec-butoxyl, tert-butoxyl, n-pentoxyl, neopentoxyl, and n-hexoxyl.

[0108] As used herein, "alkoxyalkyl" refers to alkyl-O-alkyl ethers, such as methoxyethyl groups and ethoxymethyl groups.

[0109] "Aryloxyl" refers to an aryl-O- group, which is defined as described above and includes substituted aryls. In this specification, "aryloxyl" may refer to phenyloxyl or hexyloxyl, as well as phenyloxyl or hexyloxyl substituted with alkyl, substituted alkyl, halo, or alkoxyl.

[0110] "Aralkyl" refers to an aryl-alkyl group, where aryl and alkyl are as described above, and also includes substituted aryl and substituted alkyl groups. Examples of aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.

[0111] "Aralkyloxyl" refers to the aralkyl-O- group, which is as described above. An example of an aralkyloxyl group is benzyloxyl, i.e., C6H5-CH2-O-. The aralkyloxyl group can be arbitrarily substituted.

[0112] "Alkoxycarbonyl" refers to an alkyl-OC(=O)- group. Examples of alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and tert-butyloxycarbonyl.

[0113] "Aryloxycarbonyl" refers to the aryl-OC(=O)- group. Examples of aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.

[0114] "Aralkyloxycarbonyl" refers to the aralkyl-OC(=O)- group. An example of an aralkyloxycarbonyl group is benzyloxycarbonyl.

[0115] "Carbamoyl" refers to the amide group of the formula -C(=O)NH2. "Alkylcarbamoyl" refers to the R'RN-C(=O)- group, where one of R and R' is hydrogen and the other is the aforementioned alkyl and / or substituted alkyl. "Dialkylcarbamoyl" refers to the R'RN-C(=O)- group, where R and R' are each independently the aforementioned alkyl and / or substituted alkyl.

[0116] As used herein, carbonyldioxyl refers to the carbonate group in the formula -OC(=O)-OR.

[0117] "Acyloxyl" refers to the acyl-O- group, and acyl is as described above.

[0118] "Amino" refers to the -NH2 group, and also to a nitrogen-containing group known to those skilled in the art, obtained by substituting one or more hydrogen radicals with organic radicals from ammonia. For example, "acylamino" and "alkylamino" refer to specific N-substituted organic radicals having acyl and alkyl substituents, respectively.

[0119] As used herein, "aminoalkyl" refers to a group in which an amino group is covalently bonded to an alkylene linker. More specifically, alkylamino, dialkylamino, and trialkylamino as used herein are groups in which one, two, or three alkyl groups (as defined above) are bonded to the parent molecule via a nitrogen atom. Alkylamino refers to a group having the -NHR' (R' is the alkyl group as defined above) structure, dialkylamino refers to a group having the -NR'R'' (R' and R'' are each independently alkyl groups), and trialkylamino refers to a group having the -NR'R''R''' (R', R'', and R''' are each independently alkyl groups). Furthermore, R', R'', and / or R''' may optionally be -(CH2) k -(k can be an integer between 2 and 6). Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropylamino, piperidino, trimethylamino, and propylamino.

[0120] The amino group is -NR'R'', where R' and R'' are typically selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0121] The terms alkylthioether and thioalkoxyl refer to saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl-S- and alkynyl-S-) groups that are bonded to the parent molecule via a sulfur atom. Examples of thioalkoxyl moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, and n-butylthio.

[0122] "Acylamino" refers to the acyl-NH- group, and acyl is as described above. "Aroylamino" refers to the aroyl-NH- group, and aroyl is as described above.

[0123] "Carbonyl" refers to a -C(=O)- group and may include an aldehyde group represented by the general formula RC(=O)H.

[0124] "Carboxyl" refers to the -COOH group. In this specification, such a group is also called the "carboxylic acid" portion.

[0125] "Cyano" refers to the -C≡N group.

[0126] As used herein, "halo," "halide," or "halogen" refers to fluoro, chloro, bromo, and iodo groups. Furthermore, terms such as "haloalkyl" include monohaloalkyl and polyhaloalkyl groups. For example, "halo(C) 1-4 The term "alkyl" includes, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and others.

[0127] "Hydroxyl" refers to the -OH group.

[0128] "Hydroxyalkyl" refers to an alkyl group substituted with an -OH group.

[0129] "Mercapto" refers to the -SH group.

[0130] As used herein, "oxo" means an oxygen atom double-bonded to a carbon atom or other element.

[0131] "Nitro" refers to the -NO2 group.

[0132] As used herein, "thio" refers to a compound in which a carbon or oxygen atom is substituted with a sulfur atom, as described above.

[0133] The term "sulfate group" refers to the -SO4 group.

[0134] As used herein, thiohydroxyl or thiol refers to the group of the formula -SH.

[0135] More specifically, "sulfide" refers to a compound that has a group in the formula -SR.

[0136] "Sulfone" refers to a compound that has a sulfonyl group in the form -S(O2)R.

[0137] A "sulfoxide" refers to a compound that has a sulfinyl group in the form -S(O)R.

[0138] A ureid refers to the urea group in the formula -NH-CO-NH2.

[0139] Throughout this specification and the claims, any given chemical formula or name shall encompass all tautomers, homologs, optical isomers and stereoisomers, as well as racemates, where isomers and mixtures exist.

[0140] Certain compounds in this disclosure may have chiral carbon atoms (optical or chiral centers) or double bonds, and the scope of this disclosure includes enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomer forms that can be defined by absolute stereochemistry as (R)-type or (S)-type, or for amino acids as D-type or L-type, and individual isomers. The compounds in this disclosure are not known to be technically unstable in synthesis and / or isolation. This disclosure is intended to include racemates, scaremics, and optically pure forms of compounds. Optically active (R)-type and (S)-type, or D-type and L-type isomers can be prepared using chiral synthons or chiral reagents, or can be separated by prior art. Where compounds described herein contain olephene bonds or other geometrically asymmetric centers, unless otherwise specified, these compounds are intended to include both E-type and Z-type geometric isomers.

[0141] Unless otherwise specified, the structures shown herein are intended to include all stereochemical forms of those structures, i.e., the R-type and S-type configurations of each chiral center. Accordingly, not only single stereoisomers of the compounds disclosed herein, but also enantiomer mixtures and diastereomer mixtures are included in the scope of this disclosure.

[0142] Those skilled in the art will see that certain compounds of this disclosure may exist in tautomer forms, and all tautomer forms of such compounds are included within the scope of this disclosure. As used herein, “tautomer” refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomer to the other.

[0143] Unless otherwise specified, the structures shown herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, those in which hydrogen is substituted with deuterium or tritium, or carbon 13 C or I4 Compounds of this structure having carbon substituted with carbon enriched with 1C are included within the scope of this disclosure.

[0144] The compounds of this disclosure may also contain unnatural isotopic ratios in one or more atoms constituting such compounds. For example, the compounds may be labeled and substituted with radioactive isotopes, such as tritium. 3 H), Iodine-125( 125 I), or carbon-14 ( 14 Examples include C). All isotopic variants of the compounds of this disclosure, whether radioactive or not, are included in the scope of this disclosure.

[0145] The compounds of this disclosure may exist as salts. This disclosure includes such salts. Examples of applicable salt forms include salts with hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or mixtures thereof (including racemic mixtures)), succinate, benzoate, and amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art. Also included are basic addition salts such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. If the compounds of this disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a desired acid in sufficient quantities, or in a suitable inert solvent, or by ion exchange. Examples of acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, and phosphorous acid, as well as salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Salts of amino acids such as arginine, and salts of organic acids such as glucuronic acid and galacturonic acid are also included. Certain compounds in this disclosure contain both basic and acidic functional groups, thereby allowing them to be converted into either basic or acidic addition salts.

[0146] The neutral form of a compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound using conventional methods. The form of the parent compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0147] Certain compounds in this disclosure may exist not only in solvent-free forms but also in solvated forms, including hydrated forms. Generally, the solvated forms are equivalent to the solvent-free forms and are included within the scope of this disclosure. Certain compounds in this disclosure may exist in a number of crystalline or amorphous forms. Generally, all physical forms are equivalent in the applications envisioned in this disclosure and are included within the scope of this disclosure.

[0148] In accordance with long-standing patent law convention, “a,” “an,” and “the” as used herein (including in the claims) mean “one or more.” Therefore, a reference to “subject,” for example, includes multiple subjects unless the context clearly indicates otherwise (e.g., multiple subjects).

[0149] Throughout this specification and the claims, the terms “comprise,” “comprises,” and “comprising” are used in a non-exclusive sense unless otherwise required by context. Similarly, “include” and its grammatical variations are intended to be non-restrictive and to allow other similar items to be added to or replaced in the list.

[0150] In this specification and the appended claims, unless otherwise specified, all numerical values ​​representing quantities, sizes, dimensions, ratios, shapes, formulations, parameters, percentages, numbers, characteristics, and other numerical values ​​are understood to always be modified by "about," even if "about" is not explicitly attached to the value, quantity, or range. Accordingly, unless otherwise specified, the numerical parameters described in the following specification and appended claims do not need to be exact, but may be approximations or greater or less, as desired, and may reflect tolerances, conversion factors, rounding, measurement errors, or other factors known to those skilled in the art depending on the desired characteristics to be obtained by the subject matter of this disclosure. For example, the term "about" may mean, with respect to a value, include variations of ±100%, ±50%, ±20%, ±10%, ±5%, ±1%, ±0.5%, and ±0.1% in some embodiments.

[0151] Furthermore, when the term "approximately" is used in relation to one or more numbers or ranges of numbers, it should be understood to refer to all numbers within the range, extending and modifying the upper and lower boundaries of that range. Numerical ranges specified by endpoints include all numbers contained within that range, i.e., not only integers but also fractions thereof (for example, the notation 1-5 includes not only 1, 2, 3, 4, and 5, but also 1.5, 2.25, 3.75, 4.1, etc.), as well as any range within that range. [Examples]

[0152] The following examples are included to provide guidance to those skilled in the art for carrying out typical embodiments of the subject matter of this disclosure. In light of this disclosure and the general state of the art, those skilled in the art will understand that the following examples are illustrative only and that numerous changes, modifications, and alterations are possible without departing from the scope of the subject matter of this disclosure. The following synthesis descriptions and specific examples are for illustrative purposes only and should not be construed as limiting the preparation of the compounds of this disclosure by any other means. [Examples]

[0153] PSMA-targeted PET radiotracers as imaging biomarkers in inflammatory bowel disease [ 18 F]DCFPyL

[0154] 1.1 Overview Prostate-specific membrane antigen (PSMA) is highly and specifically upexpressed in the active inflamed mucosa of patients with inflammatory bowel disease (IBD). While not intended to be bound by any particular theory, this upexpression is associated with positron emission tomography / computed tomography (PET / CT) imaging agents that target PSMA, and in some embodiments, [ 18 It was found that the inflammation could be detected using [F]DCFPyL, which would enable non-invasive visualization of inflammation. A method for non-invasively detecting active inflammation has high clinical value in the localization and management of IBD.

[0155] In this example, three IBD patients with active disease were treated with [ 18 F]DCFPyL imaging was performed. Endoscopic, histological, and immunohistochemical findings revealed abnormally increased gastrointestinal [ 18 F]DCFPyL accumulation was observed, and abnormal [ 18 A partial overlap was observed between the F]DCFPyL accumulation sites and the sites of active inflammation.

[0156] This embodiment targets PSMA [ 18 [F]DCFPyL PET has been shown to effectively detect inflamed mucosal areas in IBD patients, suggesting its usefulness as a non-invasive imaging agent for evaluating the site, extent, and disease activity in IBD.

[0157] 1.2 Background Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract characterized by remissions and relapses. See Liverani et al., 2016 and Colombel et al., 2017. Diagnosis of remission can be made based on clinical findings, biochemical markers, and endoscopic and / or histological criteria. Achieving endoscopic remission has emerged as a goal of treatment management, and macroscopically normal mucosa is associated with improved natural course of IBD and prevention of long-term disease complications. See Colombel et al., 2017, Peyrin-Biroulet et al., 2015 and Turner et al., 2021.

[0158] While endoscopic remission is the goal of treatment-targeted disease management, it is recognized that submucosal inflammation can persist even without mucosal damage, and there is no single test that can accurately detect asymptomatic inflammation in known IBD patients. (See Vermeire et al., 2006.) Histological remission is a new concept. However, its reliability is challenged because existing histological scoring systems are subjective and poorly reproducible. (See Bryant et al., 2014.) The ability to accurately and non-invasively detect and monitor gastrointestinal inflammation in IBD patients contributes to treatment management decision-making, avoids unnecessary treatments, and has far-reaching clinical implications by enhancing monitoring during both the treatment and remission periods.

[0159] Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), is emerging as a promising biomarker and therapeutic target in IBD. See Vornov et al., 2020; Rais et al., 2016; International PCT Patent Publication WO / 2016 / 022809, "Therapeutic method for inflammatory bowel disease using a prostate-specific membrane antigen (PSMA) inhibitor"; Slusher et al., published February 11, 2016; Peters et al., 2019. PSMA is a metallopeptidase responsible for the hydrolysis of glutamine-oxidized peptides, including the neurotransmitter N-acetylaspartylglutamate and the essential nutrient folate polyglutamate. See Vornov et al., 2016. Recent studies have also shown that PSMA is expressed in tumor-associated vascular endothelium and activated macrophages, suggesting a role in inflammation. See de Galiza Barbosa et al., 2020.

[0160] Although PSMA is hardly expressed in a normal gastrointestinal tract, it is highly and specifically upregulated in inflammatory endoscopic biopsies of both Crohn's disease (CD) and ulcerative colitis (UC) patients. See Troyer et al., 1995; Mhawech-Fauceglia et al., 2007; Haffner et al., 2009; Kinoshita et al., 2006; Silver et al., 1997. See Rais et al., 2016; International PCT Patent Publication WO / 2016 / 022809, "Treatment method for inflammatory bowel disease using a prostate-specific membrane antigen (PSMA) inhibitor"; Slusher et al., published February 11, 2016; Zhang et al., 2012. PSMA is also highly upregulated in prostate cancer. See Silver et al., 1997; Foss et al., 2012.

[0161] In recent years, positron emission tomography (PET) imaging agents targeting PSMA have been developed. 18F]DCFPyL (pifluforastat F-18, trade name Pylarify®) has received FDA approval in the United States for use as an imaging agent in the diagnosis of prostate cancer. (See Chen et al., 2011; Szabo et al., 2015.) This FDA approval has enabled wider use of the drug and is accelerating research into off-label uses.

[0162] While not intended to be bound by any particular theory, increased PSMA expression in active IBD is [ 18 It was hypothesized that the positive signal could be detected by [F]DCFPyL imaging and that the positive signal indicated tissue inflammation. PSMA target in inflammatory bowel disease [ 18 The use of F]DCFPyL PET imaging has been reported in only one case to date. See Chandekar et al., 2022. This single case involved a patient with elevated serum PSA levels but no genitourinary symptoms. 68 A Ga]Ga-PSMA-11 PET / CT scan was performed, and uptake was observed in the distal ileum. See Chandekar et al., 2022. The patient later reported a history of Crohn's disease and an increase in the frequency of recent diarrhea episodes, and the authors concluded that these findings were likely attributable to the patient's known history of inflammatory bowel disease. See Chandekar et al., 2022.

[0163] We have been treating patients hospitalized with active IBD [ 18 We performed F]DCFPyL PET and presented data demonstrating that PSMA imaging can non-invasively identify active inflammatory sites during relapses in IBD patients.

[0164] 1.3 Method This study included patients labeled with inflammatory bowel disease (IBD), ulcerative colitis (UC), cardiomyopathy (CD), or IBD-unclassified, who experienced relapses and required hospitalization. These patients underwent routine clinical examinations and endoscopic evaluations in accordance with standard IBD relapse assessment procedures. In addition, under the U.S. Food and Drug Administration (FDA) investigational drug application (IND 121064), [[ 18F]DCFPyL PET / CT imaging was performed. Approval for the study period was granted by the Johns Hopkins Institutional Review Board. Written informed consent was obtained from each patient prior to the start of the study. All consent forms included participant approval for the publication of results. The authors declare that the procedures were conducted in accordance with the rules defined by the Clinical Research Ethics Committee and the World Medical Association Declaration of Helsinki. 18 F]DCFPyL PET / CT images were obtained using a Siemens Biograph mCT 128-slice scanner (Siemens Healthineers, Erlangen, Germany) 18 approximately 60 minutes after intravenous administration of approximately 333 MBq (9 mCi) of F]DCFPyL. The 18 results of the F]DCFPyL PET / CT images of each patient were used to correlate with endoscopic findings.

[0165] 1.4 Results 1.4.1 Crohn's disease PSMA targeting in CD patients 18 To illustrate the use of F]DCFPyL PET / CT, two patients with different phenotypes were selected.

[0166] The first phenotype was long-standing ileocolonic Crohn's disease (CD) in a 42-year-old man, presenting with exacerbation symptoms including abdominal pain and diarrhea with more than 20 bowel movements per day. Inflammatory markers were elevated, with an erythrocyte sedimentation rate (ESR) of 36 mm / h (reference value < 15 mm / h), C-reactive protein (CRP) of 7 mg / dL (reference value < 0.5 mg / dL), and fecal calprotectin of 241 μg / g (reference value < 50 μg / g). He was being treated with ustekinumab every 6 weeks and subcutaneous methotrexate 25 mg once a week. The past medication history included infliximab, adalimumab, vedolizumab, and 6-mercaptopurine. All of these drugs had failed to control the disease, and persistent inflammation and associated ileal strictures were noted.

[0167] PET / CT scans showed an abnormal increase in the terminal ileum. 18 Long-range accumulation of F]DCFPyL was observed (Figure 1). Ileocolonoscopy was performed, revealing inflammation and pseudopolyps up to 20 cm from the anal margin, while the rest of the colonic mucosa was normal (Figure 2). Of particular note was the presence of inflammation with redness, edema, and ulceration at the terminal ileum. A short, impassable stricture was found 5 cm from the ileocecal valve at the terminal ileum, which was dilated to 12 mm with an intrascope balloon (TTS balloon). Furthermore, another impassable stricture was found 3 cm proximal to the initial stricture.

[0168] Biopsies from the terminal ileum and rectum revealed chronic inflammatory disease. To evaluate PSMA expression in the distal colon region 20 cm from the anal margin, inflammation was visualized using endoscopy, but [ 18 Since F]DCFPyL was not detected by PET / CT, PSMA immunohistochemistry (IHC) using the validated antibody 1A11 was performed on full-thickness distal colon sections obtained during abdominoperineal resection, according to previously reported methods (Figure 3). See Vornov et al., 2020, Novakova et al., 2017.

[0169] Interestingly, a heterogeneous increase in PSMA expression was detected in colonic epithelial cells adjacent to the site of severe inflammation, showing intracellular and cytoplasmic expression patterns (Figure 3C), suggesting that the radioactive tracer may not have been accessible, and thus differentiating between endoscopic and histological disease and [ 18 This could explain the clear discrepancy with [F]DCFPyL imaging. Consistent with this hypothesis, IHC performed on terminal ileal biopsies from this patient showed a remarkably different pattern of PSMA expression, with increased intracellular expression and concentrated signaling at the apical brush border membrane (Figure 3D). In particular, elevated PSMA expression was observed in 100% of the observed epithelium in the ileal specimen, while in the colon section, patchy elevated PSMA expression was detected in approximately 20% of the epithelium at the inflammatory site. Therefore, the reduced degree of elevated PSMA expression in the colon of this patient compared to the ileum [ 18 This likely contributed to the difference in F]DCFPyL integration.

[0170] The second case of CD phenotype was a 36-year-old male with colonic lesions and perianal fistulas. He had two setons in place and was hospitalized due to worsening rectal pain and bloody diarrhea. After secondary failure of adalimumab, he had recently been switched to ustekinumab. Inflammatory markers were elevated, with ESR at 33 mm / h, CRP at 7.6 mg / dL, and fecal calprotectin at over 8,000 μg / g. MRI revealed wall thickening and inflammation of the sigmoid colon and rectum, but no new fistulas were found. Colonoscopy revealed marked redness, fragility, and deep ulcers in the rectum and sigmoid colon (Figure 4). Biopsy showed chronic active inflammation, and PSMA IHC showed an increase in PSMA-positive cells at the site of inflammation (Figure 8). Intravenous steroids and infliximab were administered, but there was no response. Abdominal perineal resection was performed. Before surgery [ 18 F]DCFPyL PET / CT imaging was performed. Written informed consent was obtained before the scan. The PET / CT scan showed an abnormal increase in the mucosal inflammation sites of the sigmoid colon and rectum. 18 [F]DCFPyL accumulation was observed (Figure 5).

[0171] 1.4.2 Ulcerative colitis [ 18The usefulness of [F]DCFPyL PET / CT imaging was investigated in a 66-year-old male with ulcerative colitis and a left-sided lesion, who presented to the emergency department with exacerbating symptoms including more than 30 bloody diarrheas per day, urgency, and abdominal pain. The patient had recently been switched to vedolizumab after secondary failure of infliximab. A recent colonoscopy performed during infliximab administration every four weeks showed marked redness, fragility, spontaneous bleeding, and ulcers in the descending colon, sigmoid colon, and rectum (Mayo endoscopic subscore 2-3), but no active lesions were found proximal to the splenic flexure. The patient was hospitalized. Inflammatory markers were elevated, with ESR at 47 mm / h, CRP at 6.6 mg / dL, and fecal calprotectin at 867 μg / g. Stool tests, including Clostridioides difficile testing, were negative. A flexible sigmoidoscopy was performed on the patient, extending 20 cm from the anal margin. Spontaneous bleeding and ulcers were observed throughout the mucosa (Mayo endoscopic subscore 3) (Figure 6). Biopsy confirmed severe active chronic inflammatory disease, and immunohistochemical staining for cytomegalovirus was negative. IHC of biopsies from the inflamed areas showed occasional increases in PSMA expression in the apical epithelial membrane, and numerous PSMA-positive cells were observed throughout the mucosa (Figure 9). 18 F]DCFPyL PET / CT imaging was performed. Written informed consent was obtained before the scan. PET / CT showed abnormal increases in the descending colon, sigmoid colon, and rectum. 18 [F]DCFPyL accumulation was observed, and the distribution was consistent with endoscopic findings (Figure 7).

[0172] 1.5 Discussion Accurate and non-invasive diagnosis of active mucosal inflammation in known IBD patients is clinically challenging. There is no single non-invasive gold standard test, biomarker, or imaging agent for reliably diagnosing inflamed mucosa during exacerbations or for monitoring disease activity after the initiation of treatment. (See Vermeire et al., 2006.) Existing laboratory tests include CRP, ESR, and fecal calprotectin, but each has its limitations. CRP is widely used as an indicator of acute inflammatory response and has high specificity for inflammation, but it lacks sensitivity and can show normal values ​​even during acute exacerbations. (See Ince et al., 2019, Chang et al., 2015.) Therefore, while CRP is useful as an adjunct to clinical and endoscopic evaluation, it cannot be reliably used to definitively rule out exacerbations. (See Chang et al., 2015.)

[0173] ESR is an indirect indicator of systemic inflammation and is commonly used as another biomarker of inflammation in IBD. However, ESR correlates less with endoscopic disease activity than CRP. (Vermeire et al., 2006). Calprotectin is a neutrophil marker that correlates well with neutrophil migration to the gastrointestinal tract and, consequently, with inflammation. (See D'Haens et al., 2012). Fecal calprotectin is also a useful auxiliary indicator for determining the presence or absence of exacerbation, but false positives have been reported. (See Vermeire et al., 2006). Finally, calprotectin is more useful in the colon of UC and CD, but less accurate in the small intestinal inflammation of CD. (See Garcia-Sanchez et al., 2010). Furthermore, none of these non-invasive tests can pinpoint the location of inflammation.

[0174] Given the incompleteness of inflammatory markers using blood and stool, ileocolonoscopy is the gold standard for diagnosing active mucosal inflammation and exacerbations in IBD patients. (See Annese et al., 2013.) However, endoscopy is an invasive procedure requiring appropriate bowel preparation. In addition, patients with enteritis undergoing endoscopy have a significantly higher incidence of complications, such as perforation. (See Kothari et al., 2019.) Therefore, there is a high clinical need for alternative and non-invasive diagnostic tools to aid in the accurate diagnosis and monitoring of mucosal inflammation in IBD patients.

[0175] In patients with inflammatory bowel disease (IBD), various imaging modalities have been investigated, each with its own advantages and disadvantages. CT imaging is widely available, but has been shown to have low sensitivity for assessing the extent of inflammation in Crohn's disease (see Panes et al., 2011), and there are concerns about radiation exposure due to the frequent need for re-examination (see Loftus, 2010). MRI offers comparable diagnostic accuracy in IBD imaging, but is more time-consuming and expensive. Intestinal ultrasonography is a promising imaging modality that is readily available, non-invasive, radiation-free, and cost-effective (see Lapp et al., 2011). This imaging is widely used in Europe but remains limited in North America (see Lapp et al., 2011).

[0176] The use of molecular imaging may be a promising non-invasive approach to assess lesion site and disease activity in IBD patients. Since PSMA is specifically increased in CD and UC patient biopsies with active inflammation compared to non-lesion sites, we investigated whether PSMA-targeted imaging could be used to detect active inflammation (see Rais et al., 2016). For this purpose, we used a PET imaging agent [ 18 F]DCFPyL (Pylarify® trademark) was evaluated. 18 F]DCFPyL is FDA approved as a diagnostic agent for prostate cancer and has been shown to exhibit high sensitivity and specificity in identifying PSMA-positive prostate cancer. See Szabo et al., 2015.18 F]DCFPyL has a good safety profile. See Chen et al., 2011. Also in the normal gastrointestinal tract. 18 Although accumulation of [F]DCFPyL is observed, its biodistribution is mainly limited to the proximal small intestine, and positive sites in the more distal small intestine and colon are easily identifiable. Recently developed PET / computed tomography (CT) combines the physiological sensitivity of PET with the anatomical precision of CT, thereby enhancing the specificity of PET. See Lapp et al., 2011.

[0177] The usefulness in Crohn's disease (CD) has been established in patients with active ileocolonic type CD, [ 18 [F]DCFPyL accumulation was abnormally increased in the terminal ileum, consistent with inflammation observed on ileocolonoscopy and histological findings of mucosal biopsy. Immunohistochemistry (IHC) showed significantly elevated prostate-specific membrane antigen (PSMA) expression in this region, with increased expression of both membrane-related and cytoplasmic epithelial PSMA. Endoscopically active disease in the distal 20 cm from the anal margin was not detected by PET scan, but elevated PSMA protein expression was detected in surgically resected tissue by IHC. However, there were differences in both the magnitude and localization of PSMA expression compared to the terminal ileum, which likely contributed to the lack of PET signal detection in the colon. In inflammatory colon, PSMA was detected only in the cytoplasm of epithelial cells and showed heterogeneous elevated expression in a portion of the epithelium (approximately 20%). Currently, the decrease in expression levels in the colon and ileum is [ 18It is unclear whether the detection limit for [F]DCFPyL was below the threshold, or whether altered blood flow due to changes in tissue architecture associated with chronic inflammation such as scarring and fibrosis prevented the target from accessing the radioactive tracer. In any case, further studies in larger patient cohorts are needed to clarify the factors influencing PSMA-targeted PET accumulation in IBD. Notably, these findings suggest that PSMA-PET scans can identify inflammatory patterns that cannot be identified by clinical-grade endoscopic and histological analyses. This observation suggests the potential for inclusion in new patient stratification and / or individualized treatment algorithms.

[0178] In two other patients with colonic lesions in IBD, [ 18 Increased [F]DCFPyL uptake was observed in the descending colon, sigmoid colon, and rectum (ulcerative colitis), and also in the sigmoid colon and rectum (colonic CD), all of which indicated endoscopically active disease sites. Consistent with the uptake findings of the radioactive tracer, numerous PSMA-positive cells were identified in inflammatory colon biopsies taken from these sites during IHC. Further research characterizing PSMA localization as a function of IBD subtypes and disease sites is strongly desired and is ongoing in our laboratory.

[0179] In summary, in abnormal gastrointestinal conditions [ 18 [F]DCFPyL accumulation was detected in all three IBD patients, and in all disease phenotypes, 18 The increased areas of F]DCFPyL accumulation coincided with areas where inflammation was observed endoscopically and histologically. These findings suggest that it could be used as an adjunct diagnostic tool during exacerbations of IBD in both Crohn's disease and ulcerative colitis. 18 F]DCFPyL supports the continuous evaluation of PET / CT imaging. Future research should investigate the effect of disease severity on patients. 18 To evaluate F]DCFPyL uptake, the duration of treatment, the remission phase, and the exacerbation phase of the patient's condition. 18This includes longitudinally examining [F]DCFPyL accumulation and identifying patients with high PSMA expression for inclusion in clinical trials using therapeutic PSMA inhibitors. These inhibitors are currently under active development and have shown promising efficacy in preclinical models. See Rais et al., 2016, International PCT Patent Application Publication No. WO / 2016 / 022809, “A method for treating inflammatory bowel disease using a prostate-specific membrane antigen (PSMA) inhibitor,” Slusher et al., published February 11, 2016, and Peters et al., 2019.

[0180] 1.6 Summary This embodiment presents a promising non-invasive imaging agent for evaluating lesion site, extent, and disease activity in IBD, targeting PSMA. 18 The findings demonstrate significant utility for [F]DCFPyL PET / CT. If these findings are consistently demonstrated in larger-scale studies, it could address the unmet need for non-invasive detection of gastrointestinal inflammation and assessment of the site, extent, and activity of IBD. Furthermore, this novel inflammation detection method could enable subclassification of IBD based on molecular characteristics, bringing us closer to the goals of advancing personalized medicine and precision medicine.

[0181] References All publications, patent applications, patents, and other documents described herein represent the state of the art for those skilled in the art to which the subject matter of this disclosure pertains. All publications, patent applications, patents, and other documents described herein are incorporated herein by reference to the same extent as each publication, patent application, patent, and other document is incorporated by reference individually and specifically stated herein. It should be understood that although multiple patent applications, patents, and other documents are referred to herein, none of these documents constitute part of the general knowledge known in the art. [Prior art documents] [Non-patent literature]

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[0183] While the aforementioned subject matter has been described in some detail with explanations and examples to clarify understanding, those skilled in the art will understand that certain changes and modifications can be made within the scope of the attached claims.

Claims

1. A method for imaging inflammation associated with inflammatory bowel disease (IBD), comprising administering an imaging agent targeting prostate-specific membrane antigen (PSMA) to a subject and acquiring images.

2. The method according to claim 1, wherein the inflammation associated with IBD includes mucosal inflammation.

3. The method according to claim 1, wherein the imaging is used to evaluate one or more of the location, extent, and disease activity of IBD.

4. The method according to claim 3, wherein the range of IBD includes the percentage of inflammation in IBD stenosis.

5. The method according to claim 1, wherein the inflammatory bowel disease is selected from Crohn's disease (CD), ulcerative colitis (UC), and combinations thereof.

6. The method according to claim 1, wherein the image comprises a positron emission tomography (PET) image.

7. The method according to claim 1, wherein the image comprises a positron emission tomography / computed tomography (PET / CT) image.

8. The imaging agent targeting PSMA comprises a compound having the following formula: 【Chemistry 1】 V is selected from -NH-C(=O)-, -C(=O)-NH-, and -NH-. L is Linker, Rpt is the reporting section. The method according to claim 1.

9. V is -NH-C(=O)-, and imaging agents that target PSMA are 【Chemistry 2】 The method according to claim 8, comprising:

10. The method according to claim 9, wherein the reporting portion Rpt comprises a radiolabeled prosthetic group.

11. The radiolabeled prosthetic group is, 【Transformation 3】 Selected from, Each X is independent １１ C or １８ F is such that each R and R' is independently H or C １ -C ４ It is an alkyl group, where each n is an integer independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. The method according to claim 10.

12. The method according to claim 8, wherein the reporting portion Rpt comprises a chelate portion.

13. The aforementioned chelate portion is 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 【Chemistry 4-4】 The method according to claim 12, selected from the following.

14. The aforementioned chelate portion further ６８ Ga, ６４ Cd, ９９ｍ Tc, and [ １８ The method according to claim 12, comprising a radioactive metal selected from [F]AlF.

15. The imaging agent targeting the PSMA has a radiolabeled prosthetic group, and the imaging agent is １２５ I-DClBzL, １８ F]JK-PSMA-7, １８ F-YC88, １２５ I]DCT, １８ F]DCFBc, １１ C]DCMC, MIP-LO72, MIP-1095, １８ F]-PSMA-1007, １８ F]-flutamine, and １８ F]Fpy-DUPA-Pep, and the method according to claim 1, selected from

16. Imaging agents that target PSMA are [ １８ The method according to claim 14, comprising F)DCFPyL.

17. The method according to claim 1, wherein the imaging agent targeting PSMA comprises the chelate portion, and the imaging agent is selected from PSMA-11, PSMA-617, PSMA-I&T, PSMA I&S, PSMA-R2, PSMA-SR6, P16-093, PSMA-BCH, Bi-PSMA, MIP-1555, MIP-1519, MIP-1545, MIP-1558, MIP-1379, MIP-1427, MIP-1428, MIP-1404, and MIP-1405, and the chelate portion further comprises a radioactive metal suitable for PET imaging.

18. The method according to claim 1, further comprising administering to a subject one or more additional therapeutic agents to prevent or reduce the accumulation of the PSMA-targeting imaging agent in off-target non-cancerous tissues such as the kidney or lacrimal gland, in combination with the PSMA-targeting imaging agent.

19. The method according to claim 17, wherein the one or more additional therapeutic agents are administered to the subject before the administration of the imaging agent targeting the PSMA.

20. The method according to claim 18, wherein the one or more additional therapeutic agents are administered to the subject simultaneously with an imaging agent targeting PSMA.

21. The method according to claim 17, wherein the off-target tissue is located in an organ selected from the kidney, lacrimal gland, and salivary gland.

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