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

Abstract

Disclosed are methods for imaging inflammation associated with inflammatory bowel disease (IBD), including administering to a subject a prostate-specific membrane antigen (PSMA)-targeted imaging agent and taking an image.

Description

[0001] PROSTATE-SPECIFIC MEMBRANE ANTIGEN AS AN IMAGING BIOMARKER IN INFLAMMATORY BOWEL DISEASE

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims benefit of U.S. Provisional Application No. 63 / 533,081 filed August 16, 2023, which is incorporated herein by reference in its entirety.

[0004] BACKGROUND

[0005] Inflammatory Bowel Disease (IBD), an idiopathic, chronic and frequently disabling inflammatory disorder of the intestine, has two subtypes: Crohn's disease (CD) and ulcerative colitis (UC), each accounting for approximately 50% of IBD patients. IBD is a widespread GI disease, with a prevalence of approximately 0.2% in the Western population. In the United States alone, there are 1.4 million diagnosed IBD patients, resulting in enormous suffering and health-care costs. The ability to accurately and noninvasively detect and monitor gastrointestinal inflammation in IBD patients would have broad clinical impact by contributing to therapeutic management decisions, avoiding unnecessary treatments, and enhancing monitoring during periods of both treatment and remission.

[0006] SUMMARY

[0007] In some aspects, the presently disclosed subject matter provides a method for imaging inflammation associated with inflammatory bowel disease (IBD), the method comprising administering to a subject a prostate-specific membrane antigen (PSMA)- targeted imaging agent and taking an image.

[0008] In certain aspects, the inflammation associated with IBD comprises a mucosal inflammation. In more certain aspects, the imaging assesses one or more of a location, extent, and disease activity of IBD. In particular aspects, the extent of IBD includes a percent inflammation in an IBD stricture.

[0009] In certain aspects, the inflammatory bowel disease is selected from Crohn’s disease (CD), ulcerative colitis (UC), and combinations thereof.

[0010] In certain aspects, the image comprises a positron emission tomography (PET) image. In particular aspects, the image comprises a positron emission tomography / computed tomography (PET / CT) image.

[0011] In some aspects, the PSMA-targeted imaging agent comprises a compound having the following formula: wherein:

[0012] V is selected from -NH-C(=O)-, -C(=O)-NH-, and -NH-;

[0013] L is a linker; and

[0014] Rpt is a reporting moiety.

[0015] In certain aspects, V is -NH-C(=O)- and the PSMA-targeted imaging agent comprises:

[0016] In particular aspects, the reporting moiety Rpt comprises a radiolabeled prosthetic group. In certain aspects, the radiolabeled prosthetic group comprisesnC or18F. In particular aspects, the PSMA-targeted imaging agent comprises a radiolabeled prosthetic group and the imaging agent is selected from125I-DC1BZL, [18F]JK-PSMA-7,18F-YC88, [125I]DCIT, [18F]DCFBC, and [nC]DCMC, MIP-1072, MIP-1095, [18F]-PSMA-1007, [18F]- florastamin, and [18F]FPy-DUPA-Pep. In more particular aspects, the PSMA-targeted imaging agent comprises [18F]DCFPyL.

[0017] In other aspects, the reporting moiety Rpt comprises a chelating moiety. In certain aspects, the chelating moiety further comprises a radiometal selected from68Ga,MCu, "mTc, and [18F]A1F. In particular aspects, the PSMA-targeted imaging agent comprises a chelating moiety and the imaging agent is selected from PSMA-11, PSMA-617, PSMA-I&T, PS MA I&S, PSMA-R2, PSMA-SR6, P16-093, PSMA-BCH, Bi-PSMA, MIP-1555, MIP-1519, MIP-1545, MIP-1558, MIP-1379, MTP-1427, MIP-1428, MIP-1404, and MIP-1405, wherein the chelating moiety further comprises a radiomctal suitable for PET imaging.

[0018] In other aspects, the method further comprises administering to the subject in combination with the PSMA-targeted imaging agent one or more additional therapeutic agents to prevent or reduce an accumulation of the PSMA-targeted imaging agent in an off- target non-cancer tissue, such as the kidney or lacrimal gland. In certain aspects, one or more additional therapeutic agents is administered to the subject before the PSMA-targeted imaging agent is administered. In other aspects, the one or more additional therapeutic agents is administered to the subject simultaneously with the PSMA-targeted imaging agent. In particular aspects, the off-target tissue is in an organ selected from kidney, lacrimal glands, and salivary glands.

[0019] Certain aspects of the presently disclosed subject matter having been stated hereinabove, which are addressed in whole or in part by the presently disclosed subject matter, other aspects will become evident as the description proceeds when taken in connection with the accompanying Examples and Figures as best described herein below.

[0020] BRIEF DESCRIPTION OF THE FIGURES

[0021] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0022] Having thus described the presently disclosed subject matter in general terms, reference will now be made to the accompanying Figures, which are not necessarily drawn to scale, and wherein:

[0023] FIG. 1A, FIG. IB, FIG. 1C, and FIG. ID show long segment of abnormally increased [18F]DCFPyL uptake in the terminal ileum (identified by the black and white arrows in the subfigures). FIG. 1A: [18F]DCFPyL PET / CT uptake in terminal ileum on a coronal plane; FIG. IB: Axial CT Image; FIG. 1C: Axial PET Imaging; FIG. ID: Axial [18F]DCFPyL PET / CT fusion imaging;

[0024] FIG. 2A, FIG. 2B, and FIG. 2C show Ileocolonoscopy with inflammation and pseudopolyposis from the anal verge up to 20 cm and terminal ileum stricture (FIG. 2A) requiring balloon dilatation (FIG. 2B) with successful dilatation (FIG. 2C); FIG. 3A, FIG. 3B, FIG. 3C, and FIG. 3D show PSMA immunohistochemistry (IHC) on full-thickncss distal colon sections. Arrows and arrowheads identifying area of PSMA staining on various cross-sections of the colon and ileum (FIG. 3A-FIG. 3D);

[0025] FIG. 4A and FIG. 4B show erythema, friability, and deep ulcerations in the rectum and sigmoid colon on colonoscopy (FIG. 4A-FIG. 4B);

[0026] FIG. 5A, FIG. 5B, FIG. 5C, and FIG. 5D demonstrate abnormally increased [18F]DCFPyL uptake in the sigmoid colon and rectum on PET / CT. FIG. 5A: [18F]DCFPyL PET / CT uptake in the sigmoid colon (identified by the arrows and arrowheads) on a coronal plane; FIG. 5B: Axial CT Image with arrows identifying active inflammation in the sigmoid colon and rectum; FIG. 5C: Axial PET Imaging arrows identifying active inflammation in the sigmoid colon and rectum; FIG. 5D: Axial [18F]DCFPyL PET / CT fusion imaging with arrows identifying active inflammation in the sigmoid colon and rectum;

[0027] FIG. 6A, FIG. 6B, and FIG. 6C show flexible sigmoidoscopy demonstrating Mayo endoscopic subscore 3 (FIG. 6A-FIG. 6C);

[0028] FIG. 7A, FIG. 7B, FIG. 7C, and FIG. 7D are [18F]DCFPyL PET / CT demonstrating abnormally increased uptake in the descending colon (identified by red arrows), sigmoid colon, and rectum corresponding to findings on endoscopy. FIG. 7A: [18F]DCFPyL PET / CT uptake in the descending colon on a coronal plane; FIG. 7B: Axial CT Image with arrows identifying active inflammation in the descending colon; FIG. 7C: Axial PET Imaging arrows identifying active inflammation in the descending colon; FIG. 7D: Axial [18F]DCFPyL PET / CT fusion imaging identifying active inflammation in the descending colon;

[0029] FIG. 8A and FIG. 8B show histology demonstrating chronic active inflammation and PSMA IHC showing lack of PSMA positive cells (black arrows) in non-inflamed sections (FIG. 8 A) compared to increased PSMA positive cells in inflamed colon sections (FIG. 8B); and

[0030] FIG. 9A and FIG. 9B show lack of PSMA expression on IHC in non-inflamed tissue (FIG. 9A) compared to IHC with occasional increased PSMA expression in the apical epithelial membrane (black arrowheads) and numerous PSMA positive cells throughout the mucosa (black arrows) in inflamed colon (FIG. 9B). DETAILED DESCRIPTION

[0031] The presently disclosed subject matter now will be described more fully hereinafter with reference to the accompanying Figures, in which some, but not all embodiments of the inventions are shown. Like numbers refer to like elements throughout. The presently disclosed subject matter may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. Indeed, many modifications and other embodiments of the presently disclosed subject matter set forth herein will come to mind to one skilled in the art to which the presently disclosed subject matter pertains having the benefit of the teachings presented in the foregoing descriptions and the associated Figures. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims.

[0032] I. PROSTATE-SPECIFIC MEMBRANE ANTIGEN AS AN IMAGING BIOMARKER IN INFLAMMATORY BOWEL DISEASE

[0033] Prostate-specific membrane antigen (PSMA) is highly and specifically upregulated in active inflamed mucosa of patients with inflammatory bowel disease (IBD). The presently disclosed subject matter demonstrates that this upregulation is detectable using a PSMA-targeted positron emission tomography / computed tomography (PET / CT) imaging agent, thereby enabling non-invasive visualization of inflammation.

[0034] More particularly, in some embodiments, the presently disclosed subject matter provides a method for imaging inflammation associated with inflammatory bowel disease (IBD), the method comprising administering to a subject a prostate-specific membrane antigen (PSMA)-targeted imaging agent and taking an image.

[0035] In certain embodiments, the inflammation associated with IBD comprises a mucosal inflammation. In more certain embodiments, the imaging assesses one or more of a location, extent, and disease activity of IBD. In particular embodiments, the extent of IBD includes a percent inflammation in an IBD stricture. In certain embodiments, the inflammatory bowel disease is selected from Crohn’s disease (CD), ulcerative colitis (UC), and combinations thereof. In particular embodiments, the image comprises a positron emission tomography (PET) image. In more particular embodiments, the image comprises a positron emission tomography / computcd tomography (PET / CT) image.

[0036] A. Representative PSMA-targeted Imaging Agents

[0037] In some embodiments, low-molecular-weight (or small molecule) ligands having an affinity for PSMA can be combined with radiolabeled prosthetic groups or chelating moieties that bind radiometals to image inflammation in IBD. The main classes of PSMA low-molecular-weight ligands include phosphor(i)nate compounds and thiols; glutamate- phosphoramidates; glutamate-ureido derivatives; and so-called PSMA-targeted carbamate and reversed carbamate derivatives. See, for example, WO2016065145 and WO20 17027870, each of which is incorporated herein by reference in its entirety.

[0038] Examples of low-molecular-weight PSMA binding motifs include, but are not limited to:

[0039] 2-(phosphonomethyl)pentanedioic phosphinate derivatives 2-(thioalkyl)pentanedioic phosphoramidates acid (2-PMPA) acids urea-based glutamate derivatives carbamates reversed carbamates

[0040] Of these motifs, the urea-based glutamate derivatives have received the most attention. Accordingly, in some embodiments, the presently disclosed PSMA-targeted imaging agent comprises the glu-urea-lys PMSA binding motif or modification and derivatives thereof: wherein:

[0041] V is selected from -NH-C(=O)-, -C(=O)-NH-, and -NH-; L is a linker; and

[0042] Rpt is a reporting moiety.

[0043] In particular embodiments, V is -NH-C(=O)- and the PSM A-targeted imaging agent comprises:

[0044] The linker “L” can be any suitable linker known in the art. Representative linkers include, but are not limited to a linker selected from (a), (b), (c), or (d): wherein: pi, p2, pa and p4 may be in any order; ti and t2 are each an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8; pi, P3, and p4 are each independently 0 or 1;

[0045] P2 is an integer selected from the group consisting of 0, 1, 2, and 3, and when p2 is 2 or 3, each Ri is the same or different; mi and m2 are each an integer independently selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7 and 8;

[0046] Wi is selected from the group consisting of a bond, -S-, -C(=O)-, -C(=O)-NR- and -NR-C(=O)-;

[0047] W2 is selected from the group consisting of 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, wherein q is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8; each R or R' is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hctcrocycloalkyl, substituted hctcrocycloalkyl, aryl, substituted aryl, hctcroaryl, substituted heteroaryl, and -OR4, wherein R4 is selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl, wherein q is defined as immediately hereinabove;

[0048] Tz is a triazole group that can be present or absent and, if present, is selected from each Ri is independently H, Ci-Ce alkyl, C3-C12 aryl, -(Cthlq-Ca-Cn aryl, -C4-C16 alkylaryl, or -(CH2)q-C4-Cie alkylaryl; R2 and R3 are each independently H and -CO2R5, wherein R5 is selected from the group consisting of H, Ci-Ce alkyl, C3-C12 aryl, and C4-C16 alkylaryl, wherein when one of R2 or R3 is CO2R5, then the other is H;

[0049] V is selected from the group consisting of -C(O)-, -C(S)-, -NRC(O)-, -NRC(S)-, and -OC(O)-; wherein pi, p2, p3, mi, m2, Tz, W2, R, Ri, R2, R3, and V are defined as hereinabove;

[0050] (c) -Li-, -L2-L3-, or -L1-L2-L3-, wherein:

[0051] Li is -NR-(CH2)q-[O-CH2-CH2-O]q-(CH2)q-C(=O)-;

[0052] L2is -NR-(CH2)q-C(COOR5)-NR-; and

[0053] L3is -(O=)C-(CH2)q-C(=O)-; wherein each q is independently an integer selected from the group consisting of 1, 2, 3, 4,

[0054] 5, 6, 7, and 8; and R and R5 are as defined hereinabove; and

[0055] (d) -(CR6H)q-(CH2)q-C(=O)-NR-(CH2)q-O- or -NR-(CH2)q-O-; wherein each q and R is defined hereinabove; and Re is H or -COOR5.

[0056] In more certain embodiments, the linker “L” is selected from: wherein u is an integer selected from 1, 2, 3, 4, 5, 6, 7, and 8; and R and Rs are as defined hereinabove.

[0057] In certain embodiments, the reporting moiety “Rpt” comprises a radiolabeled prosthetic group comprising a radioisotope selected from the group consisting of18F,124I,125I,1311, and211At.

[0058] In more certain embodiments, the radiolabeled prosthetic group is selected from the group consisting of: wherein each X is independently a radioisotope selected from the group consisting of18F,124I,125I,131I, and211At; each R and R’ is defined hereinabove; and each n is independently 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.

[0059] In yet more certain embodiments, the radiolabeled prosthetic group is selected from the group consisting of:

[0060] In certain embodiments, the reporting moiety “Rpt” comprises a chelating agent. In more certain embodiments, the chelating agent is selected from the group consisting of

[0061] DOTAGA (l,4,7,10-tetraazacyclododececane,l-(glutaric acid)-4,7,10-triacetic acid), DOTA (l,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid), DOTASA (1,4,7,10- tetraazacyclododecane-l-(2-succinic acid)-4,7,10-triacetic acid), CB-DO2A (10- bis(carboxymethyl)-l,4,7,10-tetraazabicyclo[5.5.2]tetradecane), DEPA (7-[2-(Bis- carboxymcthylamino)-cthyl]-4,10-bis-carboxymcthyl-l,4,7,10-tctraaza-cyclododcc-l-yl- acetic acid)), 3p-C-DEPA (2-[(carboxymethyl)][5-(4-nitrophenyl-l-[4,7,10- tris(carboxymethyl)-l,4,7,10-tetraazacyclododecan-l-yl]pentan-2-yl)amino]acetic acid)), TCMC (2-(4-isothiocyanotobenzyl)-l ,4,7,10-tetraaza- 1,4,7, 10-tetra-(2-carbamonyl methyl)- cyclododccanc), oxo-DO3A (l-oxa-4,7,10-triazacyclododccanc-5-S-(4- isothiocyanatobenzyl)-4,7,10-triacetic acid), p-NH2-Bn-Oxo-DO3A (l-Oxa-4,7,10- tetraazacyclododecane-5-S-(4-aminobenzyl)-4,7,10-triacetic acid), TE2A ((l,8-A,A'-bis- (carboxymethyl)-l,4,8,l l-tetraazacyclotetradecane), MM-TE2A, DM-TE2A, CB-TE2A (4,1 l-bis(carboxymethyl)-l,4,8,l l-tetraazabicyclo[6.6.2]hexadecane), CB-TE1A1P (4,8,11- tetraazacyclotetradecane-l-(methanephosphonic acid)-8-(methanecarboxylic acid), CB- TE2P (l,4,8,ll-tetraazacyclotetradecane-l,8-bis(methanephosphonic acid), TETA (1,4,8,11- tetraazacyclotetradecane-1,4,8,11 -tetraacetic acid), NOTA (1,4,7-triazacyclononane- N,N',N"-triacetic acid), NODA (l,4,7-triazacyclononane-l,4-diacetate); NODAGA (1,4,7- triazacyclononane,l -glutaric acid-4, 7-acetic acid), (NOTAGA) l,4,7-triazonane-l,4- diyl)diacetic acid DFO (Desferoxamine), NETA ([4-[2-(bis-carboxymethylamino)-ethyl]-7- carboxymethl-[l,4,7]triazonan-l-yl}-acetic acid), TACN-TM (N,N',N", tris(2- mercaptoethyl)- 1,4,7-triazacyclononane), Diamsar (1 ,8-Diamino-3,6, 10,13, 16, 19- hexaazabicyclo(6,6,6)eicosane, 3,6,10,13,16,19-Hexaazabicyclo[6.6.6]eicosane-1,8- diamine), Sarar (l-A-(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.

[0062] In yet more certain embodiments, the chelating agent is selected from the group consisting of:

[0063]

[0064] In certain embodiments, the chelating agent further comprises a radiomctal. In particular embodiments, the radiometal is selected from the group consisting of60Cu,62Cu,64Cu,67Cu,203Pb,212Pb,225Ac,177LU, "mTc,68Ga,149Tb,86Y,90Y,inIn,186Re,188Re,153Sm,89Zr,213Bi,212Bi,212Pb,67Ga,47Sc,166Ho, and [18F]A1F.

[0065] More particularly, in some embodiments, the PSMA-targeted imaging agent comprises: wherein R is a reporting moiety selected from wherein n is an integer selected from 1 , 2, 3, and 4; and X is a radioisotope of iodine, chlorine, bromine, or astatine. In certain embodiments, the radioisotope of iodine, chlorine, bromine, or astatine is selected from18F,123I,124I,1251,126I,131I,75Br,76Br,77Br,80Br,80mBr,82Br,83Br, and211At. See, for example, international PCT patent application publication no. W02010 / 014933, which is incorporated herein by reference in its entirety: :

[0066] In more particular embodiments, the PSMA-targeted imaging agent is [18F]DCFPyL:

[0067] [18F]DCFPyL and related compounds and methods for preparing the same are disclosed in U.S. Patent Nos. 8,487,129; 8,778,305; 9,226,981; 9,861,713; 10,500,292; 10,947,197, each of which is incorporated by reference in its entirety;

[0068] One of ordinary skill in the art would appreciate that other PSMA-targeted imaging agents are suitable for use with the presently disclosed methods. Such PSMA-targeted imaging agents include, but arc not limited to, the following:

[0069] Other PSMA-targeted imaging agents having a prosthetic group substituted with a radiolabeled halogen include: Representative glu-urea-lys PSMA-targeting imaging agents having a chelating group include, but arc not limited to,68Ga PSMA-11, which uses an HBED-CC chelator and is FDA-approved as a new chemical entity (NCE) and also can coordinate [18F]A1F, in which the68Ga is substituted with [18F]A1F; PSMA-617, including [68Ga]PSMA-617; PSMA-I&T, including [68Ga]PSMA-I&T; [99mTc]PSMA I&S; [68Ga]PSMA-R2; PSMA- SR6; [68Ga]P 16-093; [18F]-PSMA-BCH; and [18F]-Bi-PSMA:

[0070]

[0071] Ĩ[68Ga]P16-093);

[0072] ([ F]-Bi-PSMA).

[0073] Other glu-urea-lys based PSMA ligands include those described in U.S. Pat. Nos. 8,211,401; 8,211,402; 8,465,725; 8,487,129; and 8,562,945; and in PCT / US 2014 / 011047, each of which is incorporated herein by reference in their entirety. Representative Glu-Urea based PSMA ligands linked to chelating moieties include, but are not limited to MIP-1555, MIP-1519, MIP-1545, MIP-1427, MIP-1428, MIP-1379, MIP-1558, MIP-1405, and MIP-

[0074] 1404:

[0075]

[0076]

[0077] (MIP-1405).

[0078] In other embodiments, the PSMA-targeted imaging agent includes an18F-labeled phophoramidatc :

[0079] In yet other embodiments, the PSMA-targeted imaging agent is:

[0080] [18F]CTT1057.

[0081] The “subject” treated by the presently disclosed methods in their many embodiments is desirably a human subject, although it is to be understood that the methods described herein are effective with respect to all vertebrate species, which are intended to be included in the term “subject.” Accordingly, a “subject” can include a human subject for medical purposes, such as for the treatment of an existing condition or disease or the prophylactic treatment for preventing the onset of a condition or disease, or an animal subject for medical, veterinary purposes, or developmental purposes. Suitable animal subjects include mammals including, but not limited to, primates, e.g., humans, monkeys, apes, and the like; bovines, e.g., cattle, oxen, and the like; ovines, e.g., sheep and the like; caprines, e.g., goats and the like; porcines, e.g., pigs, hogs, and the like; equines, e.g., horses, donkeys, zebras, and the like; felines, including wild and domestic cats; canines, including dogs; lagomorphs, including rabbits, hares, and the like; and rodents, including mice, rats, and the like. An animal may be a transgenic animal. In some embodiments, the subject is a human including, but not limited to, fetal, neonatal, infant, juvenile, and adult subjects. Further, a “subject” can include a patient afflicted with or suspected of being afflicted with a condition or disease. Thus, the terms “subject” and “patient” are used interchangeably herein. The term “subject” also refers to an organism, tissue, cell, or collection of cells from a subject.

[0082] B. Pharmaceutical Compositions and Administration

[0083] In another aspect, the present disclosure provides a pharmaceutical composition including one PSMA-targeted imaging agent alone or in combination with one or more additional therapeutic agents in admixture with a pharmaceutically acceptable excipient. One of skill in the art will recognize that the pharmaceutical compositions include the pharmaceutically acceptable salts of the compounds described above. Pharmaceutically acceptable salts are generally well known to those of ordinary skill in the art, and include salts of active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular’ substituent moieties found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent or by ion exchange, whereby one basic counterion (base) in an ionic complex is substituted for another. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.

[0084] When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent or by ion exchange, whereby one acidic counterion (acid) in an ionic complex is substituted for another. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, bcnzcncsulfonic, p- toluenesulfonic, citric, tartaric, methanesulfonic, trifluoroacetic acid (TFA), and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0085] Accordingly, pharmaceutically acceptable salts suitable for use with the presently disclosed subject matter include, by way of example but not limitation, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, or teoclate. Other pharmaceutically acceptable salts may be found in, for example, Remington: The Science and Practice of Pharmacy (20thed.) Lippincott, Williams & Wilkins (2000). In therapeutic and / or diagnostic applications, the compounds of the disclosure can be formulated for a variety of modes of administration, including systemic and topical or localized administration. Techniques and formulations generally may be found in Remington: The Science and Practice of Pharmacy (20thed.) Lippincott, Williams & Wilkins (2000).

[0086] Depending on the specific conditions being treated, such agents may be formulated into liquid or solid dosage forms and administered systemically or locally. The agents may be delivered, for example, in a timed- or sustained-slow release form as is known to those skilled in the art. Techniques for formulation and administration may be found in Remington: The Science and Practice of Pharmacy (20thed.) Lippincott, Williams & Wilkins (2000). Suitable routes may include oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intra-articullar, intra -sternal, intra-synovial, intra-hcpatic, intralcsional, intracranial, intraperitoneal, intranasal, or intraocular injections or other modes of delivery.

[0087] For injection, the agents of the disclosure may be formulated and diluted in aqueous solutions, such as in physiologically compatible buffers such as Hank’s solution, Ringer’s solution, or physiological saline buffer. For such transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the ail.

[0088] Use of pharmaceutically acceptable inert carriers to formulate the compounds herein disclosed for the practice of the disclosure into dosages suitable for systemic administration is within the scope of the disclosure. With proper choice of carrier and suitable manufacturing practice, the compositions of the present disclosure, in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection. The compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration. Such carriers enable the compounds of the disclosure to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject (e.g., patient) to be treated.

[0089] For nasal or inhalation delivery, the agents of the disclosure also may be formulated by methods known to those of skill in the ail, and may include, for example, but not limited to, examples of solubilizing, diluting, or dispersing substances, such as saline; preservatives, such as benzyl alcohol; absorption promoters; and fluorocarbons.

[0090] In certain embodiments, the PSMA-targeted imaging agent is administered intranasally in a form selected from the group consisting of a nasal spray, a nasal drop, a powder, a granule, a cachet, a tablet, an aerosol, a paste, a cream, a gel, an ointment, a salve, a foam, a paste, a lotion, a cream, an oil suspension, an emulsion, a solution, a patch, and a stick. As used herein, the term administrating via an "intranasal route" refers to administering by way of the nasal structures.

[0091] Pharmaceutical compositions suitable for use in the present disclosure include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. Generally, the compounds according to the disclosure are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. A non-limiting dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, the bioavailability of the compound(s), the adsorption, distribution, metabolism, and excretion (ADME) toxicity of the compound(s), and the preference and experience of the attending physician.

[0092] In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. The preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions.

[0093] Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethyl-cellulose (CMC), and / or polyvinylpyrrolidone (PVP: povidone). If desired, disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0094] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dye-stuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0095] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs). In addition, stabilizers may be added.

[0096] In general, the “effective amount” of an active agent or drug delivery device refers to the amount necessary to elicit the desired biological response. As will be appreciated by those of ordinary skill in this ail, the effective amount of an agent or device may vary depending on such factors as the desired biological endpoint, the agent to be delivered, the makeup of the pharmaceutical composition, the target tissue, and the like.

[0097] The term “combination” is used in its broadest sense and means that a subject is administered at least two agents, more particularly a compound described herein and at least one other therapeutic agent. More particularly, the term “in combination” refers to the concomitant administration of two (or more) active agents for the treatment of a, e.g., single disease state. As used herein, the active agents may be combined and administered in a single dosage form, may be administered as separate dosage forms at the same time, or may be administered as separate dosage forms that are administered alternately or sequentially on the same or separate days. In one embodiment of the presently disclosed subject matter, the active agents are combined and administered in a single dosage form. In another embodiment, the active agents are administered in separate dosage forms (e.g., wherein it is desirable to vary the amount of one but not the other). The single dosage form may include additional active agents for the treatment of the disease state.

[0098] Further, the compounds described herein can be administered alone or in combination with adjuvants that enhance stability of the compounds, alone or in combination with one or more therapeutic agents, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, and the like, including other active ingredients. Advantageously, such combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as monotherapies. The timing of administration of a compound described herein and at least one additional therapeutic agent can be varied so long as the beneficial effects of the combination of these agents are achieved. Accordingly, the phrase “in combination with” refers to the administration of a compound described herein and at least one additional therapeutic agent either simultaneously, sequentially, or a combination thereof. Therefore, a subject administered a combination of a compound described herein and at least one additional therapeutic agent can receive a compound and at least one additional therapeutic agent at the same time (i.e., simultaneously) or at different times (i.e., sequentially, in either order, on the same day or on different days), so long as the effect of the combination of both agents is achieved in the subject.

[0099] When administered sequentially, the agents can be administered within 1, 5, 10, 30, 60, 120, 180, 240 minutes or longer of one another. In other embodiments, agents administered sequentially, can be administered within 1, 5, 10, 15, 20 or more days of one another. Where the compound described herein and at least one additional therapeutic agent are administered simultaneously, they can be administered to the subject as separate pharmaceutical compositions, each comprising either a compound or at least one additional therapeutic agent, or they can be administered to a subject as a single pharmaceutical composition comprising both agents.

[0100] When administered in combination, the effective concentration of each of the agents to elicit a particular biological response may be less than the effective concentration of each agent when administered alone, thereby allowing a reduction in the dose of one or more of the agents relative to the dose that would be needed if the agent was administered as a single agent. The effects of multiple agents may, but need not be, additive or synergistic. The agents may be administered multiple times.

[0101] In some embodiments, when administered in combination, the two or more agents can have a synergistic effect. As used herein, the terms “synergy,” “synergistic,” “synergistically” and derivations thereof, such as in a “synergistic effect” or a “synergistic combination” or a “synergistic composition” refer to circumstances under which the biological activity of a combination of a compound described herein and at least one additional therapeutic agent is greater than the sum of the biological activities of the respective agents when administered individually. Synergy can be expressed in terms of a “Synergy Index (SI),” which generally can be determined by the method described by F. C. Kull ct al., Applied Microbiology 9, 538 (1961), from the ratio determined by:

[0102] Qa / Q.\ + QH / QH = Synergy Index (SI) wherein:

[0103] QA is the concentration of a component A, acting alone, which produced an end point in relation to component A;

[0104] Qais the concentration of component A, in a mixture, which produced an end point;

[0105] QB is the concentration of a component B, acting alone, which produced an end point in relation to component B; and

[0106] Qb is the concentration of component B, in a mixture, which produced an end point.

[0107] Generally, when the sum of Qa / QA and Qb / Qis is greater than one, antagonism is indicated. When the sum is equal to one, additivity is indicated. When the sum is less than one, synergism is demonstrated. The lower the SI, the greater the synergy shown by that particular mixture. Thus, a “synergistic combination” has an activity higher that what can be expected based on the observed activities of the individual components when used alone. Further, a “synergistically effective amount” of a component refers to the amount of the component necessary to elicit a synergistic effect in, for example, another therapeutic agent present in the composition.

[0108] In some embodiments, the presently disclosed PSMA-targeted imaging agents can be administered in combination with one or more additional therapeutic agents to prevent or reduce an accumulation of a prostate-specific membrane antigen (PSMA) imaging agent in an off-target non-cancer tissue, such as the kidney, lacrimal gland, and salivary gland. See, for example, WO2018191376 for Prodrugs of 2-PMPA for Healthy Tissue Protection During PSMA-Targeted Cancer Imaging or Radiotherapy to Slusher et al., published October 18, 2018. See also U.S. Patent Nos. 11,167,049; 10,668,174; and 9,956,305, each of which is incorporated herein by reference in its entirety.

[0109] C. Definitions

[0110] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this presently described subject matter belongs.

[0111] While the following terms in relation to the presently disclosed PSMA-targeted imaging agents are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter. These definitions are intended to supplement and illustrate, not preclude, the definitions that would be apparent to one of ordinary skill in the art upon review of the present disclosure.

[0112] The terms substituted, whether preceded by the term “optionally” or not, and substituent, as used herein, refer to the ability, as appreciated by one skilled in this art, to change one functional group for another functional group on a molecule, provided that the valency of all atoms is maintained. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. The substituents also may be further substituted (e.g., an aryl group substituent may have another substituent off it, such as another aryl group, which is further substituted at one or more positions).

[0113] Where substituent groups or linking groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., - CH2O- is equivalent to -OCH2-; -C(=O)O- is equivalent to -OC(=O)-; -OC(=O)NR- is equivalent to -NRC(=O)O-, and the like.

[0114] When the term “independently selected” is used, the substituents being referred to (e.g., R groups, such as groups Ri, R2, and the like, or variables, such as “m” and “n”), can be identical or different. For example, both Ri and R2 can be substituted alkyls, or Ri can be hydrogen and R2 can be a substituted alkyl, and the like.

[0115] The terms “a,” “an,” or “a(n),” when used in reference to a group of substituents herein, mean at least one. For example, where a compound is substituted with “an” alkyl or aryl, the compound is optionally substituted with at least one alkyl and / or at least one aryl. Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. A named “R” or group will generally have the structure that is recognized in the art as corresponding to a group having that name, unless specified otherwise herein. For the purposes of illustration, certain representative “R” groups as set forth above arc defined below.

[0116] Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and / or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.

[0117] Unless otherwise explicitly defined, a “substituent group,” as used herein, includes a functional group selected from one or more of the following moieties, which are defined herein:

[0118] The term hydrocarbon, as used herein, refers to any chemical group comprising hydrogen and carbon. The hydrocarbon may be substituted or unsubstituted. As would be known to one skilled in this art, all valencies must be satisfied in making any substitutions. The hydrocarbon may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic. Illustrative hydrocarbons are further defined herein below and include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, allyl, vinyl, zz-butyl, tert-butyl, ethynyl, cyclohexyl, and the like.

[0119] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a univalent group derived from an alkane by removal of a hydrogen atom from any carbon atom -Cn Un+i. The groups derived by removal of a hydrogen atom from a terminal carbon atom of unbranched alkanes form a subclass of normal alkyl (n-alkyl) groups H(CH2)n. The groups RCFb, R2CH (R H), and R3C (R H) are primary, secondary and tertiary alkyl groups, respectively. An alkyl can be a straightchain (i.e., unbranched) or branched acyclic hydrocarbon having the number of carbon atoms designated (i.e., C1-10 means one to ten carbons, including 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbons). In particular embodiments, the term “alkyl” refers to Ci-20 inclusive, including 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbons.

[0120] Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl. isopropyl, u-butyl, isobutyl, sec-butyl, tert-butyl, u-pentyl, sec-pentyl, isopentyl, neopentyl, / 7-hcxyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, and dodecyl.

[0121] “Branched” refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain. “Lower alkyl” refers to an alkyl group having 1 to about 8 carbon atoms (i.e., a C1-8 alkyl), e.g., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. “Higher alkyl” refers to an alkyl group having about 10 to about 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. In certain embodiments, “alkyl” refers, in particular, to Ci-s straight-chain alkyls. In other embodiments, “alkyl” refers, in particular, to Ci-8 branched-chain alkyls.

[0122] Alkyl groups can optionally be substituted (a “substituted alkyl”) with one or more alkyl group substituents, which can be the same or different. The term “alkyl group substituent” includes but is not limited to alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl. There can be optionally inserted along the alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as “alkylaminoalkyl”), or aryl.

[0123] Thus, as used herein, the term “substituted alkyl” includes alkyl groups, as defined herein, in which one or more atoms or functional groups of the alkyl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, cyano, and mercapto.

[0124] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain having from 1 to 20 carbon atoms or heteroatoms or a cyclic hydrocarbon group having from 3 to 10 carbon atoms or heteroatoms, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatemized. The heteroatom(s) O, N, P and S and Si may be placed at any interior position of the hctcroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -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, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.

[0125] As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a hetero atom, such as -C(O)NR’, -NR’R”, -OR’, -SR, -S(O)R, and / or -S(O2)R’. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR’R or the like, it will be understood that the terms heteroalkyl and -NR’R” are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R” or the like.

[0126] “Cyclic” and “cycloalkyl” refer to a univalent group derived from a cycloalkane by removal of a hydrogen atom from a ring carbon atom. A cycloalkane is a saturated monocyclic hydrocarbon (with or without side chains), e.g., cyclobutane. Unsaturated monocyclic hydrocarbons having one endocyclic double or one triple bond are called cycloalkenes and cycloalkynes, respectively. Those having more than one such multiple bond are cycloalkadienes, cycloalkatrienes, and the like. The inclusive terms for any cyclic hydrocarbons having any number of such multiple bonds are cyclic olefins or cyclic acetylenes. As used herein, cycloalkyls can be a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group can be optionally partially unsaturated. The cycloalkyl group also can be optionally substituted with an alkyl group substituent as defined herein, oxo, and / or alkylene. There can be optionally inserted along the cyclic alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, unsubstituted alkyl, substituted alkyl, aryl, or substituted aryl, thus providing a heterocyclic group. Representative monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Multicyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphane, and noradamantyl, and fused ring systems, such as dihydro- and tetrahydronaphthalene, and the like.

[0127] The term “cycloalkylalkyl,” as used herein, refers to a cycloalkyl group as defined hereinabove, which is attached to the parent molecular moiety through an alkylene moiety, also as defined above, e.g., a Ci-20 alkylene moiety. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.

[0128] The terms “cycloheteroalkyl” or “heterocycloalkyl” refer to a non-aromatic ring system, unsaturated or partially unsaturated ring system, such as a 3- to 10-member substituted or unsubstituted cycloalkyl ring system, including one or more heteroatoms, which can be the same or different, and arc selected from the group consisting of nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), and silicon (Si), and optionally can include one or more double bonds.

[0129] The cycloheteroalkyl ring can be optionally fused to or otherwise attached to other cycloheteroalkyl rings and / or non-aromatic hydrocarbon rings. Heterocyclic rings include those having from one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatemized. In certain embodiments, the term heterocylic refers to a non-aromatic 5-, 6-, or 7-membered ring or a polycyclic group wherein at least one ring atom is a heteroatom selected from O, S, and N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), including, but not limited to, a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring. Representative cycloheteroalkyl ring systems include, but are not limited to pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinanyl, tetrahydrofuranyl, and the like. The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3- cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, l-(l,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, 2-piperazinyl, and the like. The terms “cycloalkylene” and “heterocycloalkylene” refer to the divalent derivatives of cycloalkyl and heterocycloalkyl, respectively.

[0130] As used herein the terms “bicycloalkyl” and “bicycloheteroalkyl” refer to two cycloalkyl or cycloheteroalkyl groups that are bound to one another. Non-limiting examples include bicyclohexane and bipiperidine.

[0131] An unsaturated hydrocarbon has one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3- propynyl, 3-butynyl, and the higher homologs and isomers. Alkyl groups which are limited to hydrocarbon groups are termed “homoalkyl.”

[0132] More particularly, the term “alkenyl” as used herein refers to a monovalent group derived from a C2-20 inclusive straight or branched hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen molecule. Alkenyl groups include, for example, ethenyl (i.e., vinyl), propenyl, butenyl, l-methyl-2-buten-l-yl, pentenyl, hexenyl, octenyl, allenyl, and butadienyl.

[0133] The term “cycloalkenyl” as used herein 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.

[0134] The term “alkynyl” as used herein refers to a monovalent group derived from a straight or branched C2-20 hydrocarbon of a designed number of carbon atoms containing at least one carbon-carbon triple bond. Examples of “alkynyl” include ethynyl, 2-propynyl (propargyl), 1-propynyl, pcntynyl, hcxynyl, and hcptynyl groups, and the like.

[0135] The term “alkylene” by itself or a part of another substituent refers to a straight or branched bivalent aliphatic hydrocarbon group derived from an alkyl group having from 1 to about 20 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The alkylene group can be straight, branched or cyclic. The alkylene group also can be optionally unsaturated and / or substituted with one or more “alkyl group substituents.” There can be optionally inserted along the alkylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as “alkylaminoalkyl”), wherein the nitrogen substituent is alkyl as previously described. Exemplary alkylene groups include methylene (-CH2-); ethylene (-CH2-CH2-); propylene (-(CH2)3-); cyclohexylene (-C6HIO-); -CH=CH-CH=CH-; -CH=CH-CH2-; - CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2CSCCH2-, -CH2CH2CH(CH2CH2CH3)CH2- , -(CH2)q-N(R)-(CH2)i-, wherein each of q and r is independently an integer from 0 to about 20, e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and R is hydrogen or lower alkyl; methylenedioxyl (-O-CH2-O-); and ethylenedioxyl (-O-(CH2)2- O- ). An alkylene group can have about 2 to about 3 carbon atoms and can further have 6-20 carbons. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being some embodiments of the present disclosure. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.

[0136] The term “heteroalkylene” by itself or as part of another substituent means a divalent group derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms also can occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied 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)-.

[0137] The term “aryl” means, unless otherwise stated, a substituent group derived from an arene, i.e., a monoyclic or polycyclic aromatic hydrocarbon, by removal of a hydrogen atom from a ring carbon atom. An aryl group can include an aromatic hydrocarbon substituent that can be a single ring or multiple rings (such as from 1 to 3 rings), which arc fused together or linked covalently. The term “heteroaryl” refers to aryl groups (or rings) that contain from one to four heteroatoms (in each separate ring in the case of multiple rings) selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. 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, 5-isoxazolyl, 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 -benzo thiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1 -isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. The terms “arylene” and “heteroarylene” refer to the divalent forms of aryl and heteroaryl, respectively.

[0138] For brevity, the term “aryl” when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the terms “arylalkyl” and “heteroarylalkyl” are meant to include those groups in which an aryl or heteroaryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, furylmethyl, and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxy methyl, 2-pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like). The term “haloaryl,” however, as used herein is meant to cover only aryls substituted with one or more halogens.

[0139] Where a heteroalkyl, heterocycloalkyl, or heteroaryl includes a specific number of members (e.g. “3 to 7 membered”), the term “member” refers to a carbon or heteroatom.

[0140] Further, a structure represented generally by the formula: as used herein refers to a ring structure, for example, but not limited to a 3-carbon, a 4- carbon, a 5-carbon, a 6-carbon, a 7-carbon, and the like, aliphatic and / or aromatic cyclic compound, including a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure, comprising a substituent R group, wherein the R group can be present or absent, and when present, one or more R groups can each be substituted on one or more available carbon atoms of the ring structure. The presence or absence of the R group and number of R groups is determined by the value of the variable “n,” which is an integer generally having a value ranging from 0 to the number of carbon atoms on the ring available for substitution. Each R group, if more than one, is substituted on an available carbon of the ring structure rather than on another R group. For example, the structure above where n is 0 to 2 would comprise compound groups including, but not limited to: and the like.

[0141] A dashed line representing a bond in a cyclic ring structure indicates that the bond can be either present or absent in the ring. That is, a dashed line representing a bond in a cyclic ring structure indicates that the ring structure is selected from the group consisting of a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure.

[0142] The symbol (, / vwwwv) denotes the point of attachment of a moiety to the remainder of the molecule.

[0143] When a named atom of an aromatic ring or a heterocyclic aromatic ring is defined as being “absent,” the named atom is replaced by a direct bond.

[0144] Each of above terms (e.g. , “alkyl,” “heteroalkyl,” “cycloalkyl, and “heterocycloalkyl”, “aryl,” “heteroaryl,” “phosphonate,” and “sulfonate” as well as their divalent derivatives) are meant to include both substituted and unsubstituted forms of the indicated group. Optional substituents for each type of group are provided below.

[0145] Substituents for alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl monovalent and divalent derivative groups (including those groups often referred to as alkylene, alkenyl, hctcroalkylcnc, hctcroalkcnyl, alkynyl, cycloalkyl, hctcrocycloalkyl, cycloalkcnyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to: -OR’, =0, =NR’, =N-0R’, -NR’R”, -SR’, -halogen, -SiR’R”R’”, -0C(0)R’, -C(0)R’, - C02R’,-C(0)NR’R”, -0C(0)NR’R”, -NR”C(0)R’, -NR’-C(0)NR”R’”, -NR”C(0)0R’, - NR-C(NR’R”)=NR’”, -S(O)R’, -S(O)2R’, -S(0)2NR’R”, -NRS02R’, -CN, CF3, fluorinated Ci-4 alkyl, and -N02in a number ranging from zero to (2m’+l), where m’ is the total number of carbon atoms in such groups. R’, R”, R’” and R”” each may independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. As used herein, an “alkoxy” group is an alkyl attached to the remainder of the molecule through a divalent oxygen. When a compound of the disclosure includes more than one R group, for example, each of the R groups is independently selected as are each R’, R”, R’” and R”” groups when more than one of these groups is present. When R’ and R” are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7- membered ring. For example, -NR’R” is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3and -CH2CF3) and acyl (e.g., -C(0)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[0146] Similar to the substituents described for alkyl groups above, exemplary substituents for aryl and heteroaryl groups (as well as their divalent derivatives) are varied and are selected from, for example: halogen, -OR’, -NR’R”, -SR’, -SiR’R”R’”, -0C(0)R’, - C(0)R’, -C02R’, -C(0)NR’R”, -0C(0)NR’R”, -NR”C(0)R’, -NR’-C(0)NR”R’”, - NR”C(0)0R’, -NR-C(NR’R”R’”)=NR””, -NR-C(NR’R”)=NR’” -S(O)R’, -S(O)2R’, - S(O)2NR’R”, -NRS02R’, -CN and -N02, -R’, -N3, -CH(Ph)2, fluoro(Ci-4)alkoxo, and fluoro(Ci-4)alkyl, in a number ranging from zero to the total number of open valences on aromatic ring system; and where R’, R”, R’” and R”” may be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted hctcroaryl. When a compound of the disclosure includes more than one R group, for example, each of the R groups is independently selected as are each R’, R”, R’” and R”” groups when more than one of these groups is present.

[0147] Two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR’)q-U-, wherein T and U are independently -NR-, - O-, -CRR’- or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR’-, -O-, - NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR’- or a single bond, and r is an integer of from 1 to 4.

[0148] One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR’)s-X’- (C”R”’)d-, where s and d are independently integers of 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’” may be 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.

[0149] As used herein, the term “acyl” refers to an organic acid group wherein the -OH of the carboxyl group has been replaced with another substituent and has the general formula RC(=O)-, wherein R is an alkyl, alkenyl, alkynyl, aryl, carbocylic, heterocyclic, or aromatic heterocyclic group as defined herein). As such, the term “acyl” specifically includes arylacyl groups, such as a 2-(furan-2-yl)acetyl)- and a 2-phenylacetyl group. Specific examples of acyl groups include acetyl and benzoyl. Acyl groups also are intended to include amides, -RC(=O)NR’, esters, -RC(=O)OR’, ketones, -RC(=O)R’, and aldehydes, -RC(=O)H.

[0150] The terms “alkoxyl” or “alkoxy” are used interchangeably herein and refer to a saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O- and alkynyl-O-) group attached to the parent molecular moiety through an oxygen atom, wherein the terms “alkyl,” “alkenyl,” and “alkynyl” are as previously described and can include Ci-20 inclusive, linear, branched, or cyclic, saturated or unsaturated oxo-hydrocarbon chains, including, for example, methoxyl, cthoxyl, propoxyl, isopropoxyl, zr-butoxyl, sec-butoxyl, tert-butoxyl, and n- pentoxyl, neopentoxyl, n-hexoxyl, and the like.

[0151] The term “alkoxyalkyl” as used herein refers to an alkyl-O-alkyl ether, for example, a methoxy ethyl or an ethoxy methyl group.

[0152] “Aryloxyl” refers to an aryl-O- group wherein the aryl group is as previously described, including a substituted aryl. The term “aryloxyl” as used herein can refer to phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, halo, or alkoxyl substituted phenyloxy 1 or hexyloxyl.

[0153] “Aralkyl” refers to an aryl-alkyl-group wherein aryl and alkyl are as previously described, and included substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.

[0154] “Aralkyloxyl” refers to an aralkyl-O- group wherein the aralkyl group is as previously described. An exemplary aralkyloxyl group is benzyloxyl, i.e., C6H5-CH2-O-. An aralkyloxyl group can optionally be substituted.

[0155] “Alkoxycarbonyl” refers to an alkyl-O-C(=O)- group. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and tert- butyloxycarbonyl.

[0156] “Aryloxycarbonyl” refers to an aryl-O-C(=O)- group. Exemplary aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl.

[0157] “Aralkoxycarbonyl” refers to an aralkyl-O-C(=O)- group. An exemplary aralkoxy carbonyl group is benzyloxycarbonyl.

[0158] “Carbamoyl” refers to an amide group of the formula -C(=O)NHo. “Alkylcarbamoyl” refers to a R’RN-C(=O)- group wherein one of R and R’ is hydrogen and the other of R and R’ is alkyl and / or substituted alkyl as previously described. “Dialkylcarbamoyl” refers to a R’RN-C(=O)- group wherein each of R and R’ is independently alkyl and / or substituted alkyl as previously described.

[0159] The term carbonyldioxyl, as used herein, refers to a carbonate group of the formula - O-C(=O)-OR.

[0160] “Acyloxyl” refers to an acyl-O- group wherein acyl is as previously described. The term “amino” refers to the -NH2 group and al so refers to a nitrogen containing group as is known in the art derived from ammonia by the replacement of one or more hydrogen radicals by organic radicals. For example, the terms “acylamino” and “alkylamino” refer to specific N-substituted organic radicals with acyl and alkyl substituent groups respectively.

[0161] An “aminoalkyl” as used herein refers to an amino group covalently bound to an alkylene linker. More particularly, the terms alkylamino, dialkylamino, and trialkylamino as used herein refer to one, two, or three, respectively, alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom. The term alkylamino refers to a group having the structure -NHR’ wherein R’ is an alkyl group, as previously defined; whereas the term dialkylamino refers to a group having the structure -NR’R”, wherein R’ and R” are each independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having the structure -NR’R”R”’, wherein R’, R”, and R’” are each independently selected from the group consisting of alkyl groups. Additionally, R’, R”, and / or R’” taken together may optionally be -(CH2)k- where k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropylamino, piperidine, trimethylamino, and propylamino.

[0162] The amino group is -NR'R”, wherein 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.

[0163] The terms alkylthioether and thioalkoxyl refer to a saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl-S- and alkynyl-S-) group attached to the parent molecular moiety through a sulfur atom. Examples of thioalkoxyl moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.

[0164] “Acylamino” refers to an acyl-NH- group wherein acyl is as previously described. “Aroylamino” refers to an aroyl-NH- group wherein aroyl is as previously described.

[0165] The term “carbonyl” refers to the -C(=O)- group, and can include an aldehyde group represented by the general formula R-C(=O)H. The term “carboxyl” refers to the -COOH group. Such groups also are referred to herein as a “carboxylic acid” moiety.

[0166] The term “cyano” refers to the -C=N group.

[0167] The terms “halo,” “halide,” or “halogen” as used herein refer to fluoro, chloro, bromo, and iodo groups. Additionally, terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo (C 1-4) alkyl” is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3- bromopropyl, and the like.

[0168] The term “hydroxyl” refers to the -OH group.

[0169] The term “hydroxy alkyl” refers to an alkyl group substituted with an -OH group.

[0170] The term “mercapto” refers to the -SH group.

[0171] The term “oxo” as used herein means an oxygen atom that is double bonded to a carbon atom or to another element.

[0172] The term “nitro” refers to the -NO2 group.

[0173] The term “thio” refers to a compound described previously herein wherein a carbon or oxygen atom is replaced by a sulfur atom.

[0174] The term “sulfate” refers to the -SO4 group.

[0175] The term thiohydroxyl or thiol, as used herein, refers to a group of the formula -SH.

[0176] More particularly, the term “sulfide” refers to compound having a group of the formula -SR.

[0177] The term “sulfone” refers to compound having a sulfonyl group -S(O2)R.

[0178] The term “sulfoxide” refers to a compound having a sulfinyl group -S(O)R

[0179] The term ureido refers to a urea group of the formula -NH — CO — NH .

[0180] Throughout the specification and claims, a given chemical formula or name shall encompass all tautomers, congeners, and optical- and stereoisomers, as well as racemic mixtures where such isomers and mixtures exist.

[0181] Certain compounds of the present disclosure may possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as D- or L- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those which are known in art to be too unstable to synthesize and / or isolate. The present disclosure is meant to include compounds in racemic, scalemic, and optically pure forms. Optically active (R)- and (S)-, or D- and L-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefenic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0182] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0183] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure. The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.

[0184] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures with the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- orI4C-enriched carbon are within the scope of this disclosure.

[0185] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine- 125 (125I) or carbon- 14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0186] The compounds of the present disclosure may exist as salts. The present disclosure includes such salts. Examples of applicable salt forms include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g. (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures, succinates, benzoates and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in art. Also included arc base addition salts such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent or by ion exchange. Examples of acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like. Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0187] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0188] Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0189] Following long-standing patent law convention, the terms “a,” "‘an,” and “the” refer to “one or more” when used in this application, including the claims. Thus, for example, reference to “a subject” includes a plurality of subjects, unless the context clearly is to the contrary (e.g., a plurality of subjects), and so forth.

[0190] Throughout this specification and the claims, the terms “comprise,” “comprises,” and “comprising” are used in a non-exclusive sense, except where the context requires otherwise. Likewise, the term “include” and its grammatical variants are intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that can be substituted or added to the listed items.

[0191] For the purposes of this specification and appended claims, unless otherwise indicated, all numbers expressing amounts, sizes, dimensions, proportions, shapes, formulations, parameters, percentages, quantities, characteristics, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term “about” even though the term “about” may not expressly appear with the value, amount or range. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are not and need not be exact, but may be approximate and / or larger or smaller as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art depending on the desired properties sought to be obtained by the presently disclosed subject matter. For example, the term “about,” when referring to a value can be meant to encompass variations of, in some embodiments, ± 100% in some embodiments ± 50%, in some embodiments ± 20%, in some embodiments ± 10%, in some embodiments ± 5%, in some embodiments ±1%, in some embodiments ± 0.5%, and in some embodiments ± 0.1% from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions.

[0192] Further, the term “about” when used in connection with one or more numbers or numerical ranges, should be understood to refer to all such numbers, including all numbers in a range and modifies that range by extending the boundaries above and below the numerical values set forth. The recitation of numerical ranges by endpoints includes all numbers, e.g., whole integers, including fractions thereof, subsumed within that range (for example, the recitation of 1 to 5 includes 1, 2, 3, 4, and 5, as well as fractions thereof, e.g., 1.5, 2.25, 3.75, 4.1, and the like) and any range within that range. EXAMPLES

[0193] The following Examples have been included to provide guidance to one of ordinary skill in the ail for practicing representative embodiments of the presently disclosed subject matter. In light of the present disclosure and the general level of skill in the art, those of skill can appreciate that the following Examples are intended to be exemplary only and that numerous changes, modifications, and alterations can be employed without departing from the scope of the presently disclosed subject matter. The synthetic descriptions and specific examples that follow are only intended for the purposes of illustration, and are not to be construed as limiting in any manner to make compounds of the disclosure by other methods.

[0194] EXAMPLE 1

[0195] PSMA-Targeted PET Radiotracer [18F]DCFPyL as an Imaging Biomarker in Inflammatory Bowel Disease

[0196] 1.1 Overview

[0197] Prostate-specific membrane antigen (PSMA) is highly and specifically upregulated in active inflamed mucosa of patients with inflammatory bowel disease (IBD). Without wishing to be bound to any one particular theory, it was thought that this upregulation would be detectable using a PSMA-targeted positron emission tomography / computed tomography (PET / CT) imaging agent, in some embodiments, [18F]DCFPyL, thereby enabling non- invasive visualization of inflammation. A noninvasive means of detecting active inflammation would have high clinical value in localization and management of IBD.

[0198] In this Example, [18F]DCFPyL imaging was performed in three IBD patients with active disease. Abnormally increased gastrointestinal [18F]DCFPyL uptake was observed in areas with endoscopic, histologic, and immunohistochemical inflammation, demonstrating partial overlap of segments of bowel with abnormal [18F]DCFPyL uptake and active inflammation.

[0199] This Example demonstrates that PSMA-targeted [18F]DCFPyL PET can effectively detect regions of inflamed mucosa in patients with IBD, suggesting its utility as a noninvasive imaging agent to assess location, extent, and disease activity in IBD. 1.2 Background

[0200] Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract that is characterized by remission and relapse. Liverani et al., 2016; Colombel et al., 2017. Diagnosis of remission can be made based upon clinical findings, biochemical markers, endoscopic, and / or histologic criteria. Achievement of endoscopic remission has emerged as a goal for therapeutic management, as visibly normal mucosa has been associated with improvement in the natural course of IBD and prevention of long-term disease sequelae. Colombel et al., 2017; Peyrin-Biroulet et al., 2015; Turner et al., 2021.

[0201] Although endoscopic remission is a goal of treat-to-target disease management, it is recognized that submucosal inflammation can persist in the absence of mucosal injury, and there is no single test that can accurately detect asymptomatic inflammation in patients with known IBD. Vermeire et al., 2006. Histologic remission is an emerging concept. Its reliability, however, is challenging, as existing histologic scoring systems are subjective and difficult to reproduce. Bryant et al., 2014. The ability to accurately and noninvasively detect and monitor gastrointestinal inflammation in IBD patients would have broad clinical impact by contributing to therapeutic management decisions, avoiding unnecessary treatments, and enhancing monitoring during periods of both treatment and remission.

[0202] Prostate-specific membrane antigen (PSMA), also referred to as glutamate carboxypeptidase II (GCPII), has emerged as a promising biomarker and therapeutic target in IBD. Vomov et al., 2020; Rais et al., 2016; International PCT patent application publication no. WO / 2016 / 022809 for Methods for treating inflammatory bowel disease using prostate specific membrane antigen (PSMA) inhibitors, to Slusher et al., published February 11, 2016; Peters et al., 2019. PSMA is a metallopeptidase responsible for hydrolysis of glutamated peptides including the neurotransmitter N-acetyl-aspartyl- glutamate and the essential dietary nutrient folate poly glutamate. Vomov et al., 2016. Recent studies also have shown that PSMA is expressed in the endothelium of tumor- associated blood vessels and in activated macrophages, indicating its role in inflammation, de Galiza Barbosa et al., 2020.

[0203] PSMA is minimally expressed in the normal gastrointestinal tract, Troyer et al., 1995; Mhawech-Fauceglia et al., 2007; Haffner et al., 2009; Kinoshita et al., 2006; Silver et al., 1997, but is highly and specifically upregulated in inflamed endoscopic biopsies of both Crohn’s disease (CD) and ulcerative colitis (UC) patients. Rais et al., 2016; International PCT patent application publication no. WO / 2016 / 022809 for Methods for treating inflammatory bowel disease using prostate specific membrane antigen (PSMA) inhibitors, to Slusher et al., published February 11, 2016; Zhang et al., 2012. PSMA also is highly upregulated in prostate cancer. Silver et al., 1997; Foss et al., 2012.

[0204] Recently, the PSMA-targeted positron emission tomography (PET) imaging agent [18F]DCFPyL (piflufolastat F-18, tradename Pylarify™) has received U.S. FDA approval for diagnostic imaging in prostate cancer. Chen et al., 2011; Szabo et al., 2015. This FDA approval has led to widespread availability of the agent, facilitating investigations into off- label use.

[0205] Without wishing to be bound to any one particular theory, it was thought that the PSMA upregulation occurring in active IBD would be detectable using [18F]DCFPyL imaging, and further hypothesized that a positive signal would indicate tissue inflammation. The use of PSMA-targeted [18F]DCFPyL PET imaging in inflammatory bowel disease has only been reported in a single case report. Chandekar et al., 2022. This single case was performed for a patient with rising PSA serology levels in the absence of any genitourinary symptoms. [68Ga]Ga-PSMA-l 1 PET / CT was performed, showing uptake in the distal ileum. Chandekar et al., 2022. The patient retrospectively reported a previous diagnosis of Crohn’s disease, with recent increase in diarrheal episodes, bringing the authors to the conclusion that these findings were likely secondary to the patients known history of inflammatory bowel disease. Chandekar et al., 2022.

[0206] We performed [18F]DCFPyL PET in patients hospitalized due to active IBD to present data that PSMA imaging can be used to noninvasively identify active sites of inflammation in IBD patients during a flare.

[0207] 1.3 Methods

[0208] Patients with inflammatory bowel disease (IBD), either labeled as UC, CD, or IBD- Unclassified, presenting with symptoms of a flare who required admission to the hospital, were identified for the study. As per the usual work-up of IBD flares, they underwent routine laboratory testing, as well as endoscopic evaluation. Additionally, [18F]DCFPyL PET / CT imaging was performed under a United States Food and Drug Administration (FDA) Investigational New Drug application (IND 121064). Institutional approval for this study was granted by the Johns Hopkins Medicine Institutional Review Board. Written informed consent was obtained from each patient before the study. All consent forms included participant approval to publish results. The authors declare that the procedures were followed according to the regulations established by the Clinical Research and Ethics Committee and the Helsinki Declaration of the World Medical Association. [18F]DCFPyL PET / CT images were acquired on a Siemens Biograph mCT 128-slice scanner (Siemens Healthineers, Erlangen, Germany), approximately 60 minutes after intravenous administration of approximately 333 MBq (9 mCi) [18F]DCFPyL. The results of [18F]DCFPyL PET / CT images of each patient were used to corroborate endoscopic findings. 1.4 Results

[0209] 1.4.1 Crohn 's disease

[0210] To demonstrate the use of PSMA-targeted [18F]DCFPyL PET / CT in patients with CD, two patients with varying phenotypes were chosen.

[0211] The first phenotype was long-standing ileocolonic CD in a 42-year-old male presenting with symptoms of flare, including abdominal pain and diarrhea of more than 20 bowel movements per day. Inflammatory markers were elevated with an erythrocyte sedimentation rate (ESR) of 36 mm / h (normal <15 mm / h), C-reactive protein (CRP) of 7 mg / dL (normal <0.5 mg / dL), and fecal calprotectin of 241 pg / g (normal <50 pg / g). He had been maintained on ustekinumab every 6 weeks and subcutaneous methotrexate 25 mg weekly. Previous medications included infliximab, adalimumab, vedolizumab, and 6- mercaptopurine. All of these medications failed to control the disease, and he had ongoing inflammation with resulting ileal strictures.

[0212] The PET / CT scan demonstrated a long segment of abnormally increased [18F]DCFPyL uptake in the terminal ileum (FIG. 1). Ileocolonoscopy was performed and demonstrated inflammation and pseudopolyps from the anal verge up to 20 cm from the point of entry, with otherwise normal colonic mucosa (FIG. 2). Of note, terminal ileal inflammation was noted with erythema, edema, and ulceration. A non-traversable short stricture was noted in the terminal ileum, 5 cm from the ileocecal valve, which was dilated with a through-the-scope (TTS) balloon up to 12 mm. A further non-traversable stricture was noted 3 cm proximal to the first stricture. Biopsies from the terminal ileum and rectum demonstrated chronic inflammatory disease. To assess PSMA expression in the region of distal colon located 20 cm from the anal verge, where inflammation was visualized on endoscopic exam but was not detected by [18F]DCFPyL PET / CT, PSMA immunohistochemistry (IHC) was performed on fullthickness distal colon sections, acquired during his abdominoperineal resection using the validated antibody 1A11 (FIG. 3) according to previously described methods. Vomov et al., 2020; Novakova et al., 2017.

[0213] Interestingly, heterogeneously increased PSMA expression was detected in colon epithelial cells adjacent to sites of severe inflammation, where it displayed an intracellular, cytoplasmic expression pattern (FIG. 3C), and thus may have been inaccessible to the radiotracer, explaining the apparent discrepancy between endoscopic and histologic disease, and [18F]DCFPyL imaging at this site. In agreement with this hypothesis, IHC performed on terminal ileum biopsies from this patient exhibited a strikingly different pattern of PSMA expression, with concentrated signal at the apical brush border membrane in addition to increased intracellular expression (FIG. 3D). Notably, in the ileal specimen, PSMA was observed to be upregulated in 100% of epithelia examined, while in the colonic sections, PSMA upregulation was patchy and detected in approximately 20% of epithelia in inflamed regions. It is therefore likely that decreased magnitude of PSMA upregulation in the colon of this patient, relative to ileum, may also have contributed to the observed differences in [18F]DCFPyL uptake.

[0214] The second CD phenotype involved colonic involvement and perianal fistula in a 36- year old male with two setons in place who was admitted to the hospital with worsening rectal pain and bloody diarrhea. He had recently been switched to ustekinumab after secondary loss of response to adalimumab. Inflammatory markers were elevated with ESR of 33 mm / h, CRP of 7.6 mg / dL and fecal calprotectin of >8,000 pg / g. MRI demonstrated wall thickening and inflammation of the sigmoid colon and rectum with no new fistula. His colonoscopy showed marked erythema, friability, and deep ulcerations in the rectum and sigmoid colon (FIG. 4). Biopsies demonstrated chronic active inflammation and PSMA IHC showed increased numbers of PSMA positive cells in inflamed sections (FIG. 8). He received intravenous steroids and infliximab with no response. He underwent abdominoperineal resection. [18F]DCFPyL PET / CT imaging was performed prior to his surgery. A written, informed consent was obtained prior to the scan. PET / CT scan demonstrated abnormally increased [18F]DCFPyL uptake in the sigmoid colon and rectum (FIG. 5), in areas of mucosal inflammation.

[0215] 1.4.2 Ulcerative colitis

[0216] [18F]DCFPyE PET / CT imaging utility was investigated in ulcerative colitis with a 66-year-old man with left- sided disease presenting to the emergency department with symptoms of flare including bloody diarrhea of more than 30 bowel movements per day, urgency, and abdominal pain. He had recently been switched to vedolizumab after secondary loss of response to infliximab. His last colonoscopy, performed while on infliximab every 4 weeks, demonstrated marked erythema, friability, spontaneous bleeding, and ulcerations in the descending colon, sigmoid colon, and rectum (Mayo endoscopic subscore 2-3), with no active disease beyond the splenic flexure. He was admitted to the hospital. Inflammatory markers were elevated with ESR of 47 mm / h, CRP of 6.6 mg / dE and fecal calprotectin of 867 pg / g. Stool studies, including Clostridioides difficile test, were negative. He underwent a flexible sigmoidoscopy to 20 cm from the anal verge which demonstrated spontaneous bleeding and ulcerations throughout the examined mucosa (Mayo endoscopic subscore 3) (FIG. 6). Biopsies confirmed severe active chronic inflammatory disease, with negative immunostain for cytomegalovirus. IHC of inflamed biopsies, identified occasionally increased PSMA expression in the apical epithelial membrane, and also numerous PSMA positive cells throughout the mucosa (FIG. 9). [18F]DCFPyE PET / CT imaging was performed. A written, informed consent was obtained preceding the scan. PET / CT demonstrated abnormally increased [18F]DCFPyE uptake in the descending colon, sigmoid colon, and rectum (FIG. 7), in a distribution corresponding to the findings on endoscopy.

[0217] 1.5 Discussion

[0218] The accurate and non-invasive diagnosis of active mucosal inflammation in a patient with known IBD can be a clinical challenge. There is no single non-invasive gold standard test, biomarker, or imaging agent to reliably diagnose inflamed mucosa during a flare or to monitor disease activity after treatment is initiated. Vermeire et al., 2006. Existing laboratory tests, including CRP, ESR, and fecal calprotectin, each present their own limitations. CRP, a widely utilized indicator of the acute phase inflammatory response, is highly specific for inflammation but lacks sensitivity and can be normal during an acute flare. Ince ct al., 2019; Chang ct al., 2015. Therefore, while CRP is a valuable adjunct to clinical and endoscopic evaluation, it cannot be reliably used to rule out flares. Chang et al., 2015.

[0219] ESR, an indirect measure of systemic inflammation, is another commonly used biomarker of inflammation in IBD. ESR, however, correlates even less with endoscopic disease activity than CRP. Vermeire et al., 2006. Calprotectin is a neutrophil marker that correlates with neutrophil migration to the gastrointestinal tract and, by extension, should correlate well with inflammation. D'Haens et al., 2012. Fecal calprotectin also is a useful adjunct in determining if a flare is occurring, although false positives have been reported. Vermeire et al., 2006. Lastly, calprotectin tends to be more useful in colonic inflammation in UC and CD but is less accurate in small bowel inflammation in CD. Garcia-Sanchez et al., 2010. In addition, none of these non-invasive tests can localize inflammation.

[0220] Given the imperfect nature of the blood- and stool-based markers of inflammation, ileocolonoscopy is the gold standard for the diagnosis of active mucosal inflammation and flares in patients with IBD. Annese et al., 2013. Endoscopy, however, is an invasive procedure requiring adequate bowel preparation. In addition, there is a significant rate of complications, including perforation, in patients undergoing endoscopy while having bowel inflammation. Kothari et al., 2019. Therefore, there is a strong clinical need for alternative, non-invasive diagnostic tools to aid in the accurate diagnosis and monitoring of mucosal inflammation in patients with IBD.

[0221] Numerous imaging modalities have been studied in patients with inflammatory bowel disease, each with its advantages and disadvantages. CT imaging, although widely available, has been shown to have low sensitivity for assessing the extent of inflammation in Crohn's disease, Panes et al., 2011, and it produces concerns about radiation as recurrent imaging is often required. Loftus, 2010. MRI has a similar diagnostic accuracy for imaging IBD; however, it is more time-consuming and expensive. Intestinal ultrasound is a promising imaging modality as it is easily accessible, non-invasive, radiation-free, and costefficient. Lapp et al., 2011. Although this imaging has become widely available in Europe, it remains limited in North America. Lapp et al., 2011. The use of molecular imaging may be a promising non-invasive approach to assess the location and disease activity in patients with IBD. As PSMA is specifically increased in active, inflamed CD and UC patient biopsies relative to uninvolved areas, Rais et al., 2016, we investigated whether PSMA-targeted imaging could be used to detect active inflammation. We evaluated the PET imaging agent [18F]DCFPyL (Pylarify™) for this purpose. [18F]DCFPyL is FDA-approved as a diagnostic agent in prostate cancer and has been found to be sensitive and specific in identifying PSMA-positive prostate cancer. Szabo et al., 2015. [18F]DCFPyL has a favorable safety profile. Chen et al., 2011. While there is uptake of [18F]DCFPyL in the normal GI tract, the biodistribution is predominantly within the proximal small bowel, such that positive sites in the more distal small bowel and colon arc readily identifiable. The recent development of PET / computed tomography (CT) combines the physiological sensitivity of PET with the anatomical accuracy of CT, increasing the specificity of PET. Lapp et al., 2011.

[0222] Utility in Crohn's disease (CD) was established in our patient with active ileocolonic CD, where [18F]DCFPyL uptake was abnormally increased in the terminal ileum, corresponding to the inflammation observed in the terminal ileum on ileocolonoscopy and supported by histology on mucosal biopsies. Immunohistochemistry (IHC) demonstrated markedly upregulated prostate-specific membrane antigen (PSMA) expression at this site, with increases in both membrane- associated and cytoplasmic epithelial PSMA expression. The observed endoscopic active disease of the distal 20 cm from the anal verge was not detected on the PET scan, although PSMA protein upregulation was detectable by IHC in surgically resected tissue. Relative to the terminal ileum, however, there were differences in both the magnitude and localization of this PSMA expression, both of which likely contributed to the nondetectable PET signal in the colon. In inflamed colon, PSMA was only detected in the cytoplasm of epithelial cells, where it was heterogeneously upregulated in a portion of epithelia (approximately 20%). At this time, it is unclear if the reduced magnitude of expression in the colon vs. ileum may have been below the limit of detection for [18F]DCFPyL or if the target may not have been accessible to the radiotracer, possibly due to alterations in blood flow in this region due to chronic inflammation-associated changes in tissue architecture such as scarring and / or fibrosis. Regardless, this will need to be further investigated in larger patient cohorts to determine factors that affect PSMA-targeted PET uptake in IBD. Notably, these findings suggest that PSMA-PET scanning can identify inflammation patterns that arc currently not distinguishable with clinical grade endoscopic and histologic analyses. This observation introduces the intriguing possibility of novel patient stratification and / or inclusion in personalized treatment algorithms.

[0223] For our other two patients with colonic involvement of their IBD, [18F]DCFPyL uptake was increased in the descending colon, sigmoid colon, and rectum (ulcerative colitis), and increased in the sigmoid colon and rectum (colonic CD), indicative of regions of endoscopic active disease. In agreement with the observed radiotracer uptake, IHC identified numerous PSMA-positive cells in inflamed colon biopsies collected from these sites. Further studies to characterize PSMA localization as a function of IBD subtype and disease site are of high interest and remain ongoing in our laboratory.

[0224] In summary, abnormal gastrointestinal [18F]DCFPyL uptake was detected in all three IBD patients, and in all disease phenotypes, the sites of increased [18F]DCFPyL uptake were consistent with endoscopically and histologically inflamed regions. These findings support the continued evaluation of [18F]DCFPyL PET / CT imaging as an adjunct diagnostic tool for IBD flares in both Crohn's disease and ulcerative colitis. Future studies are warranted to evaluate [18F]DCFPyL uptake in patients as a function of disease severity, to longitudinally examine [18F]DCFPyL uptake in patients during periods of treatment, remission, and flares, and to potentially identify patients with high PSMA expression for inclusion in clinical trials using therapeutic PSMA inhibitors, which are in active development and have shown promising efficacy in preclinical models. Rais et al., 2016; International PCT patent application publication no. WO / 2016 / 022809 for Methods for treating inflammatory bowel disease using prostate specific membrane antigen (PSMA) inhibitors, to Slusher et al., published February 11, 2016; Peters et al., 2019.

[0225] 1.6 Summary

[0226] This Example demonstrates the important utility of PSMA targeted [18F]DCFPyL PET / CT as a promising non-invasive imaging agent to assess location, extent, and disease activity in IBD. If these findings are demonstrated consistently in larger studies, this will potentially address the unmet need to noninvasively detect gastrointestinal inflammation and assess the location, extent, and activity of IBD using a noninvasive modality. In addition, this novel modality of detecting inflammation may allow sub-classification of IBD based on molecular features, bringing us closer to individualized therapies and the goal of furthering precision medicine.

[0227] REFERENCES

[0228] All publications, patent applications, patents, and other references mentioned in the specification are indicative of the level of those skilled in the art to which the presently disclosed subject matter pertains. All publications, patent applications, patents, and other references are herein incorporated by reference to the same extent as if each individual publication, patent application, patent, and other reference was specifically and individually indicated to be incorporated by reference. It will be understood that, although a number of patent applications, patents, and other references arc referred to herein, such reference does not constitute an admission that any of these documents form part of the common general knowledge in the art.

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[0259] Although the foregoing subject matter has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be understood by those skilled in the art that certain changes and modifications can be practiced within the scope of the appended claims.

Claims

THAT WHICH IS CLAIMED:

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

2. The method of claim 1, wherein the inflammation associated with IBD comprises a mucosal inflammation.

3. The method of claim 1, wherein the imaging assesses one or more of a location, extent, and disease activity of IBD.

4. The method of claim 3, wherein the extent of IBD includes a percent inflammation in an IBD stricture.

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

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

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

8. The method of claim 1, wherein the PSMA-targeted imaging agent comprises a compound having the following formula:wherein:V is selected from -NH-C(=O)-, -C(=O)-NH-, and -NH-;L is a linker; andRpt is a reporting moiety.

9. The method of claim 8, wherein V is -NH-C(=O)- and the PSMA-targeted imaging agent comprises:

10. The method of claim 9, wherein the reporting moiety Rpt comprises a radiolabeled prosthetic group.11 . The method of claim 10, wherein the radiolabeled prosthetic group is selectedwherein each X is independentlynC or18F; each R and R’ is independently H or C1-C4 alkyl; and each n is independently 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.

12. The method of claim 8, wherein the reporting moiety Rpt comprises a chelating moiety.

13. The method of claim 12, wherein the chelating moiety is selected from:

13. The method of claim 12, wherein the chelating moiety further comprises a radiometal selected from68Ga,MCu, "mTc, and [18F]A1F.

14. The method of claim 1, wherein the PSMA-targeted imaging agent comprises a radiolabeled prosthetic group and the imaging agent is selected from125I-DC1BZL, [18F]JK- PSMA-7,18F-YC88, [125I]DCIT, [18F]DCFBC, and [nC]DCMC, MIP-1072, MIP-1095, [18F]- PSMA-1007, [l8F]-florastamin, and [18F]FPy-DUPA-Pep.

15. The method of claim 14, wherein the PSMA-targeted imaging agent comprises [18F]DCFPyL.

16. The method of claim 1, wherein the PSMA-targeted imaging agent comprises a chelating moiety 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, wherein the chelating moiety further comprises a radiometal suitable for PET imaging.

17. The method of claim 1, further comprising administering to the subject in combination with the PSMA-targeted imaging agent one or more additional therapeutic agents to prevent or reduce an accumulation of the PSMA-targeted imaging agent in an off-target noncancer tissue, such as the kidney or lacrimal gland.

18. The method of claim 17, wherein the one or more additional therapeutic agents is administered to the subject before the PSMA-targeted imaging agent is administered.

19. The method of claim 18, wherein the one or more additional therapeutic agents is administered to the subject simultaneously with the PSMA-targeted imaging agent.

20. The method of claim 17, wherein the off-target tissue is in an organ selected from kidney, lacrimal glands, and salivary glands.

Images