Fibroblast activation protein targeted compounds and use thereof

Abstract

The present invention relates to a fibroblast activation protein alpha (FAP)-targeting conjugate comprising the structure of Formula 3b or 3c: wherein Y comprises a chelator or a cytotoxic drug, L is a linker or bond, AA1 to AA7 comprise a FAP-targeting binding peptide sequence and are joined to one another by peptide bonds, R8 is attached to AA7, R9 is attached to AA1, and M is a bond or a cyclization moiety that connects R8 to R9, wherein R8, R9 and M together create a chain of 4 to 20 ring atoms connecting AA1 to AA7 selected from the group consisting of optionally substituted carbon, optionally substituted nitrogen, oxygen and sulfur atoms, and wherein the composition further contains a radioprotectant and / or is in a lyophilized form.

Description

[0001] FIBROBLAST ACTIVATION PROTEIN TARGETED COMPOUNDS AND USE THEREOF INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0002] This application contains references to amino acids and / or nucleic acid sequences that have been filed concurrently herewith as sequence listing XML file “PTX-005-seq.xml”, file size of 42,136 bytes, created on December 10, 2024. The aforementioned sequence listing is hereby incorporated by reference in its entirety pursuant to 37 C. F. R. § 1.52(e)(5).

[0003] Fibroblast activation protein (FAP), also known as prolyl endopeptidase, is an enzyme that in humans is encoded by the FAP gene. FAP is a cell-surface serine protease that acts on various hormones and extracellular matrix components. FAP is highly upregulated in a wide variety of cancers, and is often used as a marker for pro-tumorigenic stroma. It has also been proposed as a molecular target of cancer therapies, and. especially in recent years, a great deal of research has gone into design and testing of diverse FAP -targeted treatments, FAP is a 760 amino acid long type II transmembrane glycoprotein. It contains a very short cytoplasmic N terminal part, a transmembrane region, and a large extracellular part with an alpha / beta-hydrolase domain and an eight-bladed beta-propeller domain. FAP is a non- classical serine protease, and the active site is localized in the extracellular part of the protein which contains a catalytic triad composed of Ser624Asp702His714in humans and mice.

[0004] FAP expression is typically low to undetectable in most normal adult tissues, but is highly upregulated in a multitude of cancers, including almost all carcinomas and sarcomas. FAP is expressed in cancer cells or in cancer-associated fibroblasts of stroma tissue, including mesenchymal stem cells (MSCs), CAFs, sarcoma, and melanoma cells. FAP expression is also upregulated in non-cancer diseases and in tissue remodeling, including stromal and mesenchymal stem cells during embryogenesis, wound healing, fibrotic reactions, arthritis, atherosclerotic plaques, and ischemic heart tissue after myocardial infarction.

[0005] The high expression of FAP in the cancer microenvironment compared with adjacent normal tissue makes FAP a potential therapeutic target for drug delivery’ Within this context, radiopharmaceuticals targeting FAP are of particular potential. Radiopharmaceuticals are radiolabeled drugs that are used for imaging and / or therapy of disease. These drugs may be designed with the form Y-L-X, where Y is a chelator that stably complexes (i.e., binds tightly) a radionuclide (e.g., Pb-212, Ac-225, Lu-177, Cu-64, Cu-67, Ga-68, Pb-203) that decays by various forms of radioactive decay modes (e.g., beta-particle emission, alpha-particle emission, positron emission, gamma-ray emission, auger electron emission); X is a targeting molecular structure (e.g., peptide, antibody, small molecule, aptamer) that is designed to bind to cells, often by binding to a cell surface receptor (e.g., g-protein coupled receptor, type II glycoprotein, or other antigen, potentially expressed inside the cell); and L is a molecular linker that connects the chelator Y to the binding moiety X.

[0006] The use of certain radionuclides that emit gamma rays enables imaging that can be used for diagnosing and monitoring of disease. Other radionuclides that emit particles, such as beta and alpha particles, are used for treating diseases, such as cancers. In some cases, the radionuclides intended for the treatment of cancer or other diseases, decay further to a series of radionuclide progeny (often referred to as daughter radionuclides or “daughters’") that may¬ or may not be complexed by the chelator. The preparation of radiopharmaceuticals involves a reaction of the Y-L-X precursor with the radionuclide. Examples of radionuclides used for this purpose that have a series of daughter radionuclide progeny7in their series includes Pb-212 and Ac-225.

[0007] One known fibroblast activation protein alpha (FAP)-targeted conjugate is shown below:

[0008]

[0009] Accordingly, there remains a need for alternative radiopharmaceuticals that can be safely and effectively used for the imaging and / or treating of cancer and other disease states. DETAILED DESCRIPTION OF THE DRAWINGS

[0010] FIG. 1 is a graph showing the %ID / g of VMT-FAP-2-26 in accordance with Example 2.

[0011] FIG. 2 is a graph showing the %ID / g of VMT-FAP-2-30 in accordance with Example 2.

[0012] FIG. 3 is a graph showing the %ID / g of VMT-FAP-2-42 in accordance with Example 2.

[0013] FIG. 4 is a graph showing the %ID / g of VMT-FAP-2-43 in accordance with Example 2.

[0014] FIG. 5 is a graph showing the %ID / g of VMT-FAP-2-33 in accordance with Example 2.

[0015] FIG. 6 is a graph showing the %ID / g of VMT-FAP-2-36 in accordance with Example 2.

[0016] FIG. 7 is a graph showing the %ID / g of VMT-FAP-2-39 in accordance with Example 2.

[0017] FIG. 8 is a graph showing the %ID / g of VMT-FAP-2-48 in accordance with Example 2.

[0018] FIG. 9 is a graph showing the %ID / g of VMT-FAP-2-51 in accordance with Example 2.

[0019] FIG. 10 is a graph showing the %ID / g of VMT-FAP-2-53 in accordance with Example 2.

[0020] FIG. 11 is a graph showing the %ID / g of VMT-FAP-2-55 in accordance with Example 2.

[0021] FIG. 12 is a graph showing the %ID / g of VMT-FAP-2-57 in accordance with Example 2.

[0022] FIG. 13 is a graph showing the %ID / g of VMT-FAP-2-59 in accordance with Example

[0023]

[0024] FIG. 14 is a graph showing the %ID / g of VMT-FAP-2-60 in accordance with Example

[0025] FIG. 15 is a graph showing the %ID / g of VMT-FAP-2-61 in accordance with Example

[0026] FIG. 16 is a graph showing the %ID / g of VMT-FAP-2-62 in accordance with Example

[0027] FIG. 17 is a graph showing the %ID / g of VMT-FAP-2-67 in accordance with Example

[0028] FIG. 18 is a graph showing the %ID / g of VMT-FAP-2-68 in accordance with Example

[0029] FIG. 19 is a graph showing the %ID / g of VMT-FAP-2-69 in accordance with Example

[0030] FIG. 20 is a graph showing the %ID / g of VMT-FAP-2-70 in accordance with Example

[0031] FIG. 21 is a graph showing the %ID / g of VMT-FAP-2-72 in accordance with Example

[0032] FIG. 22 is a graph showing the %ID / g of VMT-FAP-2-74 in accordance with Example

[0033] FIG. 23 is a graph showing the %ID / g of VMT-FAP-2-75 in accordance with Example

[0034] FIG. 24 is a graph showing the %ID / g of VMT-FAP-2-76 in accordance with Example

[0035] FIG. 25 shows the structure of VMT-FAP-2-26.

[0036] FIG. 26 shows the structure of VMT-FAP-2-30.

[0037] FIG. 27 shows the structure of VMT-FAP-2-42.

[0038] FIG. 28 shows the structure of VMT-FAP-2-43.

[0039] FIG. 29 shows the structure of VMT-FAP-2-33. FIG. 30 shows the structure of VMT-FAP-2-36. FIG. 31 shows the structure of VMT-FAP-2-39. FIG. 32 shows the structure of VMT-FAP-2-48. FIG. 33 shows the structure of VMT-FAP-2-51. FIG. 34 shows the structure of VMT-FAP-2-53. FIG. 35 shows the structure of VMT-FAP-2-55. FIG. 36 shows the structure of VMT-FAP-2-57. FIG. 37 shows the structure of VMT-FAP-2-59. FIG. 38 shows the structure of VMT-FAP-2-60. FIG. 39 shows the structure of VMT-FAP-2-61. FIG. 40 shows the structure of VMT-FAP-2-62. FIG. 41 shows the structure of VMT-FAP-2-67. FIG. 42 shows the structure of VMT-FAP-2-68. FIG. 43 shows the structure of VMT-FAP-2-69. FIG. 44 shows the structure of VMT-FAP-2-70. FIG. 45 shows the structure of VMT-FAP-2-72. FIG. 46 shows the structure of VMT-FAP-2-74. FIG. 47 shows the structure of VMT-FAP-2-75. FIG. 48 shows the structure of VMT-FAP-2-76. FIG. 49 shows the structure of VMT-FAP-2-77. FIG. 50 shows the structure of VMT-FAP-2-78. FIG. 51 shows the structure of VMT-FAP-2-82. FIG. 52 shows the structure of VMT-FAP-2-83. FIG. 53 shows the structure of VMT-FAP-2-84. FIG. 54 illustrates the binding affinity of VMT-FAP-2-59 in hFAP in accordance with Example 3.

[0040] FIG. 55 illustrates a GCI binding assay of VMT-FAP-2-59 in hPREP and VMT-FAP-2-59 in hDPPIV in accordance with Example 3.

[0041] FIG. 56 illustrates the metabolic stability of [203Pb]VMT-FAP-2-59 after incubation in human serum for 96 hours with Example 4.

[0042] FIG. 57 illustrates the uptake of [203Pb]VMT-FAP-2-59 in human cancer cells and human cancer xenograft models in accordance with Example 5.

[0043] FIG. 58 are Micro-SPECT imaging of [203Pb]VMT-FAP-2-59 and [212Pb]VMT-FAP-2-59 in hFAP-HT1080 xenograft in athymic nude mice in accordance with Example 5.

[0044] FIG. 59 illustrates the tumor volume and weight in athymic nude mice bearing fFAP-HT1080 tumors following treatment with [212Pb]VMT-FAP-2-59 in accordance with Example 6.

[0045] FIG. 60 illustrates the tumor volume and weight in mice bearing U87MG tumors following treatment with [212Pb]VMT-FAP-2-59 in accordance with Example 7.

[0046] FIG. 61 illustrates the results of imaging of a patient with metastatic lung adenocarcinoma in accordance with Example 8.

[0047] FIG. 62 illustrates the results of imaging of a patient with metastatic pen am pul I ary neuroendocrine tumors in accordance with Example 8.

[0048] FIG. 63 illustrates the results of imaging of a patient with chondroblastic osteosarcoma in accordance with Example 8.

[0049] FIGS. 64 through 96 are examples of chelators that can be used to form conjugates according io embodiments herein.

[0050] DETAILED DESCRIPTION OF THE INVENTION

[0051] Definitions

[0052] As used herein, the terms “comprising”, “having”, “including”, and “containing” and grammatical variations thereof, are inclusive or open-ended and do not exclude additional, unrecited elements and / or method steps, even if a feature / component defined as a part thereof consists or consists essentially of specified feature(s) / component(s). The term “consisting essentially of’ if used herein in connection with a compound, composition, use or method, denotes those additional elements and / or method steps may be present, but that these additions do not materially affect the manner in which the recited compound, composition, method or use functions. The term “consisting of’ if used herein in connection with a feature of a compound, composition, use or method, excludes the presence of additional elements and / or method steps in that feature. A compound, composition, use or method described herein as comprising certain elements and / or steps may also, in certain embodiments consist essentially of those elements and / or steps, and in other embodiments consist of those elements and / or steps, whether or not these embodiments are specifically referred to. A use or method described herein as comprising certain elements and / or steps may also, in certain embodiments consist essentially of those elements and / or steps, and in other embodiments consist ofthose elements and / or steps, whether or not these embodiments are specifically referred to.

[0053] A reference to an element by the indefinite article “a” does not exclude the possibility that more than one of the elements is present, unless the context clearly requires that there be one and only one of the elements. The singular forms “a”, “an’’, and “the’’ include plural referents unless the context clearly dictates otherwise. The use of the word “a” or “an” when used herein in conjunction with the term “comprising” may mean “one”, but it is also consistent with the meaning of “one or more”, “at least one” and “one or more than one”.

[0054] In this disclosure, the recitation of numerical ranges by endpoints includes all numbers subsumed within that range including all whole numbers, all integers and, where suitable, all fractional intermediates (e.g., 1 to 5 may include 1, 1.5, 2, 2.75, 3, 3.80. 4, and 5 etc.).

[0055] Unless otherwise specified, “certain embodiments”, “various embodiments”, “an embodiment” and similar terms includes the particular feature(s) described for that embodiment either alone or in combination with any other embodiment or embodiments described herein, whether or not the other embodiments are directly or indirectly referenced and regardless of whether the feature or embodiment is described in the context of a method, product, use, composition, compound, et cetera.

[0056] With regard to stereoisomers, it should be understood that a solid line designation for the bonds in the compositions corresponding to the structural formulae disclosed herein for attachment of a substituent group to a chiral carbon atom of the compound may indicate that these groups may lie either in, below or above the plane of the page (i.e., all isomeric forms of the compounds disclosed herein are contemplated, including racemates, racemic mixtures, and individual enantiomers or diastereomers). Certain compounds described herein may exist in tautomeric forms, and all such tautomeric forms of the compounds being within the scope of the disclosure.

[0057] The term "acyl," as used herein alone or as part of another group, denotes the moiety7formed by removal of the hydroxyl group from the carboxy group, -COOH, of an organic carboxylic acid, e., X4C(0)-, wherein X4 is X1, X'O-. X'X2N-. or X^-. X1is hydrogen, optionally substituted hydrocarbyl, or heterocyclo, and X2is hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo. In certain embodiments, X1and X2are independently optionally substituted alkyl, optionally substituted alkenyl, aryl, or heterocyclo. Exemplary acyl moieties include acetyl, propionyl, benzoyl, pyridinyl, carbonyl, and the like.

[0058] The term "aliphatic" denotes saturated and non-aromatic unsaturated hydrocarbyl moieties having, for example, one to about twenty carbon atoms or, in specific embodiments, one to about twelve carbon atoms, one to about ten carbon atoms, one to about eight carbon atoms, or even one to about four carbon atoms. The aliphatic groups include, for example, alkyl moieties such as methyl, ethyl, n-propyl. isopropyl, n butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like, and alkenyl moieties of comparable chain length. As used herein, the term “alkyl group” encompasses saturated linear or branched carbon radicals having, for example, one to about twenty carbon atoms or, in specific embodiments, one to about twelve carbon atoms. In other embodiments, alkyl groups are "lower alkyl" groups having one to about eight carbon atoms. Examples of such groups include, but are not limited thereto, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, ethylhexyl, octyd and the like.

[0059] The term "alkyl" as used herein, alone or as part of another group, denotes saturated linear, branched or cyclic carbon radicals having, for example, one to about twenty carbon atoms or, in specific embodiments, one to about twelve carbon atoms. In certain embodiments, alkyl groups are "lower alkyl" groups having one to about six carbon atoms. Examples of such groups include, but are not limited thereto, methyl, ethyl, n-propyl, isopropyl, n butyl, isobutyl. sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like. In more specific embodiments, lower alkyl groups have one to four carbon atoms.

[0060] The term “alkylene” as used herein, alone or as part of another group, denotes a linear saturated divalent hydrocarbon radical of one to twenty carbon atoms, or, in specific embodiments, one to about six carbon atoms or a branched saturated divalent hydrocarbon radical of three to twenty carbon atoms unless otherwise stated, e.g., methylene, ethylene, propylene, 1 -methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

[0061] The term "alkenyl" as used herein, alone or as part of another group, denotes linear, branched or cyclic carbon radicals having at least one carbon-carbon double bond. The term "alkenyl group" can encompass conjugated and non-conjugated carbon-carbon double bonds or combinations thereof. An alkenyl group, for example and without being limited thereto, can encompass two to about twenty carbon atoms or, in a particular embodiment, two to about twelve carbon atoms. In certain embodiments, alkenyl groups are "lower alkenyl" groups having two to about six carbon atoms. Examples of alkenyl groups include, but are not limited thereto, ethenyl, propenyl, allyl, vinyl, butenyl and 4-methylbutenyl. The terms "alkenyl group" and "lower alkenyl group", encompass groups having "cis" or "trans" orientations, or alternatively, " E" or " Z" orientations.

[0062] The term "alkoxy," as used herein alone or as part of another group, denotes an -OX3radical, wherein X5is as defined in connection with the term "alkyl." Exemplary alkoxy moieties include methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, cyclohexyloxy and the like.

[0063] The term "amide," as used herein, alone or as part of another group, denotes a group having the formula -C(O)N(X8)(X9). wherein X8and X9are as defined in connection with the terms "amine" or "amino." For example, "substituted amide" refers to a group of formula -C(O)N(X8)(X9), wherein at least one of X8and X9are other than hydrogen and “unsubstituted amido," for example, refers to a group of formula -C(O)N(X8)(X9) wherein each of X8and X9are hydrogen.

[0064] The terms "amine" and "amino" as used herein, alone or as part of another group, are used interchangeably and denote a group of formula *-N(X8)(X9). wherein * denotes the point of attachment of the moiety to the remainder of the molecule and X8and X9are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, heteroaryl, or heterocyclo, or X8and X9 taken together form a substituted or unsubstituted alicyclic, aryl, or heterocyclic moiety, each as defined in connection with such term, typically having from 3 to 8 atoms in the ring.

[0065] " Substituted amine," for example, refers to a group having the formula -N(X8)(X9). wherein at least one of X8and X9are other than hydrogen and “unsubstituted amine’’ refers to a group having the formula -N(X8)(X9), wherein each of X8and X9are hydrogen.

[0066] The term “amino acid,” includes naturally occurring amino acids (including L and D isostereomers) and residues thereof, and unless otherwise limited, and also include known analogs of natural amino acids or amino acids derivatives that can function in a similar manner as the common natural amino acids, such as selenocysteine, naphthylalanine, anthrylalanine, norleucine, pyrrolysine, N-formylmethionine, gamma-carboxyglutamate, hydroxyprolinehypusine, pyroglutamic acid, selenomethionine, 1 -naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), 3-(4-biphenyl-alanine (Bip), 2-pyridyl-alanine (2-Pal), 3-pyridyl-alanine (3-Pal). 4-pyridyl-alanine (4-Pal), 3-benzothienyl-alanine (Bta). 2-cyano-phenylalanine, 3-cyano-phenylalanine, 4-cyano-phenylalanine, 3-borono-phenylalanine, 4-borono-phenylalanine, 4-trifluoromethyl-phenylalanine, 2-chloro-phenylalanine, 3-chloro-phenylalanine, 4-chloro-phenylalanine, 2-fluoro-phenylalanine, 3-fluoro-phenylalanine, 4-fluoro-phenylalanine, 2-iodo-phenylalanine, 3 -iodo-phenylalanine, 4-iodo-phenylalanine, 2-methyl-phenylalanine, 3-methyl-phenylalanine, 4-methyl-phenylalanine, 2-nitro-phenylalanine, 3-nitro-phenylalanine, 4-nitro-phenylalanine, 4-pentafluoro-phenylalanine, phenylglycine (Phg), 4-amino-phenylalanine, 4-methoxy-phenylalanine, 5 -hydroxy trptophan, 3, 5-diiodo-tyrosine, 4-benzoyl-phenylalanine, 5 -hydroxy -trptophan, 3, 5-diiodo-tyrosine, 4-benzoyl-phenylalanine (Bpa), cyclohexylglycine (Chg), or 2-thienyl-alanine (Thi). (see, e.g., Ho J et al., ACS Synth Biol 5: 163-71 (2016); Wang Y, Tsao M, Chembiochem 17: 2234-9 (2016)).

[0067] The terms “amino acid sequence” and “peptide sequence” are used interchangeably herein and denote a series of amino acid residues linked via amide bonds, and depending upon the number of residues in the series comprise a peptide, polypeptide or protein.

[0068] As used herein, the term "aralkylene" denotes a chain of 1 to 20 carbon atoms, typically 1 to 12 carbon atoms, more typically 1 to 10 carbon atoms, and most typically 1 to 8 carbon atoms, and in some embodiments 1 to 4 carbon atoms that can be saturated or partially unsaturated, containing one or more aryl moieties. The aryl moiety may be a part of a pendant (or side) group atached to a chain of atoms (

[0069]

[0070] e.g., r j wherein * denotes the point of atachment of the aralkyl ene moiety to the remainder of the molecule, or two or more atoms of * *

[0071] the aryl moiety may also serve as chain atoms of the aralkylene moiety (e.g.,

[0072]

[0073] v — V ).

[0074] The term "aromatic" as used herein, alone or as part of another group, includes ‘'aryl” and “heteroaryl” groups as defined herein.

[0075] The terms "aryl" and “Ar” as used herein, alone or as part of another group, are used interchangeably and denote an aromatic group having one or more rings wherein such rings may be attached together in a pendent manner or may be fused. Examples of aryl groups include, but are not limited to. phenyl, naphthyl, biphenyl, and anthryl. Unless specified otherwise, the aryl group may be substituted at one or more ring positions with hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, acyl, acyloxy, amino, aryloxy, carboxy, cyano, halogen, mercapto, oxo, nitro, thiol, sulfo, or the salts thereof.

[0076] As used herein, a “binding peptide” or a “conjugate having the binding peptide that binds a cellular target of interest” is one that binds the cellular target with sufficient affinity that is measurably different from a non-specific interaction. Selective binding can be measured, for example, by determining the binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity.

[0077] As used herein, the terms “cancer” and “cancerous” refer to or describe the pathological condition in mammals that is typically characterized by unregulated cell growth. A “tumor” comprises one or more cancerous cells. Examples of cancer include, but are not limited to. carcinoma, melanoma, lymphoma, blastoma, sarcoma, and leukemiaor lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), skin cancer, melanoma, lung cancer including small-cell lung cancer, non-small cell lung cancer (“NSCLC”), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), glioblastoma, cervical cancer, ovarian cancer (e.g., high grade serous ovarian carcinoma), liver cancer (e.g., hepatocellular carcinoma (HCC)), bladder cancer (e.g., urothelial bladder cancer), testicular (germ cell tumor) cancer, desmoid tumor, chordoma, pheochromocytoma, medullary thyroid cancer, gastric cancer, hepatoma, breast cancer, brain cancer (e.g., astrocytoma), colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer (e.g., renal cell carcinoma, nephroblastoma or Wilms’ tumor), prostate cancer, vulval cancer, thyroid cancer (including differentiated), insulinoma, hepatic carcinoma, anal carcinoma, small intestine cancer, penile carcinoma, as well as head and neck cancer. Additional examples of cancer include, without limitation, retinoblastoma, thecomas, arrhenoblastomas, hepatoma, hematologic malignancies including non-Hodgkins lymphoma (NHL), multiple myeloma and acute hematologic malignancies, endometrial or uterine carcinoma, endometriosis, fibrosarcomas, choriocarcinoma, salivary gland carcinoma, vulval cancer, thyroid cancer, esophageal carcinomas, hepatic carcinoma, anal carcinoma, penile carcinoma, nasopharyngeal carcinoma, laryngeal carcinomas, Kaposi’s sarcoma, melanoma, skin carcinomas, Schwannoma, oligodendroglioma, neuroblastomas, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcomas, urinary tract carcinomas, anaplastic astrocytoma, basal cell carcinoma (basal cell epithelioma), bile duct cancer, small cell bladder cancer, metastatic breast cancer, metastatic colorectal cancer, epithelial ovarian cancer, fallopian tube cancer, gastric adenocarcinoma, glioblastoma multiforme (GBM), recurrent glioblastoma multiforme (GBM), gliomas, gliosarcoma, head and neck squamous cell carcinoma (HNSCC), recurrent head and neck squamous cell carcinoma, malignant pleural mesothelioma head and neck cancer, Hodgkin lymphoma, metastatic renal cell carcinoma, metastatic renal clear cell carcinoma, squamous non-small cell lung cancer, squamous carcinoma of the lung, relapsed or refractory' small-cell lung cancer, treatment-resistant melanoma, metastatic melanoma, Merkel cell carcinoma, neuroendocrine cancer, large cell neuroendocrine cancer, neuroendocrine tumors (NETS), ovarian carcinoma, papillary carcinoma, peritoneal cancer, neuroendocrine prostate cancer, hormone- refractory' prostate cancer, castration-resistant prostate cancer, soft tissue sarcoma, and squamous cell carcinoma.

[0078] The terms “carbocyclic,” “carbocycle” and “carbocyclyl” as used herein alone or as part of another group, are used interchangeably and denote any mono-, bi-, or tricyclic ring system in which the ring atoms are exclusively carbon and the ring system contains at least one aliphatic carbon-carbon bond. For example, the carbocycle may be cyclohexane, cycloheptane, and norbomane. Unless specified otherwise, the carbocyclic group may be substituted at one or more ring positions as described for heterocycles. The terms "carbocycle" and "aryl" are mutually exclusive.

[0079] The term "carboxy" and ‘"carboxyl'’ as used herein alone or as part of another group, are used interchangeably and denote as used herein, alone or as part of another group denotes -COOH

[0080] The term "cyano," as used herein, alone or as part of another group, denotes a group of formula -C=N.

[0081] As used herein, the term “conjugate” refers to a compound having a binding peptide that is linked to a chelating agent, such as a radionuclide chelating agent, either via direct bond or via a linker. For example, the chelating agent may be a compound capable of chelating radionuclides, such as203Pb and / or212Pb. The binding peptide may be capable of selectively binding to fibroblast activation protein (FAP).

[0082] The term “cyclization” as used herein, refers to the formation of one or more closed rings from a linear peptide or peptide segment by the introduction of a bond or a cyclization moiety.

[0083] The terms “cyclization moiety” and “cyclization group” are used interchangeably herein and refer to the residue of a chemical moiety that facilitates cyclization of a linear peptide or peptide segment.

[0084] The term "cycloalkyl," as used herein, alone or as part of another group, denotes a cyclic saturated monovalent bridged or non-bridged hydrocarbon radical of three to ten carbon atoms. Exemplary cycloalkyl moieties include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl and bicyclo[2.2.1 ]heptyl. Unless specified otherwise, the cycloalkyd group may be substituted at one or more ring positions with hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, acyl, acyloxy, amino, aryloxy, carboxy, cyano, halogen, mercapto, oxo, nitro, thiol, sulfo, and the salts thereof.

[0085] As used herein, "cycloaliphatic" denotes a chain of 1 to 20 carbon atoms, typically 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, and in some embodiments 1 to 4 carbon atoms containing one or more optionally substituted cycloalkyl moieties that can be saturated or at least partially unsaturated (but not aromatic). The cycloalkyl moiety may be a part of a pendant (or side) group attached to a chain of atoms (

[0086]

[0087] e.g., wherein * denotes the point of attachment to the remainder of the molecule, or the chain atoms comprise

[0088] two or more carbon atoms of the cycloalkyl moiety (e.g.,

[0089]

[0090] ). Cycloaliphatic excludes aralkylene.

[0091] As used herein the term “derivative” includes any compound which has been chemically modified without substantially altering its functional character. For example, a derivative may substantially retain one or more characteristic properties of said compound.

[0092] As used herein, the term “diagnostic agent" includes an “imaging agent”. As such, a “diagnostic radionuclide” includes radionuclides that are suitable for use as imaging agents.

[0093] As used herein, the term “fibroblast activation protein (FAP)”, also known as prolyl endopeptidase FAP (a member of the propyl peptidase family), is an enzyme that in humans is encoded by the FAP gene. FAP is a 97-kDa ty pe-II transmembrane serine protease that acts on various hormones and extracellular matrix components (see, e.g., Chakravarty et al, European Journal of Nuclear Medicine and Molecular Imaging, Vol. 50, pages 2935-2939, July 15, 2023; Ma et al,. Aging. May 9. 2023:15(9);3738-3758). FAP is highly upregulated in a wide variety of cancers and is often used as a marker for pro-tumori enic stroma. FAP is also expressed in pathological conditions including arthritis, fibrosis atherosclerosis, autoimmune diseases, and metabolic diseases. As used herein, fibroblast activation protein (FAP) means fibroblast activation protein alpha (FAP a). F P and FAPa are interchangeable herein.

[0094] The terms "halo" and “halogen” as used herein, alone or as part of another group, are used interchangeably and denote halogen atoms such as fluorine, chlorine, bromine, or iodine atoms.

[0095] The term "haloalkyl group" as used herein, alone or as part of another group, denotes groups wherein any one or more of the alkyl carbon atoms is substituted with halo as defined herein. Specifically encompassed are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups including perhaloalkyl. A monohaloalkyl group, for example, may have either an iodo, bromo, chloro or fluoro atom within the group. Dihalo and polyhaloalkyl groups may have two or more of the same halo atoms or a combination of different halo groups. " Lower haloalkyl group" encompasses groups having 1-6 carbon atoms. In some embodiments, lower haloalkyl groups have one to three carbon atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.

[0096] The term “heteroacyf’ as used herein, alone or as part of another group denotes an acyl group, C(O)R group, wherein the R group can be an alkyl, aryl, or heterocyclo as defined herein, and further comprising a heteroatom such as one or more of N, S, and O wherein the heteroatom may be a part of a pendant (or side) group attached to a chain of atoms or may be a chain atom.

[0097] The term "heteroaliphatic" as used herein, alone or as part of another group, denotes a cyclic or acyclic chain of 1 to 20 carbon atoms, typically 1 to 12 carbon atoms, more typically 1 to 10 carbon atoms, and most typically 1 to 8 carbon atoms, and in some embodiments 1 to 4 carbon atoms that can be saturated or unsaturated (but not aromatic), containing one or more heteroatoms, such as halogen, oxygen, nitrogen, sulfur, phosphorus, or boron. A heteroatom atom may be a part of a pendant (or side) group attached to a chain of atoms (e.g., *-CH(OH)CH(NH2)-* wherein * denotes the point of attachment to the remainder of the molecule and the carbon atoms are member of a chain of atoms) or it may be one of the chain atoms (e.g., -ROR- or -RNHR- where each R is aliphatic). Heteroaliphatic encompasses heteroalkyl and heterocycloalkylene but does not encompass heteroaralkylene.

[0098] The term "heteroalkyl" as used herein, alone or as part of another group, denotes an alkyl group substituted by one or more hetero atoms.

[0099] As used herein, "heteroalkylene" refers to a divalent, fully -saturated heteroalkyl moiety. As used herein, "heteroaralkylene" denotes a chain of 1 to 20 carbon atoms, typically 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, and in some embodiments 1 to 4 carbon atoms that can be saturated or unsaturated, containing one or more heteroaryl moieties. The heteroaryl moiety may be a part of a pendant (or side) group attached to a chain of atoms (

[0100]

[0101] e g., wherein * denotes the point of attachment to the remainder of the molecule, or the chain atoms comprise two or more carbon atoms of the heteroaryl moiety (e.g.,

[0102]

[0103] The term "heteroatom" denotes an atom other than carbon and hydrogen. Typically, but not exclusively, heteroatoms are selected from the group consisting of halogen, sulfur, phosphorous, nitrogen, boron and oxygen atoms. Groups containing more than one heteroatom may contain different heteroatoms.

[0104] The terms “heterocyclic group”, “heterocyclic”, “heterocycle”, “heterocyclyl”, and “heterocyclo” as used herein, alone or as part of another group, are used interchangeably and refer to any mono-, bi-, or tricyclic, saturated or unsaturated, aromatic (heteroaryl) or nonaromatic ring having the number of atoms designated, generally from 5 to about 16 ring atoms, where the ring atoms are carbon and at least one heteroatom (nitrogen, sulfur or oxygen), for example, 1 to 4 heteroatoms. Heterocyclic groups include four to seven membered cyclic groups containing one, two or three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Typically, a 5-membered ring has 0 to 2 double bonds and 6- or 7-membered ring has 0 to 3 double bonds. The nitrogen or sulfur heteroatoms may optionally be oxidized (e.g., SO, SO2), and any nitrogen heteroatom may optionally be quatemized. Particular non-aromatic heterocycles are morpholinyl (morpholino), pyrrolidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 2.3 -dihydro furanyl, 2H-pyranyl. tetrahydropyranyl, thiiranyl, thietanyl. tetrahydrothietanyl, aziridinyl, azetidinyl, l-methyl-2 -pyrrolyl, piperazinyl and piperidinyl. Particular 5-membered heterocycles containing a sulfur or oxygen atom and one to three nitrogen atoms are thiazolyl, in particular thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, in particular 1,3,4-thiadiazol-5-yl and 1.2.4-thiadiazol-5-yl. oxazolyl, for example oxazol-2-yl. and oxadiazolyl, such as 1.3.4-oxadiazol-5-yl, and l,2,4-oxadiazol-5-yl. Particular 5-membered ring heterocycles containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as 1.3.4-triazol-5-yl; l,2,3-triazol-5-yl, l,2,4-triazol-5-yl, and tetrazolyl, such as lH-tetrazol-5-yl. Particular benzo-fused 5-membered heterocycles are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl. Particular 6-membered heterocycles contain one to three nitrogen atoms and optionally a sulfur or oxygen atom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as 1.3.4-triazin-2-yl and l,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl. The pyridine N-oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the l,3,4-triazin-2-yl groups, are a particular group. Unless specified otherwise, the heterocyclo group may be substituted at one or more ring positions with hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, acyl, acyloxy, amino, aryloxy, carboxy, cyano, halogen, mercapto, oxo, nitro, thiol, sulfo, and the salts thereof.

[0105] As used herein, "heterocycloalkylene" denotes a chain of 1 to 20 carbon atoms, typically 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, and in some embodiments 1 to 4 carbon atoms containing one or more heterocyclic moieties that can be saturated or unsaturated (but not aromatic). The heterocyclic moiety may be a part of a pendant (or side)

[0106] group attached to a chain of atoms (e.g.,

[0107]

[0108] Hwherein * denotes the point of attachment to the remainder of the molecule, or the chain atoms comprise two or more carbon atoms of the

[0109] heterocyclic moiety (e.g.,

[0110]

[0111] ). Heterocycloalkylene excludes heteroaralkylene.

[0112] The terms "hydrocarbon group" and "hydrocarbyl group" as used herein, alone or as part of another group, are used interchangeably and denote organic radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, and aryl moieties. These moieties also include alkyl, alkenyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl and alkenaryl. Unless otherwise indicated, these moieties preferably comprise a chain of 1 to 25 carbon atoms, 1 to 20 carbon atoms, ty pically 1 to 12 carbon atoms, more typically 1 to 10 carbon atoms, and most typically 1 to 8 carbon atoms. Hydrocarbon groups may have a linear or branched chain structure. Typical hydrocarbon groups have one or two branches, typically one branch. Typically, hydrocarbon groups are saturated. Unsaturated hydrocarbon groups will typically have one or more double bonds. As used herein, alone or as part of another group, “imine” denotes a functional group containing a carbon-nitrogen double bond (C=N).

[0113] As used herein, lead (Pb) refers to the lead element and includes isotopes of both radioactive and observationally stable. The isotopes of Pb include, but are not limited to, Pb-196, Pb-197. Pb-198. Pb-199, Pb-200. Pb-201, Pb-202, Pb-203. Pb-204, Pb-205, Pb-206, Pb-207, Pb-208, Pb-209, Pb-210, Pb- 211, Pb-212, Pb-213, Pb-214, Pb-215, and Pb-216.

[0114] As used herein, “linker” refers to any chemical group that serves to couple a FAP binding peptide to a chelating agent, such as a lead specific chelating agent. That is, the “linker” may correspond to the moiety “L” described herein. For example, in certain embodiments, the linker can comprise a polyethylene glycol group that has been modified to covalently bond to the chelating agent on one end. and the FAP binding peptide on the other.

[0115] The term “nitro” as used herein, alone or as part of another group, denotes a group of the formula -NO?.

[0116] The terms “optional” and “optionally" as used herein means that the subsequently described circumstance may but need not occur, and that the description includes instances where the circumstance occurs and instances in which it does not. For example, “optionally substituted alky l” means dial the alkyl group may or may not be further substituted. By way of further example, "optionally substituted alkoxy” means that the alkyl portion of the alkoxy group may, but need not be present, and the description includes embodiments in which the alkyl portion of the alkoxy group is substituted with one or more hetero atoms such as nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogen atom or by a heterocyclo groups.

[0117] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s). such as those individually and independently selected from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)N H(alkyl), — C(=O)N(alkyl)2, — S(=O)2NH2, — S(=O)2NH(alkyl), — S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from D. halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(Ci-C4alkyl), -C(=O)NH2, -C( =0)NH(Ci-C4alkyl), -C(=O)N(Ci-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(CI- C4alkyl), -S(=O)2N(Ci-C4alkyl)2, Ci-C4alkyl, C3-C6cycloalkyl, Ci-C4fluoroalkyl, Ci-C4heteroalkyl, Ci-C4alkoxy, Ci-C4fluoroalkoxy, -SCi-C4alkyl, -S(=O)Ci-C4alkyl, and -S(=O)2Ci-C4alkyl. In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, -NH(CHs), -N(CH3)2, -NH(cyclopropyl), -CH3, -CH2CH3, -CF3, -O CH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=0). When indicating the number of substituents, the term “one or more’’ means from one substituent to the highest possible number of substitutions, z.e., replacement of one hydrogen up to replacement of all hydrogens by substituents.

[0118] As used herein, “pharmaceutically acceptable” means suitable for in vivo use in a subject, and is not necessarily restricted to therapeutic use, but also includes diagnostic use. More generally, with respect to any pharmaceutical composition disclosed herein, non-limiting examples of suitable excipients include any suitable buffers, radioprotectants, salts, antioxidants, complexing agents, tonicity agents, cryoprotectants, lyoprotectants, suspending agents, emulsifying agents, antimicrobial agents, preservatives, chelating agents, binding agents, surfactants, wetting agents, non-aqueous vehicles such as fixed oils, or polymers for sustained or controlled release. See, for example, Berge et al. 1977. (J. Pharm Sci. 66:1-19), or Remington-The Science and Practice of Pharmacy, 21st edition (Gennaro et al editors. Lippincott Williams & Wilkins Philadelphia), each of which is incorporated by reference in its entirety.

[0119] The term “polypeptide” includes any polymer of amino acids, or amino acid residues connected together via amide bonds.

[0120] The term “polypeptide sequence” refers to a series of amino acid residues which physically comprise a polypeptide.

[0121] A “protein” is a macromolecule comprising one or more polypeptides or polypeptide sequences, such as. for example, a naturally occurring or synthetic protein.

[0122] A “peptide” is a small polypeptide having a size of 2 to 20 amino acid residues.

[0123] As used herein, the term “radionuclide” or “radioisotope” includes, but is not limited to, an alpha emitting radionuclides, beta-emitting radionuclides, and / or gamma-emitting radionuclides, such as, e.g., any one ofY-86, Y-90, Lu-177, Re-186, Re-188, Sr-89, Sm-153, Ac-225, Bi-213, Po-213, Bi-212, Ra-223, Ra-224, Th-227, Tb-149, Ga-67, Ga-68, Cu-64, Cu-67, Zr-89, Cs-137, Pb-203, Pb-212, and Pd-103, among others. For example, lead radionuclides can include any of Pb-196, Pb-197, Pb-198, Pb-199, Pb-200, Pb-201, Pb-202, Pb-203, Pb-204, Pb-205, Pb-206, Pb-207, Pb-208, Pb-209, Pb-210, Pb- 211, Pb-212, Pb-213, Pb-214, Pb-215, and Pb-216. As used herein, the expressions “XE” and “E-x”, where “E” represents the element and “x” represents the particular elemental isotope, are equivalent and have the same meaning. For example, “xPb” and “Pb-x” (and “lead-x”) are equivalent and have the same meaning, such that ”203Pb‘' is equivalent to “Pb-203” (and to “lead-203”), and “212Pb” is equivalent to “Pb-212” (and “lead-212”).

[0124] As used herein, the term “radiopharmaceutical” refers to a compound that is labeled with a radionuclide and is suitable for medical purposes, including treatment and diagnostic purposes, such as treatment of a disease state, including cancer (a radiotherapeutic), or diagnostic or imaging applications (a radiodiagnostic).

[0125] As used herein, the terms “ring backbone” and “ring atoms” are used interchangeably and refer to those atoms that are directly covalently bonded to other atoms that, in combination, define a cyclic structure. For example, in the fused cyclic structure illustrated below, (i) the ring atoms of the “Zi” ring include all of the illustrated carbon atoms with the exception of the carbon atoms at positions C3-C6 of the Z2 ring, (ii) the ring atoms of the Z2 ring include all of the carbon atoms at positions C1-C6 of the Z2 nng but no other carbon atoms comprised by the Zi ring, and (iii) Ti, T2 or T3 do not constitute ring atoms of either the Zi or Z2 rings

[0126]

[0127] The term “ring segment” as used herein refers to a segment of a cyclic peptide comprising ring atoms located between and linking two ammo acids of the cyclic peptide. As used herein, the terms “salt” and “solvate” have their usual meaning in chemistry. As such, when the compound is a salt or solvate, it is associated with a suitable counter-ion. It is well known in the art how to prepare salts or to exchange counter-ions. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g. without limitation, Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or in an organic solvent, or in a mixture of the two. Counter-ions may be changed, for example, by ion-exchange techniques such as ion-exchange chromatography. All zwitterions, salts, solvates and counter-ions are intended, unless a particular form is specifically indicated. In certain embodiments, the salt or counter-ion may be pharmaceutically acceptable, for administration to a subject.

[0128] As used herein, “selective binding” refers to a binding peptide or conjugate comprising the binding peptide that is capable of binding a cellular target with sufficient affinity such that the binding peptide and / or conjugate is useful as a diagnostic and / or therapeutic agent with respect to the target.

[0129] The term “subject” refers to an animal (e.g. a mammal or a non-mammal animal). The subject may be a human or a non-human primate. The subject may be a laboratory mammal (e.g., mouse, rat, rabbit, hamster and the like). The subject may be an agricultural animal (e.g., equine, ovine, bovine, porcine, camelid and the like) or a domestic animal (e.g., canine, feline and the like). In some embodiments, the subject is a human.

[0130] As used herein, a “target” may be fibroblast activation protein (FAP), also known as prolyl endopeptidase FAP, which may be overexpressed in certain types of cancers, and may also be used as a marker for pro-tumorigenic stroma. In one embodiment, the extent of binding of the binding peptide and / or conjugate to an unrelated target is less than about 10% of the binding of the binding peptide and / or conjugate to its target as measured, e.g., by a radioimmunoassay. A “target selective” binding peptide, as used herein, is one that specifically binds to the target with sufficient specificity and affinity to be useful in targeting a therapeutic, targeting diagnostic, or method of detecting the target in a biological sample or a tissue from a subject. In some embodiments, binding peptide and / or conjugate, has a dissociation constant (KD) of < 1 pM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., 10’6M or less, e.g., from 10'6M to 10'10M, e.g., from 10'8M to 10'13M). The term “therapeutically effective amount” as used herein to refer to an amount effective at the dosage and duration necessary to achieve the desired therapeutic result. A therapeutically effective amount of the composition may vary depending on factors such as the individual's condition, age, sex, and weight, and the ability of the protein to elicit the desired response of the individual. A therapeutically effective amount can also be an amount that exceeds any toxic or deleterious effect of the composition that would have a beneficial effect on the treatment.

[0131] The term “thiol” as used herein, alone or as part of another group, denotes a group of the formula -SH.

[0132] As used herein, the terms “treat”, “treatment”, “therapeutic” and the like include ameliorating symptoms, reducing disease progression, improving prognosis and reducing recurrence.

[0133] The term “un substituted” means that the specified group bears no substituents.

[0134] Radiopharmaceutical Conjugates

[0135] Embodiments of the present disclosure provide a conjugate that is capable of binding to fibroblast activation protein alpha (FAPa), for example in humans and mice, and may thereby release radiation or cytotoxic drugs to targeted cancer cells and other cells (e.g., tumor stromal cells) in the tumor microenvironment. In accordance with aspects of the invention, a chelator or cytotoxic drug (Y) is attached to a FAP targeted peptide (X) that contains a linear or cyclic peptide, optionally via a linker L, according to the general formula Y-L-X, where L maybe a linker or may be a bond connecting the chelator or cytotoxic drug to FAP targeted peptide. The conjugate formed can thereby bind to PAP and release radiation or cytotoxic drug at the tumor site.

[0136] According to one embodiment, there is provided a composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate comprising the structure of Formula 3b or 3c:

[0137] R9- AA1- AA2— AA3

[0138] Y - L - M \A4 RS- AA7- AA6— AA5

[0139]

[0140] Formula 3b

[0141]

[0142] Formula 3c

[0143] wherein:

[0144] - Y comprises a chelator or a cytotoxic drug,

[0145] - L is a linker or bond,

[0146] - AAi to AA7 comprise a FAP-targeting binding peptide sequence and are joined to one another by peptide bonds,

[0147] - R8 is attached to AA7,

[0148] - R9 is attached to AA1, and

[0149] - M is a bond or a cyclization moiety that connects R8 to R9, wherein R8, R9 and M together create a chain of 4 to 20 ring atoms connecting AA1 to AA7 selected from the group consisting of optionally substituted carbon, optionally substituted nitrogen, oxygen and sulfur atoms, and

[0150] wherein the composition further contains a radioprotectant and / or is in a lyophilized form.

[0151] In the sequence above, the residues AAi-AA? are written in the order from the N terminus to the C terminus, but according to certain embodiments, the FAP-targeted binding peptide may have the reverse sequence of AA7-AA6-AA5-AA4-AA3-AA2-AA1, in any of the formulas where the sequence above appears herein.

[0152] In certain embodiments, Rs, R9 and M together can comprise a chain of 4 to 20 ring atoms connecting AAi to AA7, with the ring atoms being selected from the group consisting of optionally substituted carbon, optionally substituted nitrogen, oxygen and sulfur atoms. For example, in one such embodiment Rs, R9 and M together comprise a chain of 6 to 18 ring atoms connecting AAi to AA7 with the ring atoms being selected from the group consisting of optionally substituted carbon, optionally substituted nitrogen, oxygen and sulfur atoms. By way of further example, in one such embodiment Rs, R9 and M together comprise a chain of 8 to 16 ring atoms connecting AAi to AA7 selected from the group consisting of optionally substituted carbon, optionally substituted nitrogen, oxygen and sulfur atoms. By way of further example, in one such embodiment Rs, R9 and M together comprise a chain of 10 to 14 ring atoms connecting AAi to AA7 selected from the group consisting of optionally substituted carbon, optionally substituted nitrogen, oxygen and sulfur atoms. By way of further example, in one such embodiment Rs, R9 and M together comprise a chain of 12 ring atoms connecting AAi to AA7 selected from the group consisting of optionally substituted carbon, optionally substituted nitrogen, oxygen and sulfur atoms. Rs, R9 and M together, in certain embodiments, connect to AAi and AA7 via functional groups present in the side chains of these amino acid residues. In yet another embodiment, Rs, R9 and M together may be capable of bonding to the N terminus of AAi and / or the C terminus of AA7. In certain embodiments, Rs, R9 and M together can comprise a chain of ring atoms that form a part of any one or more of a linear or cyclic moiety, such as for example a linear chain of ring atoms extending between AAi and AA7 to form the cyclic peptide, or a chain of ring atoms that form a part of one or more cyclic groups that serve to connect AAi and AA7 and form the cyclic peptide.

[0153] Rs may be attached to AA7 via the C-terminus of AA7 and / or R9 may be attached to AAi via the N-terminus of AAi. In one embodiment, M is any of a bond, optionally substituted alkylene, optionally substituted cycloaliphatic, optionally substituted heteroaliphatic, optionally substituted aralkylene or optionally substituted heteroaralkylene. Additionally, Rs and R9 may comprise moieties that are independently selected from the group consisting of amino acid residues or the derivatives thereof, optionally substituted alkylene, optionally substituted heteroaliphatic, optionally substituted aralkylene, and optionally substituted heteroaralkylene.

[0154] At least one of Rs and R9 may comprise moieties selected from the group consisting of residues of cysteine, lysine, aspartic acid, glutamic acid, penicillamine, 2-amino-3-mercaptobutanoic acid, 3 mercaptopropionic acid, 2,3-diaminopropionic acid, and cysteamine, and derivatives thereof. For example, in one such embodiment Rs and R9 each comprise moieties that are each independently selected from the group consisting of residues of cysteine, lysine, aspartic acid, glutamic acid, penicillamine, 2-amino-3-mercaptobutanoic acid, 3 mercaptopropionic acid, 2,3-diaminopropionic acid, and cysteamine, and derivatives thereof.

[0155] In one embodiment the conjugate corresponds to Formula 3 wherein M, AAi to AA7, Y and L are as defined in connection with Formula 3, each of Rs and R9 is a derivative of an amino acid and Rs is+-R66CH(C(O)R6)NH-++, wherein+indicates the point of attachment of the amino acid residue to M,++indicates the point of attachment of the amine group (-NH-) to AA7 and Res comprises the side chain of the amino acid or is a bond. According to certain embodiments, Rs is a bond to the linker, L, -NR20R21, -OR22, an amino acid residue, such as a residue of serine, or other C-terminal modification of Rs, where R20 and R21 are independently hydrogen, optionally substituted Ci-Cs alkyl, or a bond to the linker, L, and R22 is hydrogen, optionally substituted Ci-Cs alkyl, or a bond to the linker, L. For example, in one such embodiment, Rs is -NR20R21 wherein R20 is hydrogen and R21 is hydrogen, optionally substituted Ci-Cs alkyl or a bond to the linker, L.

[0156] In one embodiment the conjugate corresponds to Formula 3 wherein M, AAi to AA7, Y and L are as defined in connection with Formula 3, each of Rs and R9 is a derivative of an amino acid and R9 is *-C(O)CH(NHR7)R77-**, wherein * indicates the point of attachment of the carbonyl group (C(O)-) to AAi, ** indicates the point of attachment of the amino acid residue to M, and R77 comprises the side chain of the amino acid or is a bond. According to certain embodiments, R7 is hydrogen, optionally substituted C1-C10 alkyl or heteroalkyl, an optionally substituted C1-C10 acyl or heteroacyl group, either of which may be straight or branched and may contain one or more additional acyl groups, hydroxyl groups, carboxyl groups, amide group, amine groups or imine groups, or other N-terminal modification of R9, including an amino acid residue and / or acylated amino acid residue, such as an alanine residue, a serine residue, or an acylated amino acid residue of serine, glycine, aspartic acid, asparagine or arginine.

[0157] It has been found that modification of the N-terminus of R9 improves serum stability. Thus, embodiments in which R7 is optionally substituted C1-C10 alkyl or heteroalkyl, which may be straight or branched and may contain one or more additional acyl groups, hydroxyl groups, carboxyl groups, amide group, amine groups or imine groups, an optionally substituted C1-C10 acyl or heteroacyl group which may be straight or branched and may contain one or more additional acyl groups, hydroxyl groups, carboxyl groups, amide group, amine groups or imine groups, or other N-terminal modification of R including an amino acid residue and / or acylated amino acid residue demonstrate an improved serum stability.

[0158] In some embodiments, R7 comprises an optionally substituted C1-C10 acyl or heteroacyl group. This acyl or heteroacyl group may be straight or branched and may contain one or more additional acyl groups, hydroxyl groups, carboxyl groups, amide group, amine groups or imine groups. The acyl group may be attached to the N-terminus of R9. In some embodiments, R7 comprises a straight chain Ci-Ce acyl or heteroacyl with no substitution. In some embodiments, R7 may comprise an acyl group, a hydroxyl group, an amine group, an amide group, a carboxyl group, or an imine group at an end furthest from the N-terminus of R9.

[0159] In some embodiments, R7 is selected from the following:

[0160]

[0161] An example of a cyclic peptide, with R9 and Rs as specified above, is shown below. According to certain embodiments, in a case where Y-L is directly bonded to E (e.g. as in Formula 3b above), at least one RE can comprise a bond that connects to Y-L. According to certain embodiments, in a case where Y-L is directly bonded to Rs (e.g., as in Formula 3c above), Rs can comprise a bond that connects to Y-L. According to certain embodiments, R77 and Rg6 are cysteine side chains.

[0162] 0

[0163]

[0164] By way of further example, in one such embodiment -R9-M-R8- corresponds to the formula -C(O)CH(NHR7)R77-M-R66CH(C(O)Rs)NH- wherein R7, R77, Re, and Ree are as previously defined. By way of further example, in one such embodiment Rs and R9 are each a derivative of cysteine, and -R9-M-R8- corresponds to the formula *-C(O)CH(NHR7)CH2S-M-SCH2CH(C(O)Re)NH-** wherein R7 and Re, are as previously defined, M is a bond, optionally substituted alkylene, optionally substituted cycloaliphatic, optionally substituted heteroaliphatic, optionally substituted aralkylene or optionally substituted heteroaralkylene (e.g., C1-C12 heteroaliphatic, C5-C12 cycloalkylene or C6-C12 aralkylene or C6-C12 heteroaralkylene).

[0165] In one embodiment, Rs and R9 are independently optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted aralkylene or optionally substituted heteroaralkylene. For example, in one such embodiment at least one of Rs and R9 is optionally substituted Ci-Cs alkylene. By way of further example, in one such embodiment at least one of Rs and R9 is optionally substituted heteroalkylene wherein M, Rs and R9 comprise 1-8 atoms of the optionally substituted heteroalkylene moiety as ring atoms. By way of further example, in one such embodiment at least one of Rs and R9 is optionally substituted aralkyl ene wherein M, Rs and R9 comprise 1-8 atoms of the optionally substituted aralkylene as ring atoms. By way of further example, in one such embodiment at least one of Rs and R9 is optionally substituted heteroaralkylene wherein M, Rs and R9 comprise 1-8 atoms of the optionally substituted heteroaralkylene as ring atoms. By way of further example, in one such embodiment at least one of Rs and R9 is selected from the group consisting of amino acid residues. By way of further example, in one such embodiment at least one of R8and R9is -X(CH2)v-X(CH2)v-X(CH2)v-, wherein each v is independently an integer from 1 to 5, each X is independently selected from a bond, -C(O)-, N, O or S, and at least one X is selected from N, O or S. By way of further example, in one such embodiment, at least one of R8and R9is -X(CH2)v-X(CH2)v-X(CH2)v-, wherein each v is independently an integer from 1 to 5, each X is independently selected from a bond, -C(O)-, N, O or S, and at least one X is selected from N, O or S wherein each X is optionally substituted by one or more Rio wherein each Rio is independently halogen, -C(O)ORb, -OC(O)NRcRa, -SH, -SRa, -S(O)Ra,

[0166] -S(O)2NRcRd, -NRcRd, -NRbC(O)NRcRd, -NRbC(O)Ra, -NRbC(O)ORb, -NRbS(O)2Ra, -C(O)Ra, -C(O)ORb, -C(O)NRcRd, -Si(Ra)3, -P(O)(Rb)2, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg aminoalkyl, Ci-Cg heteroalkyl, Ci-Cg alkenyl, Ci-Cg alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted with one or more Rioa; each R10ais independently halogen, CN, NO2, OH, ORa, NRcRd, C

[0167]

[0168] (=O)Ra, — C(=O)ORb, — C(=O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C1-C6alkenyl, C5-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each Rais independently Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg aminoalkyl, Ci-Cg heteroalkyl, C2-C6 alkenyl, C2-Cg alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-Cg alkyl(cycloalkyl), Ci-Cg alkyl(heterocycloalkyl), Ci-Cg alkyl(aryl), or Ci-Cg alkyl(heteroaryl); each Rbis independently hydrogen, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg aminoalkyl, Ci-Cg heteroalkyl, C2-Cg alkenyl, C2-Cg alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-Cg alkyl(cycloalkyl), Ci-Cg alkyl(heterocycloalkyl), Ci-Cg alkyl(aryl), or Ci-Cg alkyl (heteroaryl), and each Rcand Rdis independently hydrogen, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, Ci-Cg aminoalkyl, Ci-Cg heteroalkyl, C2-C6 alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkyl(cycloalkyl), Ci-Cg alkyl(heterocycloalkyl), Ci-Cg alkyl(aryl), or Ci-Cg alkyl(heteroaryl). In one embodiment, M is a bond. For example, in one such embodiment M is a disulfide or a lactam bond directly connecting Rs to R9. By way of further example, in one such embodiment Rs to R9 comprise amino acid residues or derivatives thereof, and M is a disulfide or lactam bond connecting Rs to R9. In one embodiment, one of Rs and R9 comprises a residue of lysine or derivative thereof and the other of Rs and Ro comprises a residue of aspartic acid or lactic acid or derivative thereof and wherein M is a bond that forms a lactam bridge between R8and R9. In another embodiment, R8and R9comprise cysteine residues or derivatives thereof, and wherein the cyclization moiety M is bonded to the cysteine residues through the cysteine side chains. In one embodiment, M is optionally substituted C1-C8 alkylene.

[0169] In one embodiment, M is optionally substituted heteroalkylene, optionally substituted aralkylene or optionally substituted heteroaralkylene. For example, in one such embodiment M is optionally substituted carbocyclic alkylene or optionally substituted heterocyclic alkylene corresponding to Formula 7

[0170]

[0171] Formula 7

[0172] wherein each t is independently 1-2, n is 0 to 3, such as 0-1, each RE is independently halogen, hydroxy, thiol, amino, or Ci-Ce alkyl and ring E is an optionally substituted, 5 to 10-membered carbocycle or heterocycle, and which may be aromatic or non-aromatic. In certain embodiments, ring E is selected from the group consisting of 5-membered heterocyclic rings such as pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, furan, and thiophene. In certain embodiments, ring E is selected from the group consisting of 6-membered carbocyclic and heterocyclic rings such as benzene, pyridine, pyran, pyrimidine, pyridazine, pyrazine, piperazine, thiazine and oxazine. In other embodiments, ring E is selected from fused heterocycles having 9 or more ring atoms such as indole, isoindole, quinoline, isoquinoline, purine, naphthalene, purine, and chroman. According to certain embodiments, the groups connecting the ring E to Rs and R9 may be in the ortho, meta, or para position with respect to one another.

[0173] In one such embodiment, the conjugate corresponds to any one of Formulae 5a-5d and 6a-6d

[0174]

[0175] Formula 5a Formula 5b

[0176] Formula 5c

[0177]

[0178] Formula 5d

[0179]

[0180] Formula 6c

[0181]

[0182]

[0183] Formula 6d

[0184] wherein M, Rs and R9, in combination, comprise 4 to 20 ring atoms selected from the group consisting of optionally substituted carbon, optionally substituted nitrogen, oxygen and sulfur. Rs is selected from the group consisting of optionally substituted aryl and heteroaryl. For example, in one such embodiment, R5 is optionally substituted phenyl (e.g. phenol), naphthyl, anthryl, imidazole, or indole. In one such embodiment, R5 is indole, such as for example in a case where R5 is a part of the side chain of a tryptophan amino acid residue. Rn is a side chain of an amino acid residue selected from the group consisting of glutamine (-CH2-CH2-C(=O)-NH2), glycine (-H), alanine (-CH3), isoleucine (-CH(CH3)-CH2-CH), leucine (-CH2-CH(CH3)2), valine (-CH(CH3)2), lysine (-(CH2)4-NH2), arginine ((-CH2)3-NH-C(=NH)-NH2), aspartic acid (-CH2-C(=O)-OH), glutamic acid (-(CH2)2-C(=O)-OH), serine (-CH2-OH), threonine (-CH(OH)(CH3)), asparagine (-CH2-C(=O)-NH2), phenylalanine (-CH2C6H5), tryptophan (-C6H4CCNH3), tyrosine (-CH2C6H4OH), or histidine (-CH2C3H3N2). The side chains of phenylalanine, tryptophan, tyrosine, and histidine have the structures below, where the wavy symbol shows the point of attachment of the side chain to the peptide: Phe Trp Tyr His

[0185]

[0186] R12 is a side chain of an amino acid residue selected from the group consisting of tryptophan, phenylalanine, tyrosine, serine, threonine, methionine (-(CH₂)₂-S-CH₃), glycine, histidine, and aspartic acid and R13 is a side chain of an amino acid residue selected from the group consisting of tryptophan, methionine, phenylalanine, glycine, glutamine, serine and tyrosine, such as any selected from the group consisting of tryptophan, phenylalanine, and tyrosine. In one embodiment, R12 and R13 each comprise the side chain of a tryptophan amino acid residue. In one embodiment, A Af)and AA7 are each residues of any of tryptophan, phenylalanine, and tyrosine, such as when both AA6and AA7 are residues of tryptophan.

[0187] In one embodiment, M is any of a bond, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted aralkylene or optionally substituted heteroaralkylene.

[0188] For example, in one such embodiment the conjugate corresponds to any of Formulae 1- 6 wherein M corresponds to Formula 7 and -R9-M-R8- corresponds to Formula 8:

[0189] Formula 8

[0190]

[0191] wherein the wavy lines, indicate the point of attachment of Rs to AA7 and R9 to AAi, and n, t, Rs and R9, are as described above.

[0192] In one embodiment, Rs and R9 comprise moieties that are independently selected from amino acid residues, such as cysteine residues, or derivatives thereof, and M corresponds to Formula 7. For example, R9 can comprise *-C(O)CH2(NHR?)R77-** wherein * indicates the point of attachment of the carbonyl group (-C(O)-) to AAi, ** indicates the point of attachment of the amino acid residue to M, and R77 comprises the side chain of the amino acid or is a bond, Rs is+-R66(C(O)Re)CH2NH-++wherein+indicates the point of attachment of the amino acid residue to M, “+indicates the point of attachment of the amine group (-NH-) to AA7 and Ree comprises the side chain of the amino acid or is a bond. By way of further example, in one such embodiment, each of Rs and R9 are residues of an amino acid or a derivative thereof, e.g., cysteine or a derivative thereof, M corresponds to Formula 7, each t is 1, E is an aromatic or heteroaromatic ring comprising 5-10 ring atoms, n is 0-3, and each RE is independently, halogen, hydroxy, thiol, amino, or Ci-Ce alkyl. By way of further example, in one such embodiment each of Rs and R9 are residues of an amino acid or a derivative thereof, e.g, cysteine or a derivative thereof, M corresponds to Formula 7, each t is 1, E is benzene, naphthalene, or a 5 -membered heteroaromatic ring, n is 0-1, and RE is halogen, hydroxy, thiol, amino, or Ci-Ce alkyl.

[0193] In one embodiment, M is a bond. For example, in one such embodiment, Rs and R9 comprise moieties that are independently selected from amino acid residues and derivatives thereof, M is a disulfide or a lactam bond directly connecting Rs to R9, Rs is attached to AA7 via a peptide bond, and R9 is attached to AAi via a peptide bond. By way of further example, in one such embodiment Rs and R9 comprise moieties that are independently selected from the group consisting of a residue of cysteine, lysine, aspartic acid, glutamic acid, penicillamine, 2-amino-3 -mercaptobutanoic acid, 3 mercaptopropionic acid, 2,3-diaminopropionic acid or cysteamine, or derivatives thereof, M is a disulfide or a lactam bond directly connecting Rs to R9, Rs is attached to AA7 via a peptide bond, and R9 is attached to AAi via a peptide bond.

[0194] In one embodiment, the conjugate of the present disclosure corresponds to any of Formulas lOa-lOd Formula 10a

[0195] Formula 10b

[0196]

[0197]

[0198] wherein Rs, R7, R11, R12 and R13 are as specified above, t is 0-2, E is a 5 to 10-membered carbocycle or heterocycle, n is 0-2 and each RE is independently halogen, hydroxy, thiol, amino, or Ci-Ce alkyl. For example, in one such embodiment, the conjugate corresponds to any of Formulas lOa-lOd, R7 is hydrogen, optionally substituted C1-C10 alkyl or heteroalkyl, an optionally substituted C1-C10 acyl or heteroacyl group either of which may be straight or branched and may contain one or more additional acyl groups, hydroxyl groups, carboxyl groups, amide group, amine groups or imine groups or other N-terminal modification of R9, including an amino acid residue and / or acylated amino acid residue, such as an acylated amino acid residue of serine, t is 1, n is 0, and E is benzene, naphthylene or 5-membered heterocycle. By way of further example, in one such embodiment the conjugate corresponds to any of Formulas lOa-lOc, R?is an optionally substituted C1-C10 acyl or heteroacyl group which may be straight or branched and may contain one or more additional acyl groups, hydroxyl groups, carboxyl groups, amide group, amine groups or imine groups, or an acetylated amino acid residue of serine, t is 1, n is 0, E is benzene, naphthylene or 5-membered heterocycle. In the embodiment of any of Formulas 10a- lOd, the groups connecting the nng E to the rest of the cyclic peptide may be in the ortho, meta, or para position with respect to one another.

[0199] In one embodiment, the conjugate of the present disclosure corresponds to any of Formulas 1 la-1 Id

[0200] Formula Ila

[0201]

[0202] Formula 11c

[0203]

[0204]

[0205] wherein Rs, RH, R12, R13, Rs and R7 are as specified above, t is 0-2, E is a 5 to 10-membered carbocycle or heterocycle, n is 0-2 and each RE is independently halogen, hydroxy, thiol, amino, or Ci-Cg alkyl. For example, in one such embodiment, the conjugate corresponds to any of Formulas 1 la-1 Id, Reis -NR20R21, or -OR22, or other C-terminal modification, R20 and R21 are independently hydrogen or optionally substituted Ci-Ce alkyl, R22 is hydrogen or optionally substituted Ci-Ce alkyl, R7 is hydrogen, optionally substituted C1-C10 alkyl or heteroalkyl, an optionally substituted C1-C10 acyl or heteroacyl group either of which may be straight or branched and may contain one or more additional acyl groups, hydroxyl groups, carboxyl groups, amide group, amine groups or imine groups or other N-terminal modification of R9, including an amino acid residue and / or acylated amino acid residue, such as an alanine residue, a serine residue, or an acylated amino acid residue of serine, glycine, aspartic acid, asparagine or arginine, t is 1, n is 0, and E is benzene, naphthylene or 5-membered heterocycle. By way of further example, in one such embodiment the conjugate corresponds to any of Formulas 1 la-1 Id, Re is -NH2, R7 is an optionally substituted Ci-Ceio acyl or heteroacyl group which may be straight or branched and may contain one or more additional acyl groups, hydroxyl groups, carboxyl groups, amide group, amine groups or imine groups or acetylated amino acid residue of serine, t is 1, n is 0, E is benzene, naphthylene or 5-membered heterocycle. In the embodiment of any of Formulas 1 la-1 Id, the groups connecting the ring E to the rest of the cyclic peptide may be in the ortho, meta, or para position with respect to one another.

[0206] According to one embodiment, as shown in Formula 12 below, the group M comprises a benzene ring with substituents connecting to Rs and R9 that are in the ortho, meta, or para position with respect to one another, and where the wavy line represents the connection to Rs and R9.

[0207]

[0208] (RE)n

[0209] Formula 12

[0210] wherein RE and n are as defined in connection with Formulas 1 la-d.

[0211] For example, according to certain embodiments, the conjugate may have the following structure, where Rs and R9 comprise cysteine residues or derivatives thereof, and are each connected to the benzene group of M via ortho, meta or para positions, as show n in any of Formulas 13e-131 below. Formula 13e

[0212] Formula 13f

[0213]

[0214] R5 HO

[0215] Formula 13g

[0216]

[0217] Formula 13h Formula 13i

[0218] Formula 13j

[0219]

[0220]

[0221] Formula 131

[0222] wherein R5, Re, R7, R11, R12, R13, RE and n are as defined above. According to one embodiment, the cyclic binding peptide comprises a structure according to any of the following formulas:

[0223]

[0224] HO

[0225]

[0226] For example, the cyclic binding peptide can comprise a structure according to any of the following formulas:

[0227]

[0228]

[0229] wherein the chelator, and optionally linker, are connected at the location of one of the wavy lines in the above structures.

[0230] According to further embodiments, the moiety M that connects Rs and R9 may be any of those below:

[0231]

[0232]

[0233]

[0234] Target

[0235] Fibroblast activation protein (FAP), also known as prolyl endopeptidase FAP (a member of the propyl peptidase family), is an enzyme that in humans is encoded by the FAP gene. FAP is a 97-kDatype-II transmembrane serine protease that acts on various hormones and extracellular matrix components. FAP contains 760 ammo acids with a very short cytoplasmic N terminal part, a transmembrane region, and a large extracellular part with an alpha / beta-hydrolase domain and an eight-bladed beta-propeller domain. FAP is non- classical serine protease, and the active site is localized in the extracellular part of the protein which contains a catalytic triad composed of Ser624Asp 'u2His7 4in humans and mice. The serine acts as a nucleophile, cleaving N-terminal Pro-X peptide bonds, where X is any ammo acid except proline or hydroxy proline. FAP contains dipeptidyl peptidase enzymatic activity and endopeptidase activity, sometimes referred to as gelatinase activity (see, e.g., Fitzgerald et al, Cancer Metastasis Rev. 2020 Sep: 39(3):783-803).

[0236] FAP is highly upregulated in a wide variety of cancers, and is often used as a marker for pro-tumorigenic stroma. FAP is also expressed in pathological conditions including arthritis, fibrosis atherosclerosis, autoimmune diseases, and metabolic diseases. As used herein, fibroblast activation protein (FAP) means fibroblast activation protein alpha (FAPa). FAP and FAPct are interchangeable herein.

[0237] FAP-Targeted Peptide

[0238] According to certain embodiments, the FAP-targeted peptide comprises a sequence of amino acid residues that provide for binding to the FAP target. According to one embodiment, all of the amino acid residues may be L-amino acids. According to another embodiment, all of the amino acid residues may be D-ammo acids.. According to yet another embodiment, the sequence may comprise a mixture of some L- and some D- amino acids. One or more of the amino acids may also be beta-homo amino acids. For reference, a list of naturally occurring amino acids and their three and one letter abbreviations is provided in the table below.

[0239] Amino Acid IName Three Letter Abbreviation One Letter Abbreviation Arginine Arg R

[0240] Histidine His H

[0241] Lysine Lys K

[0242] Aspartic Acid Asp D

[0243] Glutamic Glu E

[0244] Serine Ser s

[0245] Threonine Thr T

[0246] Asparagine Asn N

[0247] Glutamine Gin Q

[0248] Cysteine Cys c

[0249] Selenocysteine Sec u

[0250] Glycine Gly G

[0251] Proline Pro P

[0252] Alanine Ala A

[0253] Valine Vai V

[0254] Isoleucine lie J

[0255] Leucine Leu I..

[0256] Methionine Met M

[0257]

[0258] Phenylalanine Phe F

[0259] Tyrosine Tyr Y

[0260] Tryptophan Trp W

[0261]

[0262] According to certain embodiments, AA1 is an amino acid residue of Thr, Ser or lie. According to one embodiment, AA1 may be an amino acid residue of Thr or Ser, such as an amino acid residue of Thr.

[0263] According to certain embodiments, AA2 is an amino acid residue of Pro or homoproline; Additionally, AA2 can be L-, D-, or beta-homo amino acid residue of any of the following amino acids: 1, 2, 3. 4-tetrahydroisoquino1in-3-carboxylic acid (Tic), pyrogluiamic acid (Pyr). Homo-Pro, 4-aminopiperidine-4-carboxy'lic acid, 2-aminobenzoic acid (2-Abz), 3- aminocyclopentanecarboxylic acid, trans-3-hydroxyproline (Hyp), cis-3-hydroxyproline, trans-4-hydroxyproline, cis-4-hydroxyproline, alpha-methyl -proline, alpha-benzyl-proline, 3,4-dehydro-proline, 4-oxa-proline, 3 -thia-proline, and 4-thia-proline. In one embodiment, AA2 is the ammo acid residue of Pro.

[0264] According to certain embodiments, AA3 is an amino acid residue of Trp, Phe, Tyr, or His. According to further embodiments, AA3 may be an amino acid residue with a side chain having the formula -CH2-R5, where R5 is defined above, and may be selected from the group consisting of optionally substituted aryl and heteroaryl. For example, in one such embodiment, Rs is optionally substituted phenyl, naphthyl, anthryl, phenol, imidazole or indole. In one such embodiment, Rs is indole, as when AA3 is the amino acid residue of Trp. In another embodiment, Rs is phenyl, as when AA3 is the amino acid residue of Phe. In another embodiment, Rs is phenol, as when AA3 is the amino acid residue of Tyr. In another embodiment, Rs is imidazole, as when AA3 is the amino acid residue of His. According to yet another embodiment, AA3 can be beta-Phe or beta-Tyr. Additionally, AA3 can be L-, D-, or beta-homo amino acid of any of the following amino acids: 1 -naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), 3-(4-biphenyl-alanine (Bip), 2-pyridyl-alanine (2-Pal), 3-pyridyl-alanine (3-Pal), 4-pyridyl-alanine (4-Pal), 3-benzothienyl-alanine (Bta), 2-cyano-phenylalanine, 3-cyano-phenylalanine, 4-cyano-phenylalanine, 3-borono-phenylalanine, 4-borono-phenylalanine, 4-trifluoromethyl-phenylalanine, 2-chloro-phenylalanine, 3-chloro- phenylalanine, 4-chloro-phenylalanine, 2-fluoro-phenylalanine, 3-fluoro-phenylalanine, 4-fluoro-phenylalanine, 2-iodo-phenylalanine, 3 -iodo-phenylalanine, 4-iodo-phenylalanine, 2-methyl-phenylalanine, 3-methyl-phenylalanine, 4-methyl-phenylalanine, 2-nitro-phenylalanine, 3-nitro-phenylalanine, 4-nitro-phenylalanine, 4-pentafluoro-phenylalanine, phenylglycine (Phg), 4-amino-phenylalanine, 4-methoxy-phenylalanine, 5-hydroxytrptophan, 3, 5 -diiodo-tyrosine, 4-benzoyl-phenylalanine, 5-hydroxy-trptophan, 3, 5-diiodo-tyrosine, 4-benzoyl-phenylalanine (Bpa), cyclohexylglycine (Chg), or 2-thienyl-alanine (Thi). In one embodiment, AA3 is an amino acid residue of Trp, Phe, Tyr, His, 2-Nal, 1-Nal, Bta, or 3-Pal. In one embodiment, AA3 is an amino acid residue of Trp or another ammo acid having a side chain including an optionally substituted aryl or heteroaryl group. AA3 may be an amino acid residue of Trp.

[0265] In certain embodiments, AA4 is an amino acid residue of Glu, Asp, Gin, or Asn;

[0266] Additionally, AA4 can be beta-Glu, or beta-Gln. In one embodiment, AA4 is an amino acid residue of Glu.

[0267] In certain embodiments, AA5 is an amino acid residue of Gin, Ala, Leu, He, Vai, Trp, Tyr, Phe, His, Lys, Arg, Asp, Glu, Ser, Thr, Asn, or Gly; Additionally, AA5 can be a residue of beta-Glu, beta-Gln, beta-Phe, beta-Tyr, or beta-Lys. Additionally, AA5 can be an L-, D-, or beta-homo amino acid residue of any of the following amino acids: norleucine (Nle), citrulline (Cit), and norvaline. Additionally, AA5 can be an L-, D-, or beta-homo amino acids of 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), 3-(4-biphenyl-alanine (Bip), 2-pyridyl-alanine (2-Pal), 3 -pyridyl -alanine (3-Pal), 4-pyridyl-alanine (4-Pal), 3-benzothienyl-alanine (Bta), 2-cyano-phenylalanine, 3-cyano-phenylalanine, 4-cyano-phenylalanine, 3-Borono-phenylalanine, 4-Borono-phenylalanine, 4-trifluoromethyl-phenylalanine, 2-chloro-phenylalanine, 3-chloro-phenylalanine, 4-chloro-phenylalanine, 2-fluoro-phenylalanine, 3-fluoro-phenylalanine, 4-fluoro-phenylalanine, 2-Iodo-phenylalanine, 3-Iodo-phenylalanine, 4-Iodo-phenylalanine, 2-methyl-phenylalanine, 3-methyl-phenylalanine, 4-methyl-phenylalanine, 2-Nitro-phenylalanine, 3-Nitro-phenylalanine, 4-Nitro-phenylalanine, 4-pentafluoro-phenylalanine, phenylglycine (Phg), 4-amino-phenylalanine, 4-methoxy-phenylalanine, 5-hydroxytrptophan, 3, 5-diiodo-tyrosine, 4-benzoyl-phenylalanine, 5-hydroxy-trptophan, 3, 5-diiodo-tyrosine, 4-benzoyl-phenylalanine (Bpa), cyclohexylglycine (Chg), or 2-thienyl-alanine (Thi). In one embodiment, AA5 is an amino acid residue of any of Gin, He. Trp, His, Lys, Arg, Asp, Qu, Ser, Thr, or Asn. In one embodiment, AA5 is an amino acid residue of any of Gin, Glu, His, Asp, Arg, Lys, Ser, Thr or Asn. In another embodiment, AA5 is an amino acid residue of any of Gin, He, His, Asp and Glu. In another embodiment, AA5 is an amino acid residue of Gin.

[0268] In certain embodiments, A Ar, is an amino acid residue of Trp, Phe, Tyr, Met, Ser, Thr, Gly, His or Asp. Additionally, A Ar, can be a residue of beta-Phe, or beta-Tyr. Additionally, AAe can be a L-, D-, or beta-homo amino acid residue of any of the following amino acids: 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), 3-(4-biphenyl)-alanine (Bip), 2-pyndyl-alanine (2-Pal), 3 -pyridyl -alanine (3-Pal), 4-pyridyl-alanine (4-Pal), 3-benzothienyl-alanine (Bta), 2-cyano-phenylalanine, 3-cyano-phenylalanine, 4-cyano-phenylalanine, 3-Borono-phenylalanine, 4-Borono-phenylalanine, 4-trifluoromethyl-phenylalanine, 2-chloro-phenylalanine, 3-chloro-phenylalanine, 4-chloro-phenylalanine, 2-fluoro-phenylalanine, 3-fluoro-phenylalanine, 4-fluoro-phenylalanine, 2-Iodo-phenylalanine, 3-Iodo-phenylalanine, 4-lodo-phenylalanine, 2-methyl-phenylalanine, 3-methyl-phenylalanine, 4-methyl-phenylalanine, 2-Nitro-phenylalanine, 3-Nitro-phenylalanine, 4-Nitro-phenylalanine, 4-pentafluoro-phenylalanine, phenylglycine (Phg), 4-amino-phenylalanine, 4-methoxy-phenylalanine, 5-hydroxytrptophan, 3, 5-diiodo-tyrosine, 4-benzoyl-phenylalanine, 5-hydroxy-trptophan, 3, 5-diiodo-tyrosine, 4-benzoyl-phenylalanine (Bpa), cyclohexylglycine (Chg), or 2-thienyl-alamne (Thi). In one embodiment, AAe is an amino acid residue of tryptophan, phenylalanine, tyrosine, serine, or threonine. In one embodiment, AAe is a residue of any of Trp, Phe, or Tyr. In one embodiment, AAe is an amino acid residue of any of Trp and Tyr. In one embodiment, AAe is an amino acid residue of Trp.

[0269] In certain embodiments, AA7 is an amino acid residue of Trp, Met, Phe, Tyr, Gly, Gin or Ser. Additionally, AA7can be a residue of beta-Phe, or beta-Tyr. Additionally, AA7 can be a L-, D-, or beta-homo amino acid residue of any of the following amino acids: norvaline (Nva), norleucine (Nle), citrulline (Cit), 1 -naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), 3-(4-biphenyl-alanine (Bip), 2-pyridyl-alanine (2-Pal), 3-pyridyl-alanine (3-Pal), 4-pyridyl-alanine (4-Pal), 3-benzothienyl-alanine (Bta), 2-cyano-phenylalanine, 3-cyano-phenylalanine, 4-cyano-phenylalanine, 3-Borono-phenylalanine, 4-Borono-phenylalanine, 4-trifluoromethyl-phenylalanine, 2-chloro-phenylalanine, 3-chloro-phenylalanine, 4-chloro-phenylalanine, 2-fluoro-phenylalanine, 3 -fluoro-phenylalanine, 4-fluoro-phenylalanine, 2-Iodo-phenylalanine, 3-Iodo-phenylalanine, 4-Iodo-phenylalanine, 2-methyl-phenylalanine, 3-methyl-phenylalanine, 4-methyl-phenylalanine, 2-Nitro-phenylalanine, 3 -Nitro-phenylalanine, 4-Nitro-phenylalanine, 4-pentafluoro-phenylalanine, phenylglycine (Phg), 4-amino-phenylalanine, 4-methoxy-phenylalanine, 5-hydroxytrptophan, 3, 5-diiodo-tyrosine, 4-benzoyl-phenylalanine, 5-hydroxy-trptophan, 3, 5-diiodo-tyrosine, 4-benzoyl-phenylalanine (Bpa), cyclohexylglycine (Chg), or 2-thienyl-alanine (Thi). In one embodiment, AA7 is an amino acid residue of any of Trp, Phe, or Tyr. In another embodiment, AA7 is an amino acid residue of any of Trp and Tyr. In another embodiment, AA7 is an amino acid residue of Trp.

[0270] Linkers L

[0271] In certain embodiments, L is a chemical linker that is inserted into a position between the FAP-targeted peptide and the chelator that is used to radiolabel the composition using radionuclides for diagnostic imaging and / or therapy or between FAP-targeted peptide and cytotoxic drug. According to certain embodiments, the linker may improve the retention of the composition on the cell surface. According to certain embodiments, the linker may improve the internalization of the composition into ceils. According to certain embodiments, the linker may improve the retention of the composition in tumors for more precise delivery' of radiation to the cancerous tissue.

[0272] In some embodiments, the linker comprises one or more of substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In some embodiments, the linker can comprise one or more amino acid residues. In some embodiments, the linker comprises 1 to 3, 1 to 5, I to 10, 5 to 10, or 5 to 20 ammo acid residues. In some embodiments, the linker comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues. In some embodiments, the linker comprises 1 to 5 amino acid residues. For example, the linker can comprise one or more lysine (K) residues, serine (S) residues, phenylalanine (F) residues, and combinations thereof. In some embodiments, one or more amino acids of the linker are unnatural amino acids or other groups such as cysteamine, and / or the amino acid may have a modified N or C terminus.

[0273] In some embodiments, the linker is attached via a peptide bond. The linker can be bonded through a chemically reactive group. Exemplary chemically reactive groups include, but are not limited to, a free amino, imino, hydroxyl, thiol or carboxyl group (e.g., to the N- or C-tennmus, to the epsilon ammo group of one or more lysine residues, the free carboxylic acid group of one or more glutamic acid or aspartic acid residues, or to the sulfhydryl group of one or more cysteinyl residues). Exemplary methods for ataching the linker includes carbodiimide reaction, reactions using bifunctional agents such as dialdehydes or imidoesters, Schiff base reaction, Suzuki-Miyaura cross-coupling reactions, isothiocyanates as coupling agents, and click chemistry. In one embodiment, the linker can be formed from a benzyl isothiocyanate moiety, which can be reacted with another part of the linker or a group on M or Rs to form benzyl thiourea linkage. In one embodiment, the linker comprises a benzyl thiourea moiety bonded to a polyethylene glycol moiety that is formed by the reaction of benzyl isothiocyanate group with an amino-polyethylene glycol-acid which may have the formula NH2-(CH2CH2-O)n-(CH2)m-C(=O)OH, where n and m are 1-10.

[0274] According to certain embodiments, the linker may have a length that is selected to provide an appropriate distance between the binding peptide and the chelator Y (or cytotoxic drug). For example, according to certain embodiments, the linker can have 1 to 100 atoms, 1 to 60 atoms, 1 to 30 atoms, 1 to 15 atoms, 1 to 10 atoms, 1 to 5, or 2 to 20 atoms in length. In some embodiments, the linker has 1 to 10 atoms in length.

[0275] In some embodiments, the linker comprises one or more of substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In some embodiments, the linker comprises substituted or unsubstituted C1-C30 alkylene.

[0276] In some embodiments, the linker comprises a polyethylene glycol moiety, such as ( — CH2— CH2— O— ) 1-10. For example, according to certain embodiments, the linker can comprise a polyethylene glycol moiety that is formed from a modified PEG to provide for covalent bonding on either end, such as amino-poly ethylene glycol-acid, having from 1 to 10 PEG groups, such as any of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 PEG groups, such as 2 PEG groups, and having an acid group on one end of the linker and an amino group on the other (e.g. NH2-(CH2CH2-O)n-(CH2)m-C(=O)OH, where n and m are 1-10). The linker formed from the modified PEG may comprise the formula -NH2-(CH2CH2O)n-(CH2)m-C(=O)-, where n and m are 1-10, such as any of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In one embodiment, m is 1-2, and n is 1-10, such as 1-8, 1-6, 1-4, 2-4, and even 4.

[0277] In some embodiments, the linker comprises a carboxylic acid, such as a fatty acid, which may be a straight chain, optionally saturated fatty acid. The carboxylic acid may be a C2 to a C10 straight chain carboxylic acid, optionally a C4 to a C’s straight carboxylic acid, such as hexanoic acid. The acid may be modified to provide for covalent bonding on either end. This can be achieved by including a free ammo, imino, hydroxyl, thiol or carboxyl group on each end. In some embodiments, the linker is formed from a compound comprising the formula R33 — (CH2)n-(C=O)OH, wherein n is 1 to 10, such as 1-10, 1-8, or 1-6, such as any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and R33 is a group that is able to form a covalent bond with a chelator or a cytotoxic drug, such as for example any of a free ammo, imino, hydroxyl, thiol or carboxyl group. In one embodiment, the linker is formed from a compound comprising the formula NH2 — (CH2)n-C(=O)OH, wherein n is 1 to 12, 1-10, 1-8, or 1-6, such as any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 such as for example a 6-amino hexanoic acid (6-AHA) or 12-amino-dodecanoic acid (12-ado). The linker thus formed comprises the formula -NH2-(CH2)n-C(=O)-, where n is 1-12, 1-10, 1-8, or 1-6, such as any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11. According to some embodiments, the linker comprises the residue of one or more amino-polyethylene glycol-acid and / or the compound having the formula

[0278]

[0279] R33-(CH2)n-C(=O)OH, such as NH2 — (CH2)n-C(=O)OH, in combination with one or more amino acid residues.

[0280] In some embodiments, the linker comprises an aliphatic chain modified with a thiol moiety on one end, and an amine group on the other, such as the residue of a compound NH2-(CH2)n-SH, where n is from 1 to 6, such as 2-4, and even 2 (as in the case of cysteamine). The linker thus formed may have the formula -NH2-(CH2)n-S-, where n is from 1 to 6, such as 2-4, and even 2.

[0281] In one embodiment the linker is a made up of a combination of different linker elements, and can comprise the general formula as follows

[0282] -((NH)a-(CH2CH2O)b-(CH2)c-C(=O))h-(NH-CH(RL)-C(=O))d-(NH-(CH2)i-CH(C(=O)NH2)-NH-)j-(NH(CH2)e)f-(S)g-wherein ais 0-1, b is 0-12, c is 0-2, his 0-4, d is 0-1, i is 0 to 6, j is 0 to 4, e is 0-6, f is 0-1, g is 0-1 and RL is hydrogen, or the side chain of an amino acid, such as any of serine and phenylalanine. For example, in one embodiment, the linker comprises the formula where a is 1, b is 2-4 (e.g.

[0283] 2, 3 or 4), c is 2, his 1, d is 1, i is 0, j is 0, e is 0, fis 0, and g is 0, and where Rj. is the side chain of serine as follows:

[0284] -(NH)-(CH2CH2O)2.4-(CH2)2-C(=O)-NH-CH(CH2OH)-C(=O)- As another example, in one embodiment, the linker comprises the formula where a is 1, b is 2-4, c is 2, h is 1, d is 0, is 0, j is 0, e is 0, f is 0, and g is 0, as follows:

[0285] -(NH)-(CH2CH2O)2-4-(CH2)2-C(=O)- As another example, in one embodiment, the linker comprises the formula where a is 1, b is 2-4 (e.g. 2, 3 or 4), c is 2, h is 1, d is 0, i is 2-4 (e.g. 2, 3 or 4), j is 1, e is 0, f is 0, and g is 0, as follows:

[0286] -(NH)-(CH2CH2O)2-4-(CH2)2-C(=O)-NH-(CH2)2-4-CH(C(=O)NH2)-NH- As another example, in one embodiment, the linker comprises the formula where a is 1, b is 2-4 (e.g. 2, 3 or 4), c is 2, h is 1, d is 2, i is 0, j is 0, e is 0, f is 0, and g is 0, and where RL is the side chain of phenylalanine and the side chain of serine, as follows:

[0287] -(NH)-(CH2CH2O)2-4-(CH2)2-C(=O)-NH-CH(CH2-C6H5)-C(=O)-NH-CH(CH2- OH)-C(=O)- As another example, in one embodiment, the linker comprises the formula where a is 1, b is 2-4 (e.g. 2, 3 or 4), c is 2, h is 1, d is 0, i is 0, j is 0, e is 2-4 (e.g., 2, 3 or 4), f is 1, and g is 1, as follows:

[0288] -(NH)-(CH2CH2O)2-4-(CH2)2-C(=O)-(NH(CH2)2.4)-S- As another example, in one embodiment, the linker comprises the formula where a is 1, b is 1, c is 2, h is 1, d is 0, i is 0, j is 0, e is 0, f is 0, and g is 0, as follows:

[0289] -(NH)-(CH2CH2O)-(CH2)2-C(=O)- As another example, in one embodiment, the linker comprises the formula where a is 1, b is 0, c is 2-6 (e.g. 2, 3, 4, 5 or 6), h is 1, d is 0, i is 0, j is 0, e is 0, fis 0, and g is 0, as follows:

[0290] -NH-(CH2)2.6-C(=O)- As another example, in one embodiment, the linker comprises the formula where a is 1, b is 0, c is 6-10 (e.g. 6, 7, 8, 9, or 10), h is 1, d is 0, i is 0, j is 0, e is 0, f is 0, and g is 0, as follows:

[0291] -NH-(CH2)6-IO-C(=0)- As another example, in one embodiment, the linker comprises the formula where a is 1, b is 0, c is 10-12 (e.g. 10, 11 or 12), h is 1, d is 0, i is 0, j is 0, e is 0, fis 0, and is 0, as follows:

[0292] -NH-(CH2)IO-12-C(=0)- According to yet another embodiment the linker comprises a benzyl thiourea group connected to any of the other linkers described herein. For example, the linker can comprise the following formula:

[0293] -(NH)k-CH2-(benzyl)-NH-C(=S)-, where k is 0 to 1, such as for example in combination with a PEG-containing linker as follows:

[0294] -(NH)o-i-CH2-(benzyl)-NH-C(=S)-NH-(CH2CH20)i-4-(CH2)2-C(=0)- In some embodiments, the linker comprises a click chemistry residue. In some embodiments, the linker is attached to the binding peptide, to the chelator or cytotoxic drug, or both via click chemistry, thereby forming a click chemistry residue. For example, the binding peptide can comprise an azide group that reacts with an alkyne moiety of the linker. For another example, the peptide can comprise an alkyne group that reacts with an azide of the linker. The chelator and the linker can be attached similarly. In some embodiments, the linker comprises an azide moiety, an alkyne moiety, or both. In some embodiments, the linker comprises a tri azole.

[0295] In some embodiments, the linker has a structure of

[0296]

[0297] wherein each L is independently — O —, — NRL—, — N(RL)2+—, — OP(=O)(ORL)O —, — S—, — S(=O)—, — S(=O)2—, =CH—, — C(=O)—, — C(=O)O—, — OC(=O)—, — OC(=O)O—, — C(=O)NRL—, — NRLC(=O)—, — OC(=O)NRL—, — NRLC(=O)O—, — N

[0298]

[0299] RLC(=O)NRL— — NRLC(=S)NRL—, — CRL=N— — N=CRL, — NRLS(=O)2—, — S(=O)2NRL—, — C(=O)NRLS(=O)2—, — S(=O)2NRLC(=O) —, substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C1-C12 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Ci-C30 alkylene, substituted or unsubstituted C2-Cso alkenylene, substituted or unsubstituted C2-C30 alkynylene, substituted or unsubstituted C1-C30 heteroalkylene, — (C1-C30 alkylene)-0 —, — 0 — (C1-C30 alkylene)-, — (C1-C30 alkylene)-NRL—, — NRL-(CI-C3O alkylene)-, — (Ci-C30 alkylene)-N(RL)2+—, — N(RL)2+— (C1-C30 alkylene)-, or a click chemistry residue; and each RLis independently hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 heteroalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-Cs alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C? heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n is 1,2, 3, 4, 5,6,7, 8,9, 10, 11, 12, 13, 14, or 15.

[0300] In some embodiments, the linker has a structure of

[0301] wherein each L is independently — 0 —, — NRL—, — N(RL)2+—, — OP(=O)(ORL)O —, — S—, — S(=O)—, — S(=O)2—, — CH=CH—, =CH—, — C<, — C(=O)—, — C(=O)O—, — OC(=O)—, — OC(=O)O—, — C(=O)NRL—, — NRLC(=O)—, — OC(=O)NRL—, — NRLC(=O)O—, — NRLC(=O)NRL—, — NRLS(=O)2—, — S(=O)2NRL—, —

[0302]

[0303] C(=O)NRLS(=O)2—, or — S(=O)2NRLC(=O)—.

[0304] In some embodiments, the linker comprises substituted or unsubstituted C1-C30 alkylene, C1-C12 alkylene, Ci-Cs alkylene, Ci-Ce alkylene, or C2-Ce alkylene. In some embodiments, the linker comprises C2-Ce alkylene. In some embodiments, the linker comprises C4-C6 alkylene.

[0305] In some embodiments, the linker comprises an amino acid residue, such as for example any of lysine, threonine, phenylalanine, and glycine.

[0306] In certain embodiments, the linker is a hydrophobic linker consisting of an aliphatic carbon chain that connects the chelator to the peptide backbone. In certain embodiments, the linker is a hydrophilic linker that includes heteroatom substitutions in the aliphatic chain that connects the chelator to the peptide backbone. In certain embodiments, the linker is a mixture of hydrophilic and hydrophobic entities. In certain embodiments, the linker is an aliphatic (ALP) linker of 2 or 4 carbons. In certain embodiments, the linker comprises a mixture of piperidine (PIP) and one or more amino acids. In certain embodiments, the linker comprises a mixture of piperazine and one or more amino acids. In certain embodiments, the linker is a mixture of benzene and one or more amino acids. In certain embodiments, the linker may be a “cleavable” linker that contains mixture of natural amino acids such as Phe, Met, He that can be cleaved in kidney brush boarder membrane to facilitate the clearance through kidneys. According to one embodiment, the linker can comprise any one or combination of 2 or more residues of lysine, serine, phenylalanine, cysteamine, 6-amino hexanoic acid; benzylisothiocyanate, 12-amino-dodecanoic acid, and amino-polyethylene glycol-acid (having from 2-4 polyethylene glycol groups).

[0307] Other linkers are known in the art. See, e.g., Bandari R P, Jiang Z, Reynolds T S, Bemskoetter N E, Szczodroski A F, Bassuner KJ, Kirkpatrick D L, Rold T L, Sieckman G L, Hoffman T J, Connors J P, Smith C J. Synthesis and biological evaluation of copper-64 radiolabeled [DUPA-6-Ahx-(NODAGA)-5-Ava-BBN(7-14)NH2], a novel bivalent targeting vector having affinity for two distinct biomarkers (GRPr / PSMA) of prostate cancer. Nucl Med Biol. 2014, 41 (4):355-363. Doi: 10.1016 / j.nucmedbio.2014.01.001. PubMed PMID; 24508213; PMCID. PMC4041584; Dumont R A, Tamma M. Braun F. Borkowski S, Reubi J C, Maecke H, Weber W A, Mansi R. Targeted radiotherapy of prostate cancer with a gastrin¬ releasing peptide receptor antagonist is effective as monotherapy and in combination with rapamycin. J Nucl Med. 2013; 54(5): 762-769. Doi; 10.2967 / jnumed.l 12.112169. PubMed PMID: 23492884; Goumi E, Mansi R, famous M. Waser B, Smerling C, Burian A, Buchegger F, Reubi J C. Maecke H R. N-terminal modifications improve the receptor affinity and pharmacokinetics of radiolabeled peptidic gastrin-releasing peptide receptor antagonists: examples of 68Ga- and 64Cu-labeled peptides for PET imaging. J Nucl Med. 2014;

[0308] 55(10);l719-1725. Doi: 10.2967 / jn ed.114.141242. PubMed PMID: 25146125; famous M, Tamma M L, Goumi E, Waser B. Reubi J C. Maecke H R, Mansi R. PEG spacers of different length influence the biological profile of bombesin-based radiolabeled antagonists. Nucl Med Biol. 2014; 41(6):464-470. Doi: 10.1016tynucniedbio.2014.03.014. PubMed PMID:

[0309] 24780298; Mansi R, Abiraj K, Wang X, Tamma M L, Goumi E, Cescato R, Berndt S, Reubi J C, Maecke H R. Evaluation of three different families of bombesin receptor radioantagonists for targeted imaging and therapy of gastrin releasing peptide receptor (GRPR) positive tumors. J Med Cheni 2015; 58(2): 682-691. Doi: 10.1021 / jm5012066. PubMed PMID:

[0310] 25474596; Pan D, Xu Y P, Yang R H, W ang L, Chen F, Luo S, Y ang M. Y n Y. A new (68)Ga-labeled BBN peptide with a hydrophilic linker for GRPR- targeted tumor imaging. Amino Acids. 2014; 46(6): 1481-1489. Doi: 10.1007 / s00726-014~1718-y. PubMed PMID: 24633452: Stott Reynolds T J, Schehr R, Liu D. Xu J. Miao Y, Hoffman T I Rold T L, Lewis M R, Smith C J. Characterization and evaluation of DOTA-conjugated Bo nbesm / RGD- antagon sts for prostate cancer tumor imaging and therapy. Nud Med Biol. 2015; 42(2):99- 108. Doi: 10.1016 / j.nucmedbio.2014.10.002. PubMed PMID: 25459113.

[0311]

[0312] In certain embodiments, Y is a chelator (also called a “chelating agent”). The chelator can be used to radiolabel the composition with radioisotopes, such as for example to provide for any of imaging, diagnostics and therapeutic treatment. For example, the chelator Y may be radiolabeled with a radionuclide that is used for medical imaging, diagnosis and / or therapy of cancerous tumors, such as in the case of FAP positive malignancies.

[0313] In some embodiments, the chelator comprises, or is, a macrocycle. In some embodiments, the chelator comprises, oris, 2,2',2",2'"-(l,4,7,10-Tetraazacyclododecane-l,4,7,10-tetrayl)tetraacetic acid (DOTA) or l,4,7-triazacyclononane-l,4,7-triacetic acid (NOTA). In some embodiments, the chelator is l,4,7,10-Tetraazacyclododecane-7-acetamide -1,4,10-triacetic acid or 2,2',2"-(10-(2-ammo-2-oxoethyl)-l,4,7,10-tetraazacyclododecane-l,4,7-triyl)triacetic acid or (2,2',2"-(10-(2-amino-2-oxoethyl)-l,4,7,10-tetraazacyclododecane-l,4,7-triyl)triaethanoic acid) (lead specific chelator, or PSC). In some embodiments, the chelator comprises a macrocycle, e.g., a macrocycle comprising an O and / or a N, DOTA, NOTA, PSC, one or more amines, one or more ethers, one or more carboxylic acids, EDTA, DTP A, TETA, DO3A, PCTA, or desferrioxamine. In some embodiments, the chelator comprises a plurality of amines. In some embodiments, the chelator includes 4 or more N, 4 or more carboxylic acid groups, or a combination thereof. In some embodiments, the chelator does not comprise S. In some embodiments, the chelating agent comprises a ring. In some embodiments, the ring comprises an O and / or an N. In some embodiments, the chelator is a ring that includes 3 or more N, 3 or more carboxylic acid groups, or a combination thereof. In some embodiments, the chelator is poly dentate.

[0314] In some embodiments, the chelator comprises a cyclic chelating agent. Exemplary chelators include, but am not limited to, AAZT, BAT, BAT-TM, Crown, Cyclen, D02A, CB-DO2A, D03A, H3HP-DO3A, Oxo-DO3A, p-NH2-Bn-Oxo-DO3A. PSC, DOTA, DOTA- 3py, DOTA-PA. DOTA-GA, D0TA-4AMP, DOTA-2py, DOTA-lpy, p-SCN-Bn-DOTA. CHX-A"-EDTA, MeO-DOTA-NCS EDTA, DOTAMAP, DOT AGA, DOTAGA-anhydride, DOTMA, DOT ASA, DOT AM, DOTP, CB-Cyclam, TE2A, CB-TE2A, CB-TE2P, DM- TE2A, MM-TE2A, NOTA. NOTP, HEHA, HEHA-NCS, p-SCN-Bn-HEH, D TEA. CHX- A''-DTPA, p-NH2-Bn-CHX-A??-DTl\A p-SCN-DTPA, p-SCN-Bz-Mx-DITA. 1B4M-DTPA, p-SCN-Bnl B-DTPA, p-SCN~Bn- 1 B4M-D’ TP A. p-SCN-Bn-CHX-A"-DTPA, PEPA, p-SCN- Bn-PEP, TETPA, DOT A, DOTMP, DOTPM, t-Bu-calix[4]arene-tetracarboxylic acid, macropa, macropa-NCS, macropid, H?, L!. HsL4, Eb.azapa, Hsdecapa, bispa2, Hspypa,

[0315] I-koctapa, l-LCHXoctapa, p-SCN-Bn-f^octapa, p-SCN-Bn-I-hoctapa, TTHA, p-NOi-Bn- neunpa, Hroctox, H?.macropa, Hjbispa2, Ihphospa, Hsphospa, p-SCN-Bn-Hephospa, TETA, p- NO2-Bn-TETA. TRAP, TP A. HBED, SHBED, HBED-CC, (HBED-CC)TFP, DMS A, DMPS, DHLA, lipoic acid, TGA, BAL, Bis-thioseminarabazones, p-SCN-NO'HA nNOTA, NOD AGA, CB-TE1A1P, 3P-C-NETA-NCS, 3p-C-DEPA, 3P-C-DEPA-NCS, TCMC, PCTA, NODIA-Me, TACN, pycupl A1B, pycup2A, TUP, DEDPA, H2DEDP, p-SCN-Bn- HjDEDPA. p-SCN-Bn-TCMC, motexafin, NTA, NOC, 3p-C-NETA, p-NH3-Bn-TE3 A, SarAr, DiAmSar, SarAr-NCS, AmBaSar, BaBaSar, TACN-TM, CP256, C-NE3TA, C- NE3TA-NCS, NODASA, NETA-monoamide, C-NETA, NOPO, BPCA, p-SCN-Bn-DFO, DFO-ChX-Mal, DFO, DFO-IAC, DFO-BAC, DiP-LICAM, EC, SBAD. BAPEN, TACHPYR, NEC-SP, Lpy, LI, L2, L3, and EuK-106. In some embodiments, the metal chelator is DOTA. TRITA, TETA, DOTA Ad A, DO3A-HP, DOTMA, DOTA-pNB, DOTP, DOTMP, DOTEP, DOTMPE, F-DOTPME. DOTPP, DOTBzP, DOTA-monoamide, p-NCS- DOTA, p-NCS-P ADOTA, BAT, DO3TMP-Monoamide, p-NCS-TRITA, NOTA. or CHX- A” D PA. In some embodiments, the chelator can comprise an acyclic chelating agent.

[0316] Exemplary acyclic chelating agents include, but are not limited to, DTA, CyEDTA, EDTMP, DTPMP, DTPA, CyDTPA, Cy2DTPA, DTPA-MA, DTPA-BA, and BOP A. In some embodiments, the chelating agent can comprise DOTA, DOTP, DOTMA. DOT AM, DTPA, NTA. EDTA, D03A. D02A, NOC, NOTA, TETA, TACN, DiAmSar, CB-Cyclam, CB- TE2A, D0TA-4AMP. or NOTP. In some embodiments, the chelating agent can comprise Htpypa, H.ioctox, Haoctapa, p-NO2-Bn-neunpa, p-SCN-Bn-Hinempa, TTHA, ‘Buapypa-C?- NHS, Hmeunpa, H2macropa, HP-DO3A, BT-DO3A, DO3A-Nprop, DO3AP, DO2A2P, DO ASP. DOTP, DOTPMB, DOTAMAE, DOTAMAP, D03AM3, DOTMA. TCE-DOT, DEPA, PCTA, p-NOz-Bn-PCTA, p-NCh-Bn-DOIA, symPC2APA, symPCA2PA, asymPC2APA, asymPCA2PA, TRAP, AAZTA, DATAm, THP, HEHA. or HBED.

[0317] In some embodiments, the chelator can comprise the following structure:

[0318] R2

[0319] Ao

[0320]

[0321] wherein R2 is -ORi, -NH2 or a bond connecting the chelator to the linker, L (or connecting to the binding peptide, in a case where L is a bond), where each Ri is independently hydrogen or an alkyl group, R4 and R5 are independently hydrogen or a bond connecting the chelator to the linker, L (or connecting to the binding peptide, in a case where L is a bond), provided (i) at least one of R4 and R5 is hydrogen, and (ii) each of R4 and R5 is hydrogen when at least one R2 is a bond connecting the chelator, to the linker, L (or connecting to the binding peptide, in a case where L is a bond). In a case where the chelator is DOTA, at least 3 of the R2 groups are -OH, and all 4 of the R2 groups may be -OH in a case where connection to the rest of the conjugate is through R4 or R5. In a case where the chelator is a lead specific chelator PSC, one of the R2 groups is -NH2. In a case where the chelator is DOTAM or TCMC, at least 3 of the R2 groups are -NH2, and all 4 of the R2 groups may be -NH2 in a case where connection to the rest of the conjugate is through R4 or R5.

[0322] For example, in some embodiments, the chelator can comprise a lead specific chelator having the following structure:

[0323]

[0324] OR!

[0325] where each Ri is independently hydrogen or an alkyl group,

[0326] R.2 is -ORi, -NH2 or a bond connecting the lead specific chelator to the linker, L (or connecting to the binding peptide, in a case where L is a bond),

[0327] R3 and R4 are independently hydrogen or a bond connecting the lead specific chelator to the linker, L (or connecting to the binding peptide, in a case where L is a bond), provided (i) at least one of R3 and Rus hydrogen, and (ii) each of R3 and R s hydrogen when R2 is a bond connecting the lead specific chelator, to the linker, L (or connecting to the binding peptide, in a case where L is a bond). According to certain embodiments, Ri, R3 and R4 are hydrogen, and R2 is a bond connecting the lead specific chelator to the linker, L (or connecting to the binding peptide, in a case where L is a bond).

[0328] As another example, in some embodiments, the chelator can comprise a NOTA chelator having the following structure:

[0329]

[0330] where each Ri is independently hydrogen or an alkyl group,

[0331] R2 is -ORi, -NH2 or a bond connecting the NOTA chelator to the linker, L (or connecting to the binding peptide, in a case where L is a bond), R3 and R4 are independently hydrogen or a bond connecting the NOTA chelator to the linker, L (or connecting to the binding peptide, in a case where L is a bond), provided (i) at least one of Rs and R s hydrogen, and (ii) each of R3 and R4 is hydrogen when R2 is a bond connecting the NOTA chelator, to the linker, L (or connecting to the binding peptide, in a case where L is a bond). According to certain embodiments, Ri, Rs and R4 are hydrogen, and R2 is a bond connecting the NOTA chelator to the linker, L (or connecting to the binding peptide, in a case where L is a bond).

[0332] In some embodiments, die chelating agent comprises DOTA, NOTA or PSC. In some embodiments, the chelating agent comprises a DOTA or PSC derivative such as p-SCN-Bn- DO A, or p-SCN-Bn-PSC. The structures of some exemplar}' metal chelators are illustrated in Figures 64 through 96.

[0333] Radionuclides

[0334] According to certain embodiments, the conjugate described herein comprises a chelator that chelates a radionuclide, and which may be a radionuclide that provides a therapeutic effect, and / or that is useful for imaging and / or diagnosis. In some embodiments, the radionuclide comprises an alpha particle-emitting radionuclide. In other embodiments, the radionuclide comprises a beta particle emitting radionuclide. In other embodiments, the radionuclide comprises a gamma ray emitting radionuclide.

[0335] In some embodiments, the radionuclide is a therapeutic radionuclide selected from the group consisting of212Pb,67Cu,64Cu,89Zr,90Y,109Pd,niAg,149Pm,153Sm,166Ho, "mTc,67Ga,68Ga,mIn,90Y,177Lu,186Re,188Re,197Au,198Au,199Au,105Rh,165Ho,161Tb,149Pm,44Sc,47Sc,70As,71As,72As,73As,74As,76As,77As,212Pb,212Bi,213Bi,225Ac,117mSn,67Ga,2O1T1,123I,1311,160Gd,148Nd,89Sr, and211At. In some embodiments, radionuclide is selected from the group consisting of diagnostic radionuclides43Sc,44Sc,51Mn,64Cu,67Ga,68Ga,86Y,89Zr, "mTc,18F,76B,77Br,niIn,123I,1241,125I,152Tb, and203Pb. In certain embodiments, the radionuclide is selected from the group consisting of therapeutic radionuclides47Sc,67Cu,89Sr,90Y,131I,153Sm,149Tb,161Tb,177Lu,186Re,188Re,211At,212Pb,212BI,223Ra,224Ra,225Ac,226Th, and227Th. In certain embodiments, the radionuclide is In-111. Pb-203; Cu-64, Ga-68, Zr-89, or other medical radionuclide used for imaging. The radionuclide for imaging may be Ga-68.

[0336] In certain embodiments, the radionuclide is Cu-67, ¥-90, Pb-212, Bi -212, Bi-213, At- 211. Ac-225, Lu-177 or other medical radionuclide used to treat the cancerous tumors. The radionuclide for treating cancerous tumors may be Pb-212.

[0337] In one embodiment, the radionuclide may be a lead radionuclide that is any selected from the group consisting of Pb-196, Pb-197, Pb-198, Pb-199, Pb-200, Pb-201, Pb-202, Pb-203, Pb-205, Pb-209, Pb-210, Pb- 211, Pb-212, Pb-213, Pb-214, Pb-215, and Pb-216.

[0338] According to certain embodiments, the lead radionuclide that is conjugated by the lead specific chelating moiety comprises any of Pb-203 or Pb-212. Pb-203 emits y-photons through electron capture, allowing detection with single-photon emission computed tomography (SPECT) for diagnostic imaging, whereas Pb-212 decays by emiting P'-particles and a-particles suitable for delivering therapeutic doses of radiation to cancer cells.

[0339] Cytotoxic Drugs and Conjugates Comprising Non-Radioactive Drugs

[0340] In certain embodiments, Y is a cytotoxic drug pas load which is conjugated to the FAP-targeted binding peptide via L to form a peptide drug conjugate. In certain embodiments, the peptide drug conjugate delivers cytotoxic drug payload as prodrug. In certain embodiments, a cytotoxic drug payload is conjugated to the binding peptide through a clea able linker. In certain embodiments, a cleavable linker can be ester, amide, carbamate, dipeptide, tripeptide, hydrazone, or disulfide as following structures:

[0341]

[0342] In certain embodiments, a cytotoxic drug payload is released as free drug upon cleavage of the linker. In certain embodiments, a cytotoxic drug payload is conjugated to the binding peptide via anon-cleavable linker.

[0343] In certain embodiments, the cytotoxic drug payload can be paclitaxel, govitecan, auristatins, epothilone, maytansinoids, taxoids, tubulysins, vinorelbine, mertansine (DM1), monomethyl auristatm E (MMAE), docetaxel, doxorubicin, ihapstgargtn, melphalan, 5- fluorouracil, calicheamicins, duocarmycin analogs, pyrrolobenzodiazepine, topotecan, bleomycin A2, dactinomycin, and / or mitomycin C.

[0344] Albumin Binding

[0345] In certain embodiments, an albumin- inding moiety7is conjugated to the FAP -targeted binding peptide, such as via a linker L, or via Rs, M, or Rs, to extend the biological half-life in circulation and to enhance the accumulation in tumor.

[0346] In certain embodiments, an albumin-binding moiety can benaphthalene-2-sulfonamide derivatives, Evans Blue derivatives, 4-(p~lodophenyi)butyric acid derivatives, palmitic acid derivatives, and maleimide derivatives. Pharmaceutical Formulation

[0347] The radiolabeled conjugates / radiopharmaceutical compounds described herein can be administered in a radiopharmaceutical formulation suitable for delivery to a subject, such as for example via intravenous, intramuscular, topical or subcutaneous administration, and may be in form of an aqueous solution (e.g. saline solution) containing the radiolabeled conjugate in a concentration sufficient for one or more of diagnostic and therapeutic purposes, as well as optional radioprotectants and / or oxidants, buffers, etc. The radiolabeled conjugate may be prepared in phosphate-buffered saline (PBS) with or without radioprotectants including any one or more of ascorbic acid, sodium acetate, gentisic acid, and ethanol, at concentrations that are suitable for human or animal use.

[0348] According to certain embodiments, the conjugate may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the conjugate or its salts can be prepared in water, isotonic saline, phosphate-buffered saline, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. In certain embodiments, the final solution contains ethanol from 0 to 20% v / v. In certain embodiments, the final pH of the solution is 2-9. In certain embodiments, the conjugate is administered with additional amino acids to reduce the uptake of radioactive compound in kidneys. In certain embodiments, the amino acids are lysine and arginine. According to certain embodiments, a preparation containing the conjugate contains a preservative excipient to prevent the growth of microorganisms.

[0349] According to one embodiment, a formulation of the conjugate described herein may be provided in lyophilized form, such as for example for storage of the conjugate prior to labelling and administration. For example, an aqueous solution of the conjugate may be prepared with additional formulation components such as buffers, radioprotectants, or other excipients, and the solution may be lyophilized (freeze dried) to provide for storage of the conjugate formulation. According to certain embodiments, the lyophilized formulation can be stored under vacuum or in an inert atmosphere. The lyophilized formulation can be reconstituted prior to administration, such as for example by combining with a sterile aqueous solution, to form a liquid composition. According to certain embodiments, an aqueous solution provided to reconstitute the lyophilized formulation may also optionally include components, such as any of buffers, radioprotectants, or other components to stabilize the composition, and / or to improve administration. According to certain embodiments, the reconstituted formulation can be combined with a radionuclide selected to provide therapeutic treatment and / or to provide for diagnosis / imaging of tissues have elevated FAP expression. The radionuclide is chelated by the chelator of the conjugate, to provide the radiolabeled conjugate for administration to a subject. The formulations may also comprise a radioprotectant, such as sodium ascorbate.

[0350] According to certain embodiments, pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the conjugate which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0351] According to certain embodiments, sterile injectable solutions are prepared by incorporating the conjugate in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques (lyophilization), which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions. According to certain embodiments, for topical administration, the conjugates may be applied in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.

[0352] According to certain embodiments, useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol / glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non¬ toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers. According to certain embodiments, thickeners such as synthetic polymers, fatty acids, fatty acid sails and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.

[0353] The dosage of the conjugates may vary depending on age, weight, and condition of the subject. Treatment may be initiated with small dosages containing less than optimal doses, and increased until a desired, or even an optimal effect under the circumstances, is reached. According to certain embodiments, the dosage may be about 450-600 mg / kg / day in patients weighing less than 20 kg, or 9.9-13.0 g / m2 / day in larger patients. Higher or lower doses, however, are also contemplated and are, therefore, within the confines of this invention. A medical practitioner may prescribe a small dose and observe the effect on the subject's symptoms. Thereafter, they may increase the dose if suitable. In general, the conjugates may be administered at a concentration that affords effective results without causing any unduly harmful or deleterious side effects, and may be administered either as a single unit dose, or if desired in convenient subunits administered at suitable times.

[0354] According to certain aspects, a pharmaceutical composition is formulated to be compatible with its intended route of administration. For example, the conjugate may be introduced directly into the cancer of interest via direct injection. Additionally, examples of routes of administration include oral, parenteral, e.g., intravenous, slow infusion, intradermal, subcutaneous, oral (e.g., ingestion or inhalation), transdermal (topical), transmucosal, and rectal administration. Such compositions can comprise the conjugate and a pharmaceutically acceptable carrier. As used herein, “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and anti-fungal agents. isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration, and a dietary food-based form. The use of such media and agents for pharmaceutically active substances is well known in the art and food as a vehicle for administration is well known in the art.

[0355] According to certain embodiments, solutions or suspensions can include the following components: a sterile diluent such as water for injection, saline solution (e.g., phosphate buffered saline (PBS)), fixed oils, a polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), glycerine, or other synthetic solvents; antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like; antioxidants such as ascorbic acid, gentisic acid, sodium bisulfite; chelating agents such as EDTA, DTP A, DMSA, DMPS; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it is preferable to include isotonic agents, for example, sugars, poly alcohols such as mannitol or sorbitol, and sodium chloride in the composition. Prolonged administration of the injectable compositions can be brought about by including an agent that delays absorption. Such agents include, for example, aluminum monostearate and gelatin. The parenteral preparation can be enclosed in ampules, disposable syringes, or multiple dose vials made of glass or plastic.

[0356] According to certain aspects, it may be advantageous to formulate compositions in dosage unit form for ease of administration and uniformity' of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for an individual to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The dosage unit forms of the invention are dependent upon the amount of a compound necessary’ to produce the desired effect(s). The amount of a compound necessary can be formulated in a single dose, or can be formulated in multiple dosage units. Treatment may require a one-time dose, or may require repeated doses. Diagnostic and Therapeutic Uses

[0357] Embodiments of the present disclosure provide methods of targeting a fibroblast activation protein alpha (FAP) comprising administering a radiolabeled compound comprising the fibroblast activation protein alpha (FAP)-targeted conjugate as discussed above.

[0358] Embodiments of the present disclosure further provide methods of imaging and / or diagnosing a subject having a disorder that is a result of or associated with upregulated FAP expression, the method comprising administering to the subject a radiolabeled compound comprising the fibroblast activation protein alpha (FAP)-targeted conjugate discussed above, and imaging the subject. Thus, aspects of the present disclosure provide methods for imaging or diagnosing a cancer or tumor in a subject in need thereof, by administering a radiopharmaceutical comprising a radiolabeled conjugate described herein to the subject, and imaging tissue having the radiolabeled conjugate bound thereto. That is, when the radiolabeled conjugate is labeled with radioisotope that is suitable for imaging purposes, the conjugate can be administered to a subject and will accumulate at target sites for which the binding moiety is selective. Imaging techniques such as single photon emission computed tomography (SPECT) imaging or positron emission tomography (PET) imaging can be performed to view the accumulation of the radiolabeled conjugate at target sites, which may be indicative of a location of cancerous cells, such as cancerous cells overexpressing FAP.

[0359] According to certain aspects,203Pb (Pb-203) may be suitable for imaging processes such as SPECT, to provide for imaging and diagnosing of the presence or extent of cancer and / or tumors in a subject.

[0360] Furthermore, according to certain embodiments, a method of treating a sub ject having a disorder that is a result of or associated with upregulated FAP expression can be provided in a subject in need thereof, the method comprising administering to the subject a radiolabeled compound comprising the fibroblast activation protein alpha (FAP)-targeted conjugate discussed above. The disorder may be selected from the group consisting of a wound healing disorder, fibrosis, arthritis, atherosclerotic plaques, autoimmune diseases, metabolic diseases, and ischemic heart tissue after myocardial infarction. Thus, the present disclosure provides methods of treatment of cancer in need thereof, by administering a radiopharmaceutical comprising a radiolabeled conjugate described herein to the subject, in therapeutically effective amounts that are sufficient to treat the subject. That is, when the radiolabeled conjugate is labeled with a radioisotope that is suitable for treatment purposes, the conjugate can be administered to a subject and will accumulate at target sites for which the binding moiety is selective, and which may be indicative of a location of cancerous cells, such as cancerous cells overexpressing FAP, or stroma cells. The radiation emitted by the radiolabeled conjugate bound to the target site may provide a cell killing effect that is selective for the target cells, thereby providing treatment. According to certain embodiments, the cancer is associated with FAP overexpression in the subject.

[0361] The cancer may be selected from the group consisting of a gastric cancer, brain cancer, myeloma, melanoma, sarcoma, salivary gland cancer, esophageal cancer, cholangiocarcinoma. breast cancer, lung cancer, prostate cancer, pancreatic cancer, thymus cancer, head and neck cancer, ovarian cancer, desmoid tumor, chordoma, colorectal cancer, anal cancer, neuroendocrine tumor, small intestine cancer, medullary thyroid cancer, cervical cancer, endometrial cancer, hepatocellular cancer, gastric cancer, adenoid cystic cancer, pheochromocytoma, differentiated thyroid cancer, insulinoma, kidney cancer, and skin cancer.

[0362] In certain embodiments, the conjugate is administered intravenously or parenterally. In certain embodiments, the conjugate is administered in a single dose. In certain embodiments, the conjugate is administered in multiple doses. In certain embodiments, the conjugate is administered sequentially daily for several days. In certain embodiments, the conjugate is administered once per week for 1 month. In certain embodiments, the conjugate is administered once per week for up to 6 months.

[0363] In certain embodiments, the conjugate is administered in a dose of 1 mCi for medical imaging. In certain embodiments, the conjugate is administered in a dose of up to 10 mCi for medical imaging. In certain embodiments, the conjugate is administered in a dose of up to 50 mCi for medical imaging. In certain embodiments, the conjugate is administered in a dose of 0.1 mCi for medical treatment of the cancerous tumors In certain embodiments, the conjugate is administered in a dose of up to 5 mCi for medical treatment of the cancerous tumors. In certain embodiments, the conjugate is administered in a dose of up to 10 mCi for medical treatment of the cancerous tumors. In certain embodiments, the conjugate is administered in a dose of up to 100 mCi for medical treatment of the cancerous tumors. In certain embodiments, the conjugate is administered in a dose of up to 200 mCi for medical treatment of the cancerous tumors. In certain embodiments, the conjugate is administered for more than a month. In certain embodiments, the conjugate is administered for more than a year. In certain embodiments, the conjugate is administered at a dosage of at least 1500 mg / day.

[0364] According to certain embodiments, the conjugate can be administered simultaneously with the one or more anti-cancer agents, or the conjugate and the one or more anti-cancer agents are administered sequentially, or administration of the one or more anti-cancer agents begins about 1 to about 10 days before administration of the conjugate, or administration of the conjugate thereof begins about 1 to about 10 days before admini strati on of the one or more a ti -cancer agents, or administration of conjugate and administration of the one or more anti- cancer agents begins on the same day.

[0365] According to certain embodiments, a method of treating a cell that has upregulated FAP expression as compared to a comparable wildtype cell is provided, that comprises contacting the cell with a peptide or with the conjugate described above, such as via administration to a subject having cells with upregulated FAP expression. In certain embodiments, the upregulation is a result of cancer. In certain embodiments, the upregulation is a result of or associ ated with a carcinoma. In certain embodiments, the upregulation is a result of or associated with a gastric cancer, brain cancer, myeloma, melanoma, sarcoma, salivary gland cancer, esophageal cancer, cholangiocarcinoma, breast cancer, lung cancer, prostate cancer, pancreatic cancer, thy mus cancer, head and neck cancer, ovarian cancer, desmoid tumor, chordoma, colorectal cancer, anal cancer, neuroendocrine tumor, small intestine cancer, medullary thyroid cancer, cervical cancer, endometrial cancer, hepatocellular cancer, gastric cancer, adenoid cystic cancer, pheochromocytoma, differentiated thyroid cancer, insulinoma, kidney cancer, skin cancer. Accordingly, in certain embodiments, the peptide or conjugate can be administered to the subject to provide for treatment of such cancers and / or carcinomas. In certain embodiments, the upregulation is a result of or associated with another disorder. For example, the upregulation may be a result of or associated with any of wound healing, fibrosis, arthritis, atherosclerotic plaques, autoimmune diseases, metabolic diseases, and ischemic heart tissue after myocardial infarction Accordingly, in certain embodiments, the peptide or conjugate can be administered to the subject to provide for treatment of such disorders.

[0366] Combination

[0367]

[0368] Aspects of present invention provides, in certain embodiments, a method of treating cancer in a patient in need thereof, comprising administering the conjugate described above. In certain embodiments, the cancer is FAP positive cancer or malignancy. In certain embodiments, the cancer is a solid tumor. Examples of FAP positive cancers or malignancies can include, but are not limited to, gastric cancer, brain cancer, myeloma, melanoma, sarcoma, salivary gland cancer, esophageal cancer, cholangiocarcinoma, breast cancer, lung cancer, prostate cancer, pancreatic cancer, thymus cancer, head and neck cancer, ovarian cancer, desmoid tumor, chordoma, colorectal cancer, anal cancer, neuroendocrine tumor, small intestine cancer, medullary' thyroid cancer, cervical cancer, endometrial cancer, hepatocellular cancer, gastric cancer, adenoid cystic cancer, pheochromocytoma. differentiated thyroid cancer, insulinoma, kidney cancer, skin cancer.

[0369] In certain embodiments, the method further comprises administering an anti-cancer composition. In certain embodiments, the anti-cancer composition comprises, but is not limited to, phenyl butyric acid (PBA) or a pharmaceutically acceptable salt thereof, chloroquine, hydroxychloroquine (laquenil, Axemal (in India), Dolquine and Quensyl, or a pharmaceutical drug that is an antimalarial or inhibits interactions between lysosomes and autophagasomes that overcome resistance that is linked to autophagy; derivative of triphenylphosphonium (TPP). PBA, a histone deacetylation inhibitor, a MAPK pathway inhibitor, such as a MEK inhibitor, a R. AS inhibitor, and / or RAF inhibitor.

[0370] In certain embodiments, an immunotherapy targeting regulator protein of the immune system is administered with the radiolabeled conjugate. In certain embodiments, the immunotherapy includes anti-CTLA-4 antibodies, anti-PDL1 antibodies, anti-PD1 antibodies, Toll-like receptor (TLR) agonist, CD40 agonist, and / or anti-ganglioside antibodies. In certain embodiments, the immuno therapy includes CTLA-4, PDL1 and PDl inhibitors.

[0371] In certain embodiments, a radiosensitizing agent is further administered, to enhance the tumor-killing efficacy. In certain embodiments, the radiosensitizing agent includes hyperbaric oxygen, carbogen, nicotinamide, metronidazole. mitomycin-C, tirapazamine, procaine, lidocaine, chlorpromazine, 5 ’fluorouracil, fluorodeoxyuridine, bromodeoxyuridine, iododeoxyuridine, hydroxyurea, gemcitabine, fludarabine, motexafin, gadolinium, N- ethylmalemide, diamide, diethjylmaleate, hyperthermia, paclitaxel, docetaxel, irinotecan) In certain embodiments, a DNA damage repair inhibitor is further administered to enhance the tumor-killing efficacy. In some embodiments, the DNA damage repair inhibitor includes PARP inhibitor, ATR inhibitor, CHK inhibitor, WEE1 inhibitor; ATM inhibitor, HD AC inhibitor.

[0372] Preparation of

[0373]

[0374] An exemplary embodiment of a binding peptide synthesis and creation of the conjugate is provided herein, for purposes of illustration.

[0375] Stage 1: Solid Phase Peptide Synthesis

[0376] The linear peptide was synthesized on Rink amide resin by Fmoc-based chemistry using an automated peptide synthesizer. After swelling of the resin, the sequence was assembled from the C- to N-terminus by repetitive cycles of 1. Fmoc-removal by treatment with 20% piperidine / N-methylpiperidine (NMP) to liberate the amine and 2. Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium (HATU)Zbase-mediated coupling of the appropriate Fmoc-protected building block in dimethylformamide (DMF) (3 equivalents). All steps were performed at room temperature under nitrogen atmosphere. After coupling of the PEG-linker, the (final) N-terminal Fmoc-group was removed and the resin was washed with alternating dichloromethane and methanol followed by drying in vacuo.

[0377] Stage 2: Cleavage from the resin and side-chain deprotection

[0378] The peptide was detached from the resin with simultaneous removal of the side chain protecting groups by treatment of the peptide-loaded resin with trifluoroacetic acid (TFA) in the presence of suitable scavengers. The crude peptide was precipitated by addition of pre-cooled diethyl ether / pentane (1:1, v / v). The suspension was centrifuged, the supernatant removed and the pellet was washed once with ether / pentane (1:1, v / v). After centrifugation and decanting the liquids, the pellet was air dried. Finally, the crude peptide was dissolved in a mixture of acetic acid / water (1:4, v / v) and lyophilized (room temperature, vacuum < 0.700 mbar, >48 h). A sample was taken to confirm the sequence by high-resolution mass spectrometry (HR-MS) / mass spectrometry (MS).

[0379] Stage 3: cyclization-reaction

[0380] The crude peptide was cyclized by introduction of a cyclization group, such as 1, 2-bis(bromomethyl)benzene, between the two cysteines in the peptide. The reaction with a,a’-dibromo-o-xylene was performed in aqueous conditions in the presence of base. The course of the reaction was monitored by ultra-high performance liquid chromatography-ultraviolet (UPLC-UV215nm) / Electrospray ionization mass spectrometry (ESI-MS) analysis.

[0381] The crude cyclized-peptide was purified by reversed-phase high performance liquid chromatograph (HPLC) (Cis-column; gradient of 0.05% TFA / acetonitrile (ACN) in 0.05% TFA / water; UV detection at 215 nm).

[0382] Stage 4: DO2A-NHS preparation, coupling to the cyclized-peptide and purification DO2AtBu-monoamide monoacid was converted to its N-Hydroxysuccinimide (NHS) -ester using / V, / V’-Disuccinimidyl carbonate (DSC) in the presence of base. The tert-buty l groups on the DO2AtBu-NHS were removed by treatment with aqueous TFA. After removal of the TFA; the crude DO2A-NHS ester was on a small-scale reacted with the cyclized-peptide in the presence of base to confirm the performance of the active ester and to establish the ratio of active ester versus cyclized-peptide. Next, the reaction was performed on the desired scale. Crude product was purified by reversed-phase HPLC (Cis-column; gradient of 0.15% Acetic acid / ACN in 0.15% Acetic acid / water; UV detection at 215 nm). Fractions containing the peptide with the correct identity and meeting the purity defined in the specifications were lyophilized. Stage 5: Combining fractions and ali quoting

[0383] The dried conjugate product fractions were combined and the total amount was determined by weighing. The peptide was dissolved in (ACN / water (1:1, v / v), aliquoted into 250 mg portions in 25 mL amber glass bottles with screw cap and lyophilized.

[0384] The following examples are intended to further illustrate the invention. They are not intended to limit the invention in any manner.

[0385] EXAMPLE 1

[0386]

[0387] An enzyme inhibition assay was performed to determine IC50 values and then the Cheng-Prusoff equation used to calculate the Ki given a known Kmof the substrate Z-GP-AMC for FAP. To perform the assay, FAP (5ng / well) and the test peptide at varying concentrations (i.e.

[0388] 10-6to 10-12) were incubated in a black 96-well plate for 10 minutes at RT on a shaker plate. Then, the substrate Z-GP-AMC was added to give a final concentration of 50pM. The total reaction volume per well was 100µL. The reaction was allowed to incubate at RT on a shaker plate for 1 hour protected from light, and then fluorescence read with a BioTek Synergy LX plate reader at an ex / em (360 / 40 and 460 / 40). Experiments were performed in at least duplicate, and controls of buffer only, buffer and FAP enzyme, and buffer with substrate and FAP enzyme only were included for comparison. The buffer used for the assay was 50mM Tris-HCl, IM NaCl, and Img / mL BSA, pH=7.5. Data was plotted in GraphPad Prism and non-linear regression used to calculate IC50 values. The compounds tested and Ki values of each w'ere as follows:

[0389] Compound Compound sequence Ki (nM)

[0390] VMT-FAP-2-12 Ac-S[C(oXdB)TPFEQWWC]-NH2 (SEQ ID 0.55

[0391] NO: 1)

[0392] VMT-FAP-2-19 A[C(oXdB)TPFEQWWC]-NH2 (SEQ ID NO: 2) 0.45

[0393]

[0394] VMT-FAP-2-23 S[C(oXdB)TPFEAWWC]-NH2 (SEQ ID NO: 3) 0.29

[0395] VMT-FAP-1-1 Ac-G[C(oXdB)TPFEQWWC]-NH2 (SEQ ID: 10.45 i NO: 4)

[0396] VMT-FAP-1-13 Ac-R| C(oXdB (I PI l-QW WC | -NH2 (SEQ ID 2.82

[0397] NO: 5)

[0398] i VMT-FAP-1-14 Ac-D|0(oXdB)Tl’lEQ\\ \\('|-\H2 (SEQ ID; 0.36

[0399] NO: 6)

[0400] VMT-FAP-I-I7 Ac-N|C(oXdB) I PI I: QV\ \\ ( |-NI 12 (Si: Q ID: 10.72

[0401] NO: 7)

[0402] \AH-I AP-l-62 AcA|(’(o. XdB)TP\VEQ\V\\ C|-\II2 (SEQ ID FO46

[0403] | NO: 8)

[0404] i VMT-FAP-1-64 Ac-N|( (o. XdB) rPHUQW \V( I-NH2 (SI^Q ID UO.72

[0405] | NO: 9)

[0406] : VMT-FAP-1-94 Ac-S| ( (oXdB) I PI i: I\\ \\ ( |-NH2 (SEQ ID NO: 5.61

[0407] | Ki)

[0408] : VMT-FAP-1-101: Ac-S[C(oXdB)TPFEHWWC]-NH2 (SEQ ID 11.24

[0409] NO: 11)

[0410] : VMT-FAP-1-104 Ac-S[C(oXdB)TPFEDWWC]-NH2 (SEQ ID: 1.83

[0411] NO: 12)

[0412] i VMT-FAP-1-105 Ac-S[C(oXdB)TPFEEWWC]-^ (SEQ ID: 6.38 i NO: 13)

[0413] VMT-FAP-2-26 Ac-S-[C(oXdB)TPFEQWWC]-Lys(NH2)-PEG2- 0.38

[0414] PSC (SEQ ID NO: 14)

[0415] VMT-FAP-2-28 Ac-S|C(o. XdB) I PFFQW YC|-\H2 (SEQ ID NO:: 2.29

[0416] !5) j VMf-FAP-2-29 Ac-S| C(oXdB) I PI liQYW C |-M 12 (SEQ ID NO:: 13.55

[0417] H6)

[0418]

[0419] VMT-FAP-2-30 PSC-PEG2-S-[C(oXdB)TPFEQWWC]-NH2 0.04

[0420] (SEQ ID NO: 17) i VMT-FAP-2-33 Ac-S-|Dap(bGlu(F-PFG2-: 1.26

[0421] PSC))TPFEQWWDap]-NH2 (SEQ ID NO: 18) VMT-FAP-2-36 PSC-P1: G2-|( (oXdB) I PI'liQWW ( |-NH2 (SliQ Hl76 I ID NO: 19) i VMT-FAP-2-39: PSC-PEG2-F-S-[C(oXdB)TPFEQWWC]-NH2 0.67

[0422] | (SEQ ID NO: 20): VMT-FAP-2-40 Ac-[C(oXdB)TPFEQWWC]-NH2 (SEQ ID NO: H.27

[0423] 21 ) VMT-FAP-2-41 l,SC-PFG2-D-|C(oXdB)lPFEQ\W\ C|-\H2 Hl 19

[0424] (SEQ ID NO: 22): VMT-FAP-2-42: PSC-PFCi2-S-|(’(oXdB)TP\\ FQ\\'n 0.29

[0425] (SEQ ID NO: 23): VMT-FAP-2-43: PSC-PEG2-S-[C(oXdB) fPFEEWWC]-NH2 Hl 07

[0426] | (SEQ ID NO: 24) i VMT-FAP-2-48 PSC-PEG2-S-[C(mXdB)TPWEQ^W 0.35 i (SEQ ID NO: 25) VMT-FAP-2-51 Ac-|( (niXlB(( A-PLG2-PS( ))TP\VLQ\VWC|-; 6.28

[0427] NH2 (SEQ ID NO: 26) VMT-FAP-2-53 PSC-PEG2-S|C(oXdB)TP2-NalEQ\VWC|-NH2: 0.34

[0428] (SEQ ID NO: 27) rVMT4FAP-2-55 Ac-S-|C(mXtB(CA-Pi: G2- H. I2 j PSC))TPWEQWWC]-NH2 (SEQ ID NO: 28) \AH-I AP-2-57 But-|( (inXtB(C \-Pl: G2-PS(')l I PW 1: Q\\ \\ ( |- H171 |

[0429] NH2 (SEQ ID NO: 29)

[0430]

[0431] VMT-FAP-2-59 PSC-PEG2-[C(oXdB)TPWEQWWC]-NH2 0.36

[0432] (SEQ ID NO: 30) i VMT-FAP-2-60 PSC-PEG2-S-[C(oXdB) TP l-\alFQ\\ \VC|-XH2: 0.48

[0433] (SEQ ID NO: 31)

[0434]

[0435] \AH-IAP-2-6l p(S-PlXi2-S-|( (oXdBirPBtai: Q\V\\('|-MI2 | 0.30 I (SEQ ID NO: 32) i VMT-FAP-2-62: PCS-PEG2-S-[C(oXdB)TP3-PalEQWWC]-NH2 0.61

[0436] | (SEQ ID NO: 33): VMT-FAP-2-67: PSC-PEGl-[C(oXdB)TPWEQWWC]-NH2: 0.08

[0437] | (SEQ ID NO: 34): VMT-FAP-2-68 PSC-PEG3-|C(oXdB) 1PW EQ\\ \\ C|-\H2 0.64

[0438] (SEQ ID NO: 35): VMT-FAP-2-69: PSC-PEG4-|( (oXdBjTPWTQW \\;C|-\H2 A. OI (SEQ ID NO: 36): VMT-FAP-2-70: PS( -6x\[ IA-|('(oXdB) I I3\\i ()\\ \^ 0.64

[0439] | (SEQ ID NO: 37) i VMT-FAP-2-72 PSC-Bn-NCS-PEGl-[C(oXdB)TPWEQ\WCL 0.79

[0440] NH2 (SEQ ID NO: 38) VMT-FAP-2-73 PSC-Bn-XCS-PLG2-|C(oXdB)l P\\ LQW \VC ]- 3.61

[0441] NH2 (SEQ ID NO: 39) VMT-FAP-2-74 PSC-l2-Ado-|C(oXdB)TPWEQWWC|-NH2: 6.66

[0442] (SEQ ID NO: 40)

[0443]

[0444] PvMT^AP-2-75 PS( AAIIA-|( (oXdB)rP\Vi: Q\V\V( |-('OOII H.26 j (SEQ ID NO: 41)

[0445] \AH-I AP-2-76 PS( -Pi: G2-|( (oXdB)rP\Vi: Q\\ \V( |-COOH I 31.37 I (SEQ ID NO: 42)

[0446]

[0447] VMT-FAP-2-77 NODA-PEG2-[C(oXdB)TPWEQWWC]-NH2 0.17

[0448] (SEQ ID NO: 43)

[0449] VMT-FAP-2-78 NOTA-PEG2-[C(oXdB)TPWEQWWC]-NH2 0.01

[0450] (SEQ ID NO: 44)

[0451] VMT-FAP-2-82 2.68

[0452] (SEQ ID NO: 45)

[0453] VMT-FAP-2-83 PSC-PEG2-[C(mXdB)TPWEQWWC]-NH2 0.54

[0454] (SEQ ID NO: 46)

[0455] VMT-FAP-2-84 PSC-PEG2-[C(oXdB)WWQEWPTC] S-NH2 115

[0456] (SEQ ID NO: 47)

[0457] (reverse sequence)

[0458] VMT-FAP-2-85 NOTA-bn-NCS- PEG2- 2.84

[0459] [C(oXdB)TPWEQWWC]-NH2 (SEQ ID NO:

[0460] 48)

[0461] Abbreviations: oXdB: residue of 1, 2-bis(bromomethyl)benzene; mXdB: 1, 3- bis(bromomethyl)benzene; mXtB: 1, 3, 5-Tris(bromomethyl) benzene; 6-AHA - 6-amino hexanoic acid; Bn-NCS - Benzyl-isothiocyanate; 12-ado - 12-amino-dodecanoic acid; PEG- amino-polyethylene glycol-acid; CA: cysteamine; bGlu - beta-glutamic acid; Dap: 2,3- diaminopropionic acid; Ac: acetic acid; But: butryric acid

[0462]

[0463] The structures of certain exemplary binding peptide sequences and conjugates are provided below. VMT-FAP-2-30 (PSC-PEG2-S-[C(oXdB)TPFEQWWC]-NH2)

[0464]

[0465] 5 VMT-FAP-2-36 (PSC-PEG2-[C(oXdB)TPFEQWWC]-NH2)

[0466]

[0467] VMT-FAP-2-26: Ac-S-[C(oXdB)TPFEQWWC]-Lys(NH2)-PEG2-PSC

[0468]

[0469] 5 VMT-FAP-2-39 (PSC-PEG2-F-S-[C(oXdB)TPFEQWWC]-NH2)

[0470]

[0471] VMT-FAP-2-42 (PSC-PEG2-S-[C(oXdB)TPWEQWWC]-NH2)

[0472]

[0473] VMT-FAP-2-43 (PSC-PEG2-S-[C(oXdB)TPFEEWWC]-NH2)

[0474]

[0475] VMT-FAP-2-82 (PSC-PEG2-[C(pXdB)TPWEQWWC]-NH2)

[0476]

[0477] VMT-FAP-2-83 (PSC-PEG2-[C(mXdB)TPWEQWWC]-NH2)

[0478]

[0479] VMT-FAP-2-84 (PSC-PEG2-[C(oXdB)WWQEWPTC]S-NH2)

[0480]

[0481] VMT-FAP-2-48 (PSC-PEG2-S-[C(mXdB)TPWEQWWC]-NH2)

[0482]

[0483] VMT-FAP-2-51 (Ac-[C(mXtB(CA-PEG2-PSC))TPWEQWWC]-NH2)

[0484]

[0485] VMT-FAP-2-53 (PSC-PEG2-S[C(oXdB)TP2-NalEQWWC]-NH2)

[0486]

[0487] VMT-FAP-2-55 (Ac-S-[C(mXtB(CA-PEG2-PSC))TPWEQWWC]-NH2)

[0488]

[0489] VMT-FAP-2-57 (But-[C(mXtB(CA-PEG2-PSC))TPWEQWWC]-NH2)

[0490]

[0491] VMT-FAP-2-59 (PSC-PEG2-[C(oXdB)TPWEQWWC]-NH2)

[0492]

[0493] VMT-FAP-2-60 (PSC-PEG2-S-[C(oXdB)TPl-NalEQWWC]-NH2)

[0494]

[0495] VMT-FAP-2-61 (PCS-PEG2-S-[C(oXdB)TPBtaEQWWC]-NH2)

[0496]

[0497] VMT-FAP-2-62 (PCS-PEG2-S-[C(oXdB)TP3-PalEQWWC]-NH2)

[0498]

[0499] VMT-FAP-2-67 (PSC-PEGl-[C(oXdB)TPWEQWWC]-NH2)

[0500]

[0501] VMT-FAP-2-68 (PSC-PEG3-[C(oXdB)TPWEQWWC]-NH2)

[0502]

[0503] VMT-FAP-2-69 (PSC-PEG4-[C(oXdB)TPWEQWWC]-NH2)

[0504]

[0505] VMT-FAP-2-70 (PSC-6AHA-[C(oXdB)TPWEQWWC]-NH2)

[0506]

[0507] VMT-FAP-2-72 (PSC-Bn-NCS-PEGl-[C(oXdB)TPWEQWWC]-NH2)

[0508]

[0509] VMT-FAP-2-75 (PSC-6AHA-[C(oXdB)TPWEQWWC]-COOH)

[0510]

[0511] VMT-FAP-2-76 (PSC-PEG2-[C(oXdB)TPWEQWWC]-COOH)

[0512]

[0513] VMT-FAP-2-77 (NODA-PEG2-[C(oXdB)TPWEQWWC]-NH2)

[0514]

[0515] VMT-FAP-2-78 (NOTA-PEG2-[C(oXdB)TPWEQWWC]-NH2)

[0516]

[0517] VMT-FAP-2-33 (Ac-S-[Dap(bGlu(F-PEG2-PSC))TPFEQWWDap]-NH2)

[0518] VMT-FAP-2-41 (PSC-PEG2-D-[C(oXdB)TPFEQWWC]-NH2)

[0519]

[0520] VMT-FAP-2-73 (PSC-Bn-NCS-PEG2-[C(oXdB)TPWEQWWC]-NH2)

[0521] VMT-FAP-2-74 (PSC-12-Ado-[C(oXdB)TPWEQWWC]-NH2)

[0522]

[0523] VMT-FAP-2-40 (Ac-[C(oXdB)TPFEQWWC]-NH2)

[0524] VMT-FAP-2-12 (Ac-S[C(oXdB)TPFEQWWC]-NH2)

[0525]

[0526] VMT-FAP-2-19 (A[C(oXdB)TPFEQWWC]-NH2)

[0527]

[0528] VMT-FAP-2-23 (S[C(oXdB)TPFEAWWC]-NH2)

[0529]

[0530] VMT-FAP-1-1 (Ac-G[C(oXdB)TPFEQWWC]-NH2)

[0531] VMT-FAP-1-13 (Ac-R[C(oXdB)TPFEQWWC]-NH2)

[0532]

[0533] VMT-FAP-1-14 (Ac-D[C(oXdB)TPFEQWWC]-NH2)

[0534]

[0535] VMT-FAP-1-62 (Ac-N[C(oXdB)TPWEQWWC]-NH2)

[0536] VMT-FAP-1-64 (Ac-N[C(oXdB)TPHEQWWC]-NH2)

[0537]

[0538] VMT-FAP-1-94 (Ac-S[C(oXdB)TPFEIWWC]-NH2)

[0539]

[0540] VMT-FAP-1-104 (Ac-S[C(oXdB)TPFEDWWC]-NH2)

[0541]

[0542] VMT-FAP-2-28 (Ac-S[C(oXdB)TPFEQWYC]-NH2)

[0543] VMT-FAP-2-29 (Ac-S[C(oXdB)TPFEQYWC]-NH2)

[0544]

[0545] EXAMPLE 2

[0546]

[0547] Pb-203-labeled FAP-targeted radiopeptides in tumor models To determine the biodistribution of the example conjugates, athymic nude mice were inoculated with hFAP-HT1080 FAP overexpressing cells with 50% Cultrex matrigel, and tumors allowed to grow for 2-3 weeks. The conjugates were then radiolabeled with203Pb and 74 kBq was injected through i.v. injection into mice bearing hFAP-HT1080 tumors. The molar activity was between 5-50 MBq / nmol. At 2 hours, and 24 hours, mice were euthanized following the animal protocol and blood, lungs, spleen, muscle, tumor, kidneys, and liver were collected. The samples were then analyzed via a Packard COBRA II automatic gamma counter and compared to reference doses to determine %ID / g (n=2). The results are illustrated in FIGS. 1-24.

[0548] EXAMPLE 3

[0549] Binding specificity of VMT-FAP-2-59

[0550] The enzyme inhibition assay was performed to determine inhibitor constant (i.e., Ki) values against human FAP, mouse FAP, human dipeptidyl peptidase 4 (DPPIV) and human prolyl endopeptidase (PREP). Z-GP-AMC was used as substrate for human FAP, mouse FAP and human PREP. GP-AMC was used as substrate for human DPPIV. To perform the assay, VMT-FAP-2-59 at varying concentrations (i.e. 10-6to 10-12) were incubated with 5 ng hFAP, 5 ng mFAP, 2.5 ng DPPIV, or 5 ng PREP in a black 96-well plate for 10 minutes at RT on a shaker plate. The substrate was added to give a final concentration of 50 pM for Z-GP-AMC and GP-AMC. The total reaction volume per well was 100µL. The reaction was allowed to incubate at RT on a shaker plate for 1 hour protected from light, and then fluorescence was read with a BioTek Synergy LX plate reader at an ex / em (360 / 40 and 460 / 40). Experiments were performed in at least duplicate. Buffer only, buffer / enzymes. buffer / substrate and enzyme only were included as controls. Data was plotted in GraphPad Prism and non-linear regression used to calculate IC50 values. Binding kinetics (Kd) of VMT-FAP-2-59 against human FAP, human DPPIV and human PREP were also determined by grating-coupled interferometry (GCI). hFAP, hDPPIV and hPREP proteins were fixed on PCH (N=3) chips or PCP(N=2). On PCH chips, binding affinity of VMT-FAP-2-29 to hFAP was determined at concentration from 61 pM to 125 nM. Binding affinity of VMT-FAP-2-29 to hDPPIV and hPREP was determined at concentration from 61 pM to 1µM. On PCP chips, the binding affinity of VMT-FAP-2-29 to hFAP was determined from 61 pM to 125 nM. Binding affinity of VMT-FAP-2-29 to hDPPIV and hPREP was determined from 61 pM to 1 pM. On PCP chips, the binding affinity of VMT-FAP-2-29 to hFAP was determined from 39 pM to 20 nM. Binding affinity to hDPPIV and hPREP was determined at concentration from 39 pM to 50 nM. The results were summarized in the following table. Representative GCI kinetic curves were shown in FIGS. 54-55.

[0551] Kd Ki

[0552] Human FAP 2 nM 0.4 nM

[0553] Mouse FAP N / A 4.2 nM

[0554] Hum® DPPIV No binding No binding

[0555] Human PREP No binding 152nM

[0556]

[0557] EXAMPLE 4

[0558] Radiochein ^ stability

[0559]

[0560] Fresh human serum was collected from blood, obtained from the University of Iowa DeGowin Blood Center. Blood was allowed to clot at room temperature for 1 hour, and then centrifuged at 1500g for lOmin and the supernatant serum was collected. The human serum was then incubated with 3.3 MBq [203Pb]VMT-FAP-2-59 at 37°C for 96 hours. An aliquot of serum containing radiotracer was obtained after 96 hours and protein was precipitated via methanol. 1.5-fold v / v ice-cold methanol was added and incubated on ice for 15 minutes. Then, the aliquot containing methanol was centrifuged for 10 minutes at 10,000 g to precipitate protein and the supernatant was collected. To determine stability in serum, the supernatant was analyzed via HPLC with a radio-detector. The HPLC gradient used 5% to 60% of 0.1% TFA in acetonitrile over 0.1% TFA in water in 10 min on an Agilent 1200 series. Stable [203Pb]VMT-FAP-2-59 in human serum was found after 96-hour incubation in fresh human serum at 37°C, as shown in FIG. 56.

[0561] EXAMPLE 5

[0562] Ill .gdi.s butien ami imaging of [251 I¥M^^

[0563] models

[0564] In vivo biodistribution of [203Pb]VMT-FAP-2-59 was determined m female athymic nude mice bearing hF AP-HT1080 human fibrosarcoma xenograft (n:::4 at each timepoint) and in U87MG human glioma xenograft (n=3 at each timepoint) following injection of 74 kBqydPb]VMT-FAP-2-59 (10-12 MBq / nmole). At each designated timepoint, tumor and organs of interest were harvest, and weighed Radioactivity of [2C3Pb] VMT-FAP-2-59 was measured on automated gamma and normalized to percent of injected dose per gram (%ID / g). Of note, HT1080 human fibrosarcoma cells were engineered to express human FAP on the membrane of the cancer cells, whereas the expression of human FAP on U87MG human glioma cells were limited, as shown in the in vitro cell binding assays, indicating that the expression of FAP in in vivo U87MG xenograft is located in stroma as mouse FAP, Results were shown in 57.

[0565] Micro-SPECT imaging of hFAP -HT1080 xenograft in athymic nude mice were harvested at 2 h and 24 h post injection of 0.8 MBq [2C,jPb] VMT-FAP-2-59 or 1.2 MBq J1Pb] VMT-FAP-2-59. Fast accumulation, rapid clearance and low retention in normal tissues were observed Results were shown in FIG. 58.

[0566] EXAMPLE 6

[0567] Radiothera eadc efliciwn tri 311 d'AF-2-59 in a hunian fiiarwarcoma xenograft made!

[0568]

[0569] In vivo efficacy was determined in a sarcoma model wherehFAP is expressed on die membrane of cancer cell surface. HIT 080 cells engineered to express hFAP Eight days prior to treatment, athymic nude mice were inoculated with approximately 2 million ceils. The mice were then randomized by tumor size and divided into two groups for control and treatment. The treated group was treated with 4.5-5.4 MBq [212Pb]-Pb-VMT-FAP-2-59 over three fractionated doses approximately 2 weeks apart. Two mice were treated a fourth time, at day 48 and day 53 with an additional 1.9-2.1 MBq. Tumor volume was measured via caliper, and weight recorded over 70 days. No treatment-related toxicity was observed. Efficacy of VMT- FAP-2-59 tn athymic nude mice bearing HT1080-FAP tumors. Tumor volume and weight was monitored over 70 days. The treatment group was given 4.5-5.4MBq12Pb-VMT-FAP-2- 59 over 3 fractionated doses. Two mice with tumor recurrence were given an additional 1.9- 2.1 MBq, as indicated by dashed arrows. Results are shown in FIG. 59.

[0570] EXAMPLE 7

[0571] Radiotherapeiitie efficacy of [212PblPb-VMT-FAP-2-59 in a human glioma xenograft model

[0572] In vivo efficacy was determined in U87MG human glioma xenograft model. In this U87MG xenograft model, FAP is expressed in stroma as mouse FAP. whereas human FAP expression on U87MG cell surface is limited. Two million U87MG cells vzere subcutaneously inoculated athymic nude mice. The mice were then randomized by tumor size and divided into two groups for control and treatment. The treated group was treated with 4.6 MBq [21zPb]-Pb- VMT-FAP-2-59 over three fractionated doses approximately 2 weeks apart. Tumor volume was measured via caliper, and weight recorded over 40 days. Following treatment with (? ZPb]VMT" FAP*2“59. significant inhibition on growth of U87MG tumor xenograft was observed, indicating that |21zPbjVMT-FAP-2-59 is capable of suppress tumor growth in tumors that express high level of FAP in stroma but low level of FAP on cancer cells. Results are shown in FIG. 60.

[0573] EXAMPLE S

[0574] 120jPbl Y TcF

[0575]

[0576] SPE CT / CT im agin g in O feats wi th di ITeren soli d fom ors Using the diagnostic SPECT imaging isotope203Pb (half-life 52 hours), the first-in-human SPECT / CT imaging of [203Pb]VMT-FAP-2-59 was performed in patients with different types of solid tumors, including metastatic lung adenocarcinoma (51 years old male, FIG. 61), metastatic periampullary neuroendocrine tumors (71 years old male, FIG. 62), and chondroblastic osteosarcoma (16 years old male, FIG. 63) at Fortis Memorial Research Institute (Gurgaon, India). [203Pb] VMT-FAP-2-59 was radiolabeled and purified following routine manufacturing protocols. The radiochemical purity in finished products was above 96%. Average injected activity was 262.7 MBq (7.1 mCi). Serial SPECT / CT imaging was performed at 1, 4, and 18 hours following injection. Patients also received18F-FDG and / or [68Ga]FAP-2286 for PET / CT imaging. Rapid tumor uptake of [203Pb]VMT-FAP-2-59 was observed at 1 hour post injection, along with rapid renal clearance through bladder in all three patients. Minimal accumulation in normal organs (brain, heart, liver, kidneys) were observed, suggesting highly specific tumor-targeting and favorable pharmacokinetics. Tumor uptake of [203Pb]VMT-FAP-2-59 was in good accordance with [68Ga]FAP-2286, a clinically validated FAP -targeted PET imaging agent, in the same patients. Importantly, excellent retention of [203Pb] VMT-FAP-2-59 in the tumors were observed in all three patients for 18 hours (approximately 2 half-life of therapeutic isotope212Pb), suggesting the favorable pharmacodynamics of [212Pb] VMT-FAP-2-59 to delivery optimal alpha-radiation to tumors. These first-in-human data have demonstrated the excellent pharmacodynamics and pharmacokinetics performance of VMT-FAP-2-59 in patients with different solid tumors.

[0577] EXAMPLE 9

[0578] Amino Acid Screening

[0579] FAP-targeted peptide variants were synthesized based on Fmoc solid phase synthesis. In each variant, a single amino acid in the sequence AA1-AA7 was replaced with other proteinogenic (natural) amino acids, except cysteine. The binding affinity of each variant to hFAP (FAP-H5263, AcroBiosystem) was determined by an enzyme inhibition assay as crude peptide (i.e., purity >50%). Z-GP-AMC (4002518 BACHEM) was used as substrate for human FAP in the assay. In the assay, each peptide was prepared at varying final concentrations (0, 5, 50, 500 nM). 50 ng / mL hFAP and 62.5 pM Z-GP-AMC substrates were also added in black 96-well plate. The inhibition reaction was conducted for 10 minutes at room temperature, followed by measurement of fluorescence at an ex / em 360 / 40 and 460 / 40. Experiments were performed in duplicate. Results were presented as percent of FAP enzyme activity. Alternative amino acids that result in comparable or improved binding affinity are summarized in the following Table. N- AA AA AA AA AA AA AA c- RA(%)

[0580] term R9 1 2 3 4 5 6 7 R8 term 500nM Activity

[0581] acetyl C T P F E Q W w c NH2 19 Good acetyl C G P F E Q w w c NH2 94 Poor acetyl c A P F E Q w w c NH2 92 Poor acetyl c L P F E Q w w c NH2 91 Poor acetyl c 1 P F E Q w w c NH2 60 Medium acetyl c V P F E Q w w c NH2 81 Poor acetyl c M P F E Q w w c NH2 85 Poor acetyl c P P F E Q w w c NH2 71 Poor acetyl c F P F E Q w w c NH2 76 Poor acetyl c W P F E Q w w c NH2 87 Poor acetyl c Y P F E Q w w c NH2 85 Poor acetyl c H P F E Q w w c NH2 86 Poor acetyl c K P F E Q w w c NH2 98 Poor acetyl c R P F E Q w w c NH2 100 Poor acetyl c D P F E Q w w c NH2 102 Poor acetyl c E P F E Q w w c NH2 103 Poor acetyl c S P F E Q w w c NH2 54 Medium acetyl c N P F E Q w w c NH2 103 Poor acetyl c Q P F E Q w w c NH2 86 Poor acetyl c T G F E Q w w c NH2 105 Poor acetyl c T A F E Q w w c NH2 99 Poor acetyl c T L F E Q w w c NH2 94 Poor acetyl c T 1 F E Q w w c NH2 95 Poor acetyl c T V F E Q w w c NH2 80 Poor acetyl c T M F E Q w w c NH2 96 Poor acetyl c T F F E Q w w c NH2 95 Poor acetyl c T W F E Q w w c NH2 105 Poor acetyl c T Y F E Q w w c NH2 105 Poor acetyl c T H F E Q w w c NH2 100 Poor acetyl c T K F E Q w w c NH2 94 Poor acetyl c T R F E Q w w c NH2 94 Poor acetyl c T D F E Q w w c NH2 93 Poor acetyl c T E F E Q w w c NH2 95 Poor acetyl c T S F E Q w w c NH2 83 Poor acetyl c T T F E Q w w c NH2 80 Poor acetyl c T N F E Q w w c NH2 96 Poor acetyl c T Q F E Q w w c NH2 95 Poor acetyl c T P G E Q w w c NH2 93 Poor acetyl c T P A E Q w w c NH2 89 Poor

[0582]

[0583] acetyl c T P L E Q w w c NH2 85 Poor acetyl C T P 1 E Q W w c NH2 92 Poor acetyl C T P V E Q W w c NH2 85 Poor acetyl C T P M E Q W w c NH2 68 Poor acetyl C T P P E Q W w c NH2 94 Poor acetyl C T P W E Q W w c NH2 3 Good acetyl C T P Y E Q W w c NH2 46 Medium acetyl C T P H E Q W w c NH2 20 Good acetyl C T P K E Q W w c NH2 100 Poor acetyl C T P R E Q W w c NH2 102 Poor acetyl C T P D E Q W w c NH2 103 Poor acetyl C T P E E Q W w c NH2 88 Poor acetyl C T P S E Q W w c NH2 96 Poor acetyl C T P T E Q W w c NH2 98 Poor acetyl C T P N E Q W w c NH2 88 Poor acetyl C T P Q E Q W w c NH2 66 Poor acetyl C T P F G Q W w c NH2 101 Poor acetyl C T P F A Q W w c NH2 89 Poor acetyl C T P F L Q W w c NH2 106 Poor acetyl C T P F 1 Q W w c NH2 96 Poor acetyl C T P F V Q W w c NH2 102 Poor acetyl C T P F M Q w w c NH2 97 Poor acetyl C T P F P Q w w c NH2 95 Poor acetyl C T P F F Q w w c NH2 92 Poor acetyl c T P F W Q w w c NH2 93 Poor acetyl c T P F Y Q w w c NH2 90 Poor acetyl c T P F H Q w w c NH2 101 Poor acetyl c T P F K Q w w c NH2 96 Poor acetyl c T P F R Q w w c NH2 96 Poor acetyl c T P F D Q w w c NH2 97 Poor acetyl c T P F S Q w w c NH2 93 Poor acetyl c T P F T Q w w c NH2 91 Poor acetyl c T P F N Q w w c NH2 95 Poor acetyl c T P F Q Q w w c NH2 93 Poor acetyl c T P F E G w w c NH2 32 Good acetyl c T P F E A w w c NH2 32 Good acetyl c T P F E L w w c NH2 64 Medium acetyl c T P F E 1 w w c NH2 20 Good acetyl c T P F E V w w c NH2 35 Good acetyl c T P F E M w w c NH2 95 Poor acetyl c T P F E P w w c NH2 95 Poor acetyl c T P F E F w w c NH2 58 Medium acetyl c T P F E W w w c NH2 31 Good

[0584]

[0585] acetyl c T P F E Y w w c NH2 32 Good acetyl C T P F E H W w C NH2 20 Good acetyl C T P F E K W w C NH2 20 Good acetyl C T P F E R w w c NH2 31 Good acetyl C T P F E D w w c NH2 17 Good acetyl C T P F E E w w c NH2 7 Good acetyl C T P F E S w w c NH2 21 Good acetyl C T P F E T w w c NH2 30 Good acetyl C T P F E N w w c NH2 21 Good acetyl C T P F E Q G w c NH2 60 Medium acetyl C T P F E Q A w c NH2 86 Poor acetyl C T P F E Q L w c NH2 102 Poor acetyl C T P F E Q 1 w c NH2 93 Poor acetyl C T P F E Q V w c NH2 96 Poor acetyl C T P F E Q M w c NH2 65 Medium acetyl C T P F E Q P w c NH2 78 Poor acetyl C T P F E Q F w c NH2 36 Medium acetyl C T P F E Q Y w c NH2 46 Medium acetyl C T P F E Q H w c NH2 63 Medium acetyl C T P F E Q K w c NH2 80 Poor acetyl C T P F E Q R w c NH2 70 Poor acetyl C T P F E Q D w c NH2 59 Medium acetyl C T P F E Q E w c NH2 76 Poor acetyl C T P F E Q S w c NH2 38 Medium acetyl c T P F E Q T w c NH2 32 Good acetyl c T P F E Q N w c NH2 69 Poor acetyl c T P F E Q Q w c NH2 78 Poor acetyl c T P F E Q W G c NH2 62 Medium acetyl c T P F E Q W A c NH2 71 Poor acetyl c T P F E Q w L c NH2 89 Poor acetyl c T P F E Q w 1 c NH2 85 Poor acetyl c T P F E Q w V c NH2 92 Poor acetyl c T P F E Q w M c NH2 48 Medium acetyl c T P F E Q w p c NH2 97 Poor acetyl c T P F E Q w F c NH2 23 Good acetyl c T P F E Q w Y c NH2 32 Good acetyl c T P F E Q w H c NH2 67 Poor acetyl c T P F E Q w K c NH2 81 Poor acetyl c T P F E Q w R c NH2 84 Poor acetyl c T P F E Q w D c NH2 81 Poor acetyl c T P F E Q w E c NH2 80 Poor acetyl c T P F E Q w S c NH2 65 Medium acetyl c T P F E Q w T c NH2 85 Poor

[0586]

[0587] acetyl c T P F E Q w N c NH2 83 Poor | acetyl | C | T | P | F | E | Q. | W | Q. | C | NH2 | 63 | Medium |

[0588] Further embodiments of the invention are outlined in the clauses below:

[0589] 1. A composition comprising a fibroblast activation protein alpha (FAP)riargeted conjugate comprising the structure of Formula 3b or 3c:

[0590] AA2 AA3

[0591] Formula 3b

[0592] AA3

[0593]

[0594] Formula 3c

[0595] wherein:

[0596] - Y comprises a chelator or a cytotoxic drug,

[0597] - L is a linker or bond,

[0598] - AA] to AA- comprise a FAP-targeted binding peptide sequence and are joined to one another by peptide bonds,

[0599] - R8 is attached to AA7,

[0600] - R9 is attached to AA1, and

[0601] - M is a bond or a cyclization moiety that connects Rs to R9, wherein Rs, R9 and M together create a chain of 4 to 20 ring atoms connecting AAi to AA7 selected from the group consisting of optionally substituted carbon, optionally substituted nitrogen, oxygen and sulfur atoms, and

[0602] wherein the composition further contains a radi oproteciant and / or is in a lyophilized form.

[0603] 2. The composition comprising a fibroblast activation protein alpha (FAP)-targeted peptide according to clause I, w herein

[0604] -AAi is an amino acid residue of threonine, serine, or isoleucine;

[0605] -AA? is an amino acid residue of proline, 1, 2, 3, 4-tetrahydroisoquinolin-3-carboxylic acid (Tic), pyroglutamic acid (Pyr), Homo-Pro. 4-aminopiperidine-4-carboxylic acid, 2-aminobenzoic acid (2-Abz), 3-aminocyclopentanecarboxylic acid. transhydroxy proline, cis-3-hydroxyproline, trans -4-hydroxy proline, cis-4- hydroxyproline, alpha-methyl-proline, alpha-benzyl-proline, 3,4-dehydro-proline, 4- oxa-proline, 3 -thia-proline, or 4-thia-proline;

[0606] -AAs is an amino acid residue of tryptophan, phenylalanine, tyrosine, histidine, beta- Phe, beta-Tyr, 1 -naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), 3 -(4-bi phenylalanine (Bip), 2-pyridyl-alanine (2-Pal), 3-pyridyl-alanine (3-Pal), 4-pyridyl-alanine (4-Pal), 3-benzothienyl-alanine (Bta), 4-trifluoromethyl-phenylalanine, 2-cyano- phenylalanine, 3-cyano-phenylalanine, 4-cyano-phenylalanine, 3-Borono- phenylalanine, 4-Borono-phenylalanine, 2-chloro-phenylalanine, 3 -chlorophenylalanine, 4-chloro-phenylalanine, 2-fluoro-phenylalanine, 3-fluoro- phenylalanine, 4-fluoro-phenylalanine, 2-Iodo-phenylalanine, 3-Iodo-phenylalanine, 4- lodo-phenylalanine, 2-methyl-phenylalanine, 3-methyl-phenylalanine, 4-methyl- phenylalanine, 2-Nitro-phenylalanine, 3-Nitro-phenylalanine, 4-Nitro-phenylalanine, 4-pentafluoro-phenylalanine, phenylglycine (Phg), 4-amino-phenylalanine, 4- methoxy-phenylalanine, 5-hydroxytrptophan, 3, 5-diiodo-tyrosine. 4-benzoyl- phenylalanine, 5-hydroxy-trptophan, 3, 5-diiodo-tyrosine, 4-benzoyl-phenylalanine (Bpa), cyclohexylglycine (Chg), 2-thienyl-alanine (Thi), or is a residue of an amino acid comprising a side chain having an optionally substituted aryl or heteroaiyl group; -A. A-i is an amino acid residue of glutamic acid, aspartic acid, glutamine, asparagine, beta-Glu, or beta-Gln;

[0607] -AA is an amino acid residue of glutamine, glycine, alanine, isoleucine, valine, tryptophan, tyrosine, histidine, lysine, arginine, aspartic acid, glutamic acid, serine, threonine, asparagine, phenylalanine, leucine, beta-Glu, beta-Gln, beta-Phe, beta-Tyr, beta-Lys, beta-Arg, norleucine (Nle), citrulline (Cit), norvaline, 1 -naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), 3-(4-biphenyl-alanine (Bip), 2-pyridyl-alanine (2-Pal), 3-pyridyl-alanine (3-Pal), 4-pyridyl-alanine (4-Pal), 3-benzothienyl-alanine (Bta), 4-trifluoromethyl-phenylalanine, 2-cyano-phenylalanine, 3 -cyano-phenylalanine, 4-cyano-phenylalanine, 3-Borono-phenylalanine, 4-Borono-phenylalanine, 2-chloro-phenylalanine, 3-chloro-phenylalanine, 4-chloro-phenylalanine, 2-fluoro-phenylalanine, 3-fluoro-phenylalanine, 4-fluoro-phenylalanine, 2-Iodo-phenylalanme, 3-Iodo-phenylalanine, 4-Iodo-phenylalanine, 2-methyl-phenylalanine, 3-methyl-phenylalanine, 4-methyl-phenylalanine, 2-Nitro-phenylalanine, 3-Nitro-phenylalanine, 4-Nitro-phenylalanine, 4-pentafluoro-phenylalanine, phenylglycine (Phg), 4-amino-phenylalanine, 4-methoxy-phenylalanine, 5-hydroxytrptophan, 3, 5-diiodo-tyrosine. 4-benzoyl-phenylalanine, 5-hydroxy-trptophan, 3, 5-diiodo-tyrosine, 4-benzoyl-phenylalanine (Bpa), cyclohexylglycine (Chg), and 2-thienyl-alanine (Thi);

[0608] -AA6 is an amino acid residue of tryptophan, phenylalanine, tyrosine, serine, threonine, methionine, glycine, histidine, aspartic acid, beta-Phe, beta-Tyr, 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), 3-(4-biphenyl-alanine (Bip), 2-pyridyl-alanine (2-Pal), 3-pyridyl-alanine (3-Pal), 4-pyridyl-alanine (4-Pal), 3-benzothienyl-alanine (Bta), 4-trifluoromethyl-phenylalanine, 2-cyano-phenylalanine, 3-cyano-phenylalanine, 4-cyano-phenylalanine, 3-Borono-phenylalanine, 4-Borono-phenylalanine, 2-chloro-phenylalanine, 3-chloro-phenylalanine, 4-chloro-phenylalanine, 2-fluoro-phenylalanine, 3-fluoro-phenylalanine, 4-fluoro-phenylalanine, 2-Iodo-phenylalanine, 3-Iodo-phenylalanine, 4-Iodo-phenylalanine, 2-methyl-phenylalanine, 3-methyl-phenylalanine, 4-methyl-phenylalanine, 2-Nitro-phenylalanine, 3-Nitro-phenylalanine, 4-Nitro-phenylalanine, 4-pentafluoro-phenylalanine, phenylglycine (Phg), 4-amino-phenylalanine, 4-methoxy-phenylalanine, 5-hydroxytryptophan, 3, 5-diiodo-tyrosine, 4-benzoyl-phenylalanine, 5-hydroxy-trptophan, 3, 5 -diiodo-tyrosine, 4-benzoyl-phenylalanine (Bpa), cyclohexylglycine (Chg), or 2-thienyl-alanine (Thi); and

[0609] -AA3 is an amino acid residue of tryptophan, methionine, phenylalanine, tyrosine, glycine, glutamine, serine, beta-Phe, beta-Tyr, Non aline (Nva), norleucine (Nle), citrulline (Cit), norvaline, 1 -naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), 3-(4- biphenyl-alanine (Bip), 2-pyridyl-alanine (2 -Pal), 3-pyridyl-alanine (3-Pal), 4-pyridyl- alanine (4-Pal), 3-benzothienyl-alanine (Bta), 4-trifluoromethyl-phenylalanine, 2- cyano-phenylalanine, 3 -cyano-phenylalanine, 4-cyano-phenylalanine, 3-Borono- phenylalanine, 4-Borono-phenylalanine, 2-chloro-phenylalanine, 3 -chlorophenylalanine, 4-chloro-phenylalanine, 2-fluoro-phenylalanine, 3-fluoro- phenylalanine, 4-fluoro-phenylalanine, 2-Iodo-phenylalanine, 3-Iodo-phenylalanine, 4- lodo-phenylalanine, 2-methyl-phenylalanine, 3-methyl-phenylalanine, 4-methyl- phenylalanine, 2-Nitro-phenylalanine, 3-Nitro-phenylalanine, 4-Nitro-phenylalanine, 4-pentafluoro-phenylalanine, phenylglycine (Phg), 4-amino-phenylalanine, 4- methoxy-phenylalanine, 5-hydroxytrptophan, 3, 5-diiodo-tyrosine. 4-benzoyl- phenylalanine, 5-hydroxy-trptophan, 3, 5-diiodo-tyrosine, 4-benzoyl-phenylalanine (Bpa), cyclohexylglycine (Chg), and 2-thienyl-alanine (Thi).

[0610] 3. The composition comprising a fibroblast activation protein alpha (FAP)-targeted peptide according to clause 1 or clause 2, having the following sequence of residues:

[0611] - AA; is a residue of Thr or Ser,

[0612] - A?;is a residue of Pro or homoproline,

[0613] -AA3 is a residue of Trp or another ammo acid having a side chain including an optionally substituted aryl or heteroaryl group,

[0614] -A 4 is a resi ue of Ghi

[0615] -AA-j is a residue of Gin, Glu, He, His, Asp, Trp, Lys, Arg, Ser, Thr or Asn, -AAg is a residue of Trp, Phe, Tyr, Ser or Thr, and

[0616] -AA? is a residue of Trp, Phe or Tyr. 4. The composition comprising a fibroblast activation protein alpha (FAP)- targeted peptide according to any preceding clause, having the following sequence of residues:

[0617] ■ AAi is a residue of Tin;

[0618] -A A? is a residue of Pro,

[0619] -AA? is a residue of Trp, Phe, Tyr, or His,

[0620] -AA4 is a residue of Glu,

[0621] -A A? is a residue of Gin, Glu, He, His, Asp, Arg, Lys, Ser, Thr or Asn,

[0622] " AAe is a residue of Trp, Phe, or Tyr, and

[0623] -AA? is a residue of Trp, Phe, or Tyr.

[0624] 5. The composition comprising a fibroblast activation protein alpha (FAP)- targeted peptide according to any one of clauses 1 to 3, having the following sequence of residues:

[0625] - AA; is a residue of Thr,

[0626] -AA? is a residue of Pro,

[0627] -AA? is a residue of Trp or other ammo acid having a side chain including an optionally substituted aryl or heteroaryl group,

[0628] -AA4 is a residue of Glu,

[0629] -A A; is a residue of Gin,

[0630] -AAi, is a residue of Trp, and

[0631] -AA7 is a residue of Trp.

[0632] 6. The composition comprising a fibroblast activation protein alpha (FAP)-targeted peptide according to any of the preceding clauses, having the following sequence of residues:

[0633] - AAi is a residue of Thr.

[0634] -AA? is a residue of Pro,

[0635] -AA? is a residue of Trp, Phe, Tyr. or His, -AA.-1 is a residue of Glu.

[0636] • is a residue of Gin,

[0637] -AAg is a residue of Trp. and

[0638] -AA7 is a residue of Trp.

[0639] The composition comprising a fibroblast activation protein alpha (F API-targeted peptide according to clauses 1 to 4 having the following sequence of residues:

[0640] - AA, is a residue of Thr,

[0641] -AA2 is a residue of Pro.

[0642] “A A3 is a residue of Trp,

[0643] -A. A4 is a residue of Glu.

[0644] -AA, is a residue of Gin, Glu, Ala, Leu, He, Vai, Phe, Trp, Tyr, Lys, Arg, His, Asp, Ser, Thr, Asn, or Gly,

[0645] -AAg is a residue of Trp. and

[0646] -AA? is a residue of Trp.

[0647] 8. The composition comprising a fibroblast activation protein alpha (FAP)-targeted peptide according to clauses 1 to 4, having the following sequence of residues:

[0648] - AA; is a residue of Thr,

[0649] -AA is a residue of Pro.

[0650] " AA3 is a residue of Trp,

[0651] " AA4 is a residue of Glu.

[0652] -A As is a residue of Gin,

[0653] -AAg is a residue of Trp, Phe, or Tyr, and

[0654] -A A? is a residue of Trp. 9. The composition comprising a fibroblast activation protein alpha (FAP)-targeted peptide according to clauses 1 to 4 having the following sequence of residues:

[0655] ■ AAi is a residue of Thr,

[0656] -AA2is a residue of Pro,

[0657] -A A? is a residue of Trp,

[0658] -AA4 is a residue of Glu,

[0659] ~ Aj is a residue of Gin,

[0660] " AAe is a residue of Trp. and

[0661] -AA7IS a residue of Trp, Phe or Tyr.

[0662] 10. Ute composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate according to any preceding clause, wherein Rs, R9 and M together comprise a chain of 6 to 18 ring atoms, 8 to 16 ring atoms or 10 to 14 ring atoms connecting AAi to AA7.

[0663] 11. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate according to any preceding clause, wherein Rs and R9 comprise moieties that are each independently selected from the group consisting of amino acid residues or derivatives thereof, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted aralkylene or optionally substituted heteroaralkylene.

[0664] 12. The composition comprising a fibroblast activation protein alpha (FAP)- targeted conjugate of clause I I, wherein:

[0665] R8 and R9 are each a derivative of an amino acid,

[0666] R9 is *-C(O)CH2(NHR7)R77-**, wherein * indicates the point of attachment of the carbonyl group (-C(O)-) to AAi, ** indicates the point of attachment of the amino acid residue to M, and R77 comprises the side chain of the amino acid or is a bond, Rs is+-RS6(C(O)R6)CH2NH-++, wherein+indicates the point of attachment of the amino acid residue to M, ~+indicates the point of attachment of the amine group (-NH-) to AA? and S6 comprises the side chain of the amino acid or is a bond,

[0667] Re is L in embodiments where Y-L is bound to Rs, or is -NR20R21, -OR22, an amino acid residue, or other C-terminal modification of Rs in embodiments where Y-L is bound to M, where R20 and R21 are independently hydrogen or optionally substituted Ci-Ce alkyd, and R22 is hydrogen or optionally substituted Ci-Ce alkyl, and

[0668] R7 is hydrogen, optionally substituted C1-C10 alkyl or heteroalkyl, an optionally substituted C1-C10 acyl or heteroacyl group either of which may be straight or branched and may contain one or more additional acyl groups, hydroxyl groups, carboxy l groups, amide group, amine groups or imine groups or other N-terminal modification of R9, including an amino acid residue and / or acylated amino acid residue.

[0669] 13. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of clause 12. wherein R? comprises an optionally substituted C1-C10 acyl or heteroacyl group, which may be straight or branched and may contain one or more additional acyl groups, hydroxyl groups, carboxyl groups, amide group, amine groups or imine groups at an end furthest from the N-terminus of R9.

[0670] 14. The composition comprising a fibroblast activation protein alpha (F API-targeted conjugate of clause 12, wherein R? is selected from the following group:

[0671]

[0672] 15. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one of clauses 11 to 14, wherein Rg and Rs comprise moieties that are independently selected from the group consisting of residues of cysteine, lysine, aspartic acid, glutamic acid, penicillamine, 2-amino-3-mercaptobutanoic acid, 3 mercaptopropionic acid, 2,3-diaminopropionic acid, and cysteamine, or derivatives thereof.

[0673] 16. The composition comprising a fibroblast acti ation protein alpha (F PI-targeted conjugate of any one of the preceding clauses wherein the cyclization moiety, M, comprises a cyclic or acyclic moiety that includes 2 to 8 ring atoms connecting Rg to Ity selected from the group consisting of optionally substituted carbon, optionally substituted nitrogen, oxygen and sulfur. 17. The composition comprising a fibroblast activation protein alpha (FAPHargeting conjugate of any of clauses 11*16 wherein one of Rs and Ry comprises a residue of lysine or derivative thereof, and the other of Rs and Ry comprises a residue of aspartic acid or lactic acid or derivative thereof, and wherein M is a bond that forms a lactam bridge between Rs and Ry.

[0674] 18. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any of clauses 11-17 wherein Rg and Rs comprise cysteine residues or derivatives thereof, and wherein the cyclization moiety M is bonded to the cysteine residues through the cysteine side chains.

[0675] 19 The composition comprising a fibroblast acti ation protein alpha (FAP)-targeted conjugate of any one of the preceding clauses, wherein the conjugate comprises any of the following Formulas 5a-5d, or 6a-6d as outlined above, wherein R5 is selected from the group consisting of optionally substituted aryl and heteroaryl, Rn is a side chain of an amino acid residue selected from the group consisting of glutamine, glycine, alanine, isoleucine, leucine, valine, lysine, arginine, aspartic acid, glutamic acid, serine, threonine, asparagine, phenylalanine, tryptophan, tyrosine, or histidine, R12 is a side chain of an amino acid residue selected from the group consisting of tryptophan, phenylalanine, tyrosine, serine, threonine, methionine, glycine, histidine, and aspartic acid and R13 is a side chain of an amino acid residue selected from the group consisting of tryptophan, methionine, phenylalanine, glycine, glutamine, senne and tyrosine.

[0676] 20. The composition comprising a fibroblast activation protein alpha (FAP)- targeted conjugate of any one of the preceding clauses, wherein M is an optionally substituted carbocyclic alkylene or optionally substituted heterocylic alkylene corresponding to Formula 7

[0677]

[0678] Formula 7

[0679] wherein each t is independently 1-2, n is 0 to 2, each RE is independently halogen, hydroxy, thiol, amino, or Ci-Ce alkyl and ring E is an optionally substituted, 5 to 10-membered carbocycle or heterocycle.

[0680] 21. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of clause 20, wherein ring E is selected from the group consisting of pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, furan, thiophene, benzene, pyridine, pyran, pyrimidine, pyridazine, pyrazine, piperazine, thiazine, oxazine, indole, isoindole, quinoline, isoquinoline, purine, naphthalene, purine, and chroman.

[0681] 22. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one of clause 20-21, wherein M corresponds to Formula 7 and -R9-M-R8-corresponds to Formula 8 below:

[0682]

[0683] Formula 8

[0684] wherein the wavy lines, indicate the point of attachment of Rs to AA7 and R9 to AAi. 23. The composition comprising a fibroblast activation protein alpha (FAP)- targeted conjugate of any one of clause 20-22, wherein each of Rs and Rs comprise residues of an amino acid or derivative thereof each t is 1, E is an aromatic or heteroaromatic ring comprising 5-10 ring atoms, n is 0-3, and each RE is independently, halogen, hydroxy, thiol, amino, or Ci-Ce alkyl.

[0685] 24. The composition comprising a fibroblast activation protein alpha (FAP)-iargeted conjugate of clause 23, wherein E is any of benzene, naphthylene, or a 5-membered heteroaromatic ring.

[0686] 25. The composition comprising a fibroblast activation protein alpha (FAP (-targeted conjugate of any one of clauses 20-24 having the following structure:

[0687] o

[0688] Res - CHNH — AA7-AA6

[0689]

[0690] wherein AAi to AA7, Re, R7, Res, R77, t, n, E and RE are as described above, and wherein at least one of Re or at least one RE comprises L-Y.

[0691] 26. The fibroblast activation protein alpha (FAP (-targeted conj agate of any one of the preceding clauses, wherein the conjugate comprises a structure according to any of Formulas J Oa- lOd as outlined above wherein R5 is selected from the group consisting of optionally substituted aryl and heteroaryl, Rn is a side chain of an amino acid residue selected from the group consisting of glutamine, glycine, alanine, isoleucine, leucine, valine, lysine, arginine, aspartic acid, glutamic acid, serine, threonine, asparagine, phenylalanine, tryptophan, tyrosine, or histidine, R12 is a side chain of an amino acid residue selected from the group consisting of tryptophan, phenylalanine, tyrosine, serine, threonine, methionine, glycine, histidine, and aspartic acid, and R13 is a side chain of an amino acid residue selected from the group consisting of tryptophan, methionine, phenylalanine, glycine, glutamine, serine and tyrosine.

[0692] 27. The fibroblast activation protein alpha (FAP)-targeted conjugate of any one of the preceding clauses, wherein the conjugate comprises a structure according to any of Formulas I la-1 Id as outlined wherein R5 is selected from the group consisting of optionally substituted aryl and heteroaryl, Rn is a side chain of an amino acid residue selected from the group consisting of glutamine, glycine, alanine, isoleucine, leucine, valine, lysine, arginine, aspartic acid, glutamic acid, serine, threonine, asparagine, phenylalanine, tryptophan, tyrosine, or histidine, R12 is a side chain of an amino acid residue of tryptophan, phenylalanine, tyrosine, serine, threonine, methionine, glycine, histidine, aspartic acid, and R13 is a side chain of an amino acid residue selected from the group consisting tryptophan, methionine, phenylalanine, glycine, glutamine, serine and tyrosine.

[0693] 28. The composition comprising a fibroblast activation protein alpha (FAP)~ targeted conjugate of any one of the preceding clauses, wherein M comprises ihe structure according to Formula 1, having substituent in the ortho, meta, or para position with respect to each other:

[0694]

[0695] (RE)n

[0696] Formula 12

[0697] wherein n is 0-2 and each RE is independently halogen, hydroxy, thiol, amino, or Ci-Ce alkyl. 29. The composition comprising a fibroblast activation protein alpha (F API-targeted conjugate of any one of the preceding clauses, wherein the chelator (Y) comprises the following structure

[0698]

[0699] where each Ri is independently hydrogen or an alkyl group,

[0700] R-2 is -ORi, -NH2 or a bond connecting the chelator to the linker, L, or directly bonds to the binding peptide, in a case where L is a bond,

[0701] R3 and R4 are independently hydrogen or a bond connecting the chelator to the linker, L, or directly bonds to the binding peptide, in a case where L is a bond, provided (i) at least one of R3 and R-iis hydrogen, and (ii) each of R3 and Ros hydrogen when R2 is a bond connecting the chelator, to the linker, L, or directly bonds to the binding peptide, in a case where L is a bond.

[0702] 30. The composition comprising a fibroblast activation protein alpha (FAP)~ targeted conjugate of any one of clauses 1 to 28, wherein the chelator (Y) comprises the following structure

[0703]

[0704] where each Ri is independently hydrogen or an alkyl group,

[0705] R.2 is -ORi, -NH2 or a bond connecting the chelator to the linker, L, or connecting to the binding peptide, in a case where L is a bond,

[0706] R3 and R4 are independently hydrogen or a bond connecting the chelator to the linker, L, or connecting to the binding peptide, in a case where L is a bond, provided (i) at least one of R3and RHs hydrogen, and (ii) each of R3 and Riis hydrogen when R2 is a bond connecting the NOTA chelator, to the linker, L, or connecting to the binding peptide, in a case where L is a bond.

[0707] 31. The composition comprising a fibroblast activation protein alpha (F. AP)~ targeted conjugate of any one of clauses 1 to 28, wherein the chelator (Y) is any selected from the group consisting of AAZTA, BAT, BAT-TM, Crown, Cyclen, D02A. CB-D02A, D03A. H3HP-DO3, Oxo-DO3A, p-NH2-Bn-Oxo-DO3A. PSC, DOTA, DOTA-Spy, DOTA-PA, DOTA-GA, D0TA-4AMP, DOTA-2py, DOTA-lpy, p-SCN-Bn-DOTA, CHX-A"-EDTA, MeO-DOTA-NCS EDTA, DOTAMAP, DOTAGA, DOTAGA-anhydride, DOTMA, DOTASA, DOTAM, DOTP, CB-Cyclam, TE2A, CB-TE2A, CB-TE2P, DM-TE2A, MM- TE2A, NOTA, NOTP, HEHA_ HEHA-NCS, p-SCN-Bn-HEHA_ DTP A, CHX-A;;-DTP, p- NH2-Bn-CHX-A''-DTPA, p-SCN~DTPA_ p-SCN-Bz-Mx-DTPA. 1B4M-DTPA, p-SCN- BnlB-DTPA, p-SCN-Bn-lB4M-DTPA, pXCN-Bn-CHX-A;;-DTPA, PEPA, p-SCN-Bn- PEP, TETPA, DOTP A, DOTMP, DOTPM, t-Bu-calix|4]arene-tetracarboxylic add, macropa, macropa-NCS, macropid. H3L1, H3L4, H?.azapa, Hsdecapa, bi spa2, Hspypa, H-ioctapa, FLCHXoctapa, p-SCN-Bn-HiOCtapa, p-SCN~Bn-H4OCtapa, TTHA, p-NOz-Bn- neunpa, FLoctox, I-fcmacropa, H2bispa2, FLphospa, EUphospa, p-SCN-Bn-BUphospa, TETA, p- h-Bn-TETA, TRAP, TP A, HBED, SHBED. HBED-CC, ( HBED-CC )TFP, DAIS A, DMPS, DHL. A lipoic acid, TGA, BAL, Bis-thiosemiuarabazones, p-SCN-NOTA, nNO’F. A NODAGA, CB-TE1A1P, 3P-C-NETA-NCS, 3p-C-DEPA, 3P-C-DEPA-NCS, TCMC, PCTA. NODIA-Me, TACN, pycuplAlB, pycup2A, TUP, DEDPA, H2DEDPA, p-SCN-Bn-I: I2DEDP A. p-SCN-Bn-TCMC, motexafm, NT A, NOC, 3p-C-NETA, p-NH2-Bn-TE3 A, SarAr, Di AmSar, SarAr-NCS, AmBaSar, BaBaSar, TACN-TM, CP256, C-NE3TA, C- NE3TA-NCS, NODASA, NETA-monoamide, C-NETA, NOPO, BPCA. p-SCN-Bn-DFO, DFO-ChX-Mak DFO, DFO-IAC, DFO-BAC, DiP-LICAM, EC, SBAD, BAPEN, TACHPYR, NEC-SP, Lpy. LI, L2, L3, EuK- 106, D i A. CyEDTA, EDI MP, DTPMP, I PA CyDTPA, Cy2DTPA, DTP A-MA, DTPA-BA, 2,2',2"-(10-(2-amino-2-oxoethyl)-l,4,7,10-tetraazacyclododecane-l,4,7-triyl)triacetic acid, (2,2',2"-(10-(2-amino-2-oxoethyl)-l,4,7,10-tetraazacyclododecane-l,4,7-triyl)triaethanoic acid), and BOP A.

[0708] 32. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one of clauses 1 to 28, wherein the chelator (Y) is any selected from the group consisting of 2,2',2",2'"-(l,4,7,10-Tetraazacyclododecane- 1,4,7,10-tetrayl)tetraacetic acid (DOTA), l,4,7-triazacyclononane-l,4,7-triacetic acid (NOTA), or 1,4,7,10-Tetraazacyclododecane-7-acetamide -1,4,10-triacetic acid or 2,2',2"-(10-(2-amino-2-oxoethyl)-l,4,7,10-tetraazacyclododecane-l,4,7-triyl)triacetic acid or (2,2',2"-(10-(2-amino-2-oxoethyl)-l,4,7,10-tetraazacyclododecane-l,4,7-triyl)triaethanoic acid) (lead specific chelator, or PSC).

[0709] 33. The composition comprising a fibroblast activation protein alpha (PAP)-targeted conjugate of any one of the preceding clauses, wherein L comprises a linker that comprises any one or more of an amino acid residue, a polyethylene glycol group having from 1 to 10 repeat groups, a piperidine group, a benzyl isothiocyanate group, a pyrazine group, and the residue of compound having the formula NHi (CH2)n-(C:::O)OH, wherein n is 1 to 10.

[0710] 34 The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one of the preceding clauses, wherein the linker comprises any one or combination of 2 or more residues of lysine, serine, phenylalanine, cysteamine, 6-amino hexanoic acid, benzyl-isothiocyanate, and an amino-polyethylene glycol-acid having from 1 to 4 polyethylene glycol groups.

[0711] 35. 'The composition comprising a fibroblast activation protein alpha (FAP)~targeted conjugate of any one of the preceding clauses, wherein L comprises the residue of a modified polyethylene gly col group comprising the formula NH2-(CH2-CH2-O)n-(CH2)m-C(=O)OH, where n = 1-4 and m = 1-2. 36. The composition comprising a fibroblast activation protein alpha (F API-targeted conjugate of any one of the preceding clauses, wherein the conj ugate is radiolabeled with a radionuclide comprising any selected from the group consisting of212Pb,67Cu4Cu,8yZr.9C'Y,f09Pd,1 f fAg,f 49Pnx! S5Sm,166Ho,9

[0712]

[0713] 9'’'Tc,t’‘Ga,6^Ga111In,99Y,,7Xu,1^Tle,: SSRe,97Au,9y8Aii,: 9Au?05Illi,1'''5Ho,16!Tb,149Pm.44Sc,47S c,70As,7’As,72As,73As,74As,76As,77As,2l2Pb,2’2Bi,2’3Bi,22Ac,f f7™Sn,67Ga,29;Ti,’23L53!I,’60Gd,!4SNd,8SSr,2nAt,43Sc,44Sc,51Mn,64Cu,67Ga,6*Ga,86Y,89Zr,Sft31Tc,18F,76B, " Br, In,123I.1241,1 5I,152Tb,293Pb,196Pb,197Pb,198Pb,199Pb,200Pb,201Pb,202Pb,205Pb,209Pb,210Pb,211Pb,213Pb,214Pb,215Pb, and216Pb.

[0714] 37. The fibroblast activation protein alpha (F API-targeted conjugate of any one of the preceding clauses, wherein the binding peptide comprises a structure according to any of the following formulas:

[0715]

[0716]

[0717] wherein the chelator, and optionally linker, are connected at the location of one of the wavy lines in the above structures.

[0718] 38 The fibroblast activation protein alpha (FAP)-targeted conjugate of any one of the preceding clauses, wherein the conjugate is radiolabeled with a radionuclide that is used for medical imaging and / or therapy of the cancerous tumors.

[0719] 39. The fibroblast activation protein alpha (FAP)-targeted conj agate of any one of the preceding clauses, comprising any of the following formulas:

[0720] VMT-FAP-2-26: (Ac-S-[C(oXdB)TPFEQWWC]-Lys(NH2)-PEG2-PSC)

[0721]

[0722] VMT-FAP-2-51 (Ac-[C(mXtB(CA-PEG2-PSC))TPWEQWWC]-NH2)

[0723] VMT-FAP-2-55 (Ac-S-[C(mXtB(CA-PEG2-PSC))TPWEQWWC]-NH2)

[0724]

[0725] VMT-FAP-2-57 (But-[C(mXtB(CA-PEG2-PSC))TPWEQWWC]-NH2)

[0726]

[0727] 40. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one of the preceding clauses, wherein the FAP -targeting conjugate further comprises an albumin-binding moiety.

[0728] 41. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one of the preceding clauses, wherein Y comprises a cytotoxic drug.

[0729] 42. A method of targeting a fibroblast activation protein alpha (FAP) comprising administering a composition comprising a fibroblast activation protein alpha (FAP (-targeted conjugate according to any one of clauses 1-41, wherein the conjugate is radiolabeled.

[0730] 43. A method of imaging and / or diagnosing a subject having a disorder that is a result of or associated with upregulated FAP expression, the method comprising administering to the subject a composition comprising a fibroblast activation protein alpha (FAP (-targeted conjugate of any one of clauses 1-41, wherein the conjugate is radiolabeled, and imaging the subject.

[0731] 44. A method of treating a subject having a disorder that is a result of or associated with upregdated FAP expression, the method comprising administering to the subject a composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one of clauses 1-41, wherein the conjugate is radiolabeled.

[0732] 45 A method of treating cancer in a subject in need thereof the method compri sing administering to the subject a composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one clauses 1-41, wherein the conjugate is radiolabeled.

[0733] 46. The method according to clauses 45, wherein the cancer is any selected from the group consisting of astric cancer, brain cancer, myeloma, melanoma, sarcoma, salivary gland cancer, esophageal cancer, cholangiocarcinoma, breast cancer, lung cancer, prostate cancer, pancreatic cancer, thymus cancer, head and neck cancer, ovarian cancer, desmoid tumor, chordoma, colorectal cancer, anal cancer, neuroendocrine tumor, small intestine cancer, medullary thyroid cancer, cervical cancer, endometrial cancer, hepatocellular cancer, gastric cancer, adenoid cystic cancer, pheochromocytoma, differentiated thyroid cancer, insulinoma, kidney cancer, and skin cancer.

[0734] 45 A method of treating a disorder in a subject in need thereof, the method comprising administering to the subject a composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one of the preceding clauses 1-41, wherein the conjugate is radiolabeled and wherein the disorder is any selected from the group consisting of a w ound healing disorder, fibrosis, arthritis, atherosclerotic plaques, autoimmune diseases, metabolic diseases, and ischemic heart tissue after myocardial infarction. It should be appreciated that minor dosage and formulation modifications of the composition and the ranges expressed herein may be made and still come within the scope and spirit of the present invention.

[0735] Having described the invention with reference to particular compositions, theories of effectiveness, and the like, it will be apparent to those of skill in the art that it is not intended that the invention be limited by such illustrative embodiments or mechanisms, and that modifications can be made without departing from the scope or spirit of the invention, as defined by the appended claims. It is intended that all such obvious modifications and variations be included within the scope of the present invention as defined in the appended claims. The claims are meant to cover the claimed components and steps in any sequence which is effective to meet the objectives there intended, unless the context specifically indicates to the contrary.

[0736] The foregoing description has been presented for the purposes of illustration and description. It is not intended to be an exhaustive list or limit the invention to the precise forms disclosed. It is contemplated that other alternative processes and methods obvious to those skilled in the art are considered included in the invention. The description is merely examples of embodiments. It is understood that any other modifications, substitutions, and / or additions may be made, which are within the intended spirit and scope of the disclosure. From the foregoing, it can be seen that the exemplary aspects of the disclosure accomplishes at least all of the intended objectives.

Claims

CLAIMS1. A composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate comprising the structure of Formula 3b or 3c:5Formula 3b‘5Formula 3cwherein:- ¥ comprises a chelator or a cytotoxic drug,- L is a linker or bond,- AA1 to AA7 comprise a FAP-targeted binding peptide sequence and are joined to one another by peptide bonds,- R8 is attached to AA7,- R9 is attached to AA1, and- M is a bond or a cyclization moiety that connects R8 to R9, wherein R8, R9 and M together create a chain of 4 to 20 ring atoms connecting AA1 to AA7 selected from the group consisting of optionally substituted carbon, optionally substituted nitrogen, oxygen and sulfur atoms, andwherein the composition further contains a radioprotectant and / or is in a lyophilized form.

2. The composition comprising a fibroblast activation protein alpha (FAP)-targeted peptide according to claim 1, wherein-AA1 is an amino acid residue of threonine, serine, or isoleucine;-AA2 is an amino acid residue of proline, 1, 2, 3, 4-tetrahydroisoquinolin-3-carboxylic acid (Tic), pyroglutamic acid (Pyr), Homo-Pro, 4-aminopiperidine-4-carboxylic acid, 2- aminobenzoic acid (2-Abz), 3-aminocyclopentanecarboxylic acid, transhydroxyproline, cis-3-hydroxyproline, trans -4-hydroxy proline, cis-4- hydroxyproline, alpha-methyl-proline, alpha-benzyl-proline, 3,4-dehydro-proline, 4- oxa-proline, 3 -thia-proline, or 4-thia-proline;-AA3 is an amino acid residue of tryptophan, phenylalanine, tyrosine, histidine, beta- Phe, beta-Tyr, 1 -naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), 3 -(4-bi phenylalanine (Bip), 2-pyridyl-alanine (2-Pal), 3-pyridyl-alanine (3-Pal), 4-pyridyl-alanine (4-Pal), 3-benzothienyl-alanine (Bta), 4-trifluoromethyl-phenylalanine, 2-cyano- phenylalanine, 3-cyano-phenylalanine, 4-cyano-phenylalanine, 3-Borono- phenylalanine, 4-Borono-phenylalanine, 2-chloro-phenylalanine, 3 -chlorophenylalanine, 4-chloro-phenylalanine, 2-fluoro-phenylalanine, 3-fluoro- phenylalanine, 4-fluoro-phenylalanine, 2-Iodo-phenylalanine, 3-Iodo-phenylalanine, 4- lodo-phenylalanine, 2-methyl-phenylalanine, 3-methyl-phenylalanine, 4-methyl- phenylalanine, 2-Nitro-phenylalanine, 3-Nitro-phenylalanine, 4-Nitro-phenylalanine, 4-pentafluoro-phenylalanine, phenylglycine (Phg), 4-amino-phenylalanine, 4- methoxy-phenylalanine, 5-hydroxytrptophan, 3, 5-diiodo-tyrosine.4-benzoyl- phenylalanine, 5-hydroxy-trptophan, 3, 5-diiodo-tyrosine, 4-benzoyl-phenylalanine (Bpa), cyclohexylglycine (Chg), 2-thienyl-alanine (Thi), or is a residue of an amino acid comprising a side chain having an optionally substituted aryl or heteroaryl group; -AA4 is an amino acid residue of glutamic acid, aspartic acid, glutamine, asparagine, beta-Glu, or beta-Gln;-AA5 is an amino acid residue of glutamine, glycine, alanine, isoleucine, valine, tryptophan, tyrosine, histidine, lysine, arginine, aspartic acid, glutamic acid, serine, threonine, asparagine, phenylalanine, leucine, beta-Glu, beta-Gln, beta-Phe, beta-Tyr, beta-Lys, beta-Arg, norleucine (Nle), citrulline (Cit), norvaline, 1 -naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), 3-(4-biphenyl-alanine (Bip), 2-pyridyl-alanine (2-Pal), 3-pyridyl-alanine (3-Pal), 4-pyridyl-alanine (4-Pal), 3-benzothienyl-alanine (Bta), 4-trifluoromethyl-phenylalanine, 2-cyano-phenylalanine, 3 -cyano-phenylalanine, 4-cyano-phenylalanine, 3-Borono-phenylalanine, 4-Borono-phenylalanine, 2-chloro-phenylalanine, 3-chloro-phenylalanine, 4-chloro-phenylalanine, 2-fluoro-phenylalanine, 3-fluoro-phenylalanine, 4-fluoro-phenylalanine, 2-Iodo-phenylalanine, 3-Iodo-phenylalanine, 4-Iodo-phenylalanine, 2-methyl-phenylalanine, 3-methyl-phenylalanine, 4-methyl-phenylalanine, 2-Nitro-phenylalanine, 3-Nitro-phenylalanine, 4-Nitro-phenylalanine, 4-pentafluoro-phenylalanine, phenylglycine (Phg), 4-amino-phenylalanine, 4-methoxy-phenylalanine, 5-hydroxytrptophan, 3, 5-diiodo-tyrosine. 4-benzoyl-phenylalanine, 5-hydroxy-trptophan, 3, 5-diiodo-tyrosine, 4-benzoyl-phenylalanine (Bpa), cyclohexylglycine (Chg), and 2-thienyl-alanine (Thi);-AA6 is an amino acid residue of tryptophan, phenylalanine, tyrosine, serine, threonine, methionine, glycine, histidine, aspartic acid, beta-Phe, beta-Tyr, 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), 3-(4-biphenyl-alanine (Bip), 2-pyridyl-alanine (2-Pal), 3-pyridyl-alanine (3-Pal), 4-pyridyl-alanine (4-Pal), 3-benzothienyl-alanine (Bta), 4-trifluoromethyl-phenylalanine, 2-cyano-phenylalanine, 3-cyano-phenylalanine, 4-cyano-phenylalanine, 3-Borono-phenylalanine, 4-Borono-phenylalanine, 2-chloro-phenylalanine, 3-chloro-phenylalanine, 4-chloro-phenylalanine, 2-fluoro-phenylalanine, 3-fluoro-phenylalanine, 4-fluoro-phenylalanine, 2-Iodo-phenylalanine, 3-Iodo-phenylalanine, 4-Iodo-phenylalanine, 2-methyl-phenylalanine, 3-methyl-phenylalanine, 4-methyl-phenylalanine, 2-Nitro-phenylalanine, 3-Nitro-phenylalanine, 4-Nitro-phenylalanine, 4-pentafluoro-phenylalanine, phenylglycine (Phg), 4-amino-phenylalanine, 4-methoxy-phenylalanine, 5-hydroxytryptophan, 3, 5-diiodo-tyrosine, 4-benzoyl-phenylalanine, 5-hydroxy-trptophan, 3, 5-diiodo-tyrosine, 4-benzoyl-phenylalanine (Bpa), cyclohexylglycine (Chg), or 2-thienyl-alanine (Thi); and-AA7 is an amino acid residue of tryptophan, methionine, phenylalanine, tyrosine, glycine, glutamine, serine, beta-Phe, beta-Tyr, Norvaline (Nva), norleucine (Nle), citrulline (Cit), norvaline, 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), 3-(4-biphenyl-alanine (Bip), 2-pyridyl-alanine (2-Pal), 3-pyridyl-alanine (3-Pal), 4-pyridyl- alanine (4-Pal), 3-benzothienyl-alanine (Bta), 4-trifluoromethyl-phenylalanine, 2- cyano-phenylalanine, 3 -cyano-phenylalanine, 4-cyano-phenylalanine, 3-Borono- phenylalanine, 4-Borono-phenylalanine, 2-chloro-phenylalanine, 3 -chlorophenylalanine, 4-chloro-phenylalanine, 2-fluoro-phenylalanine, 3-fluoro- phenylalanine, 4-fluoro-phenylalanine, 2-Iodo-phenylalanine, 3-Iodo-phenylalanine, 4- lodo-phenylalanine, 2-methyl-phenylalanine, 3-methyl-phenylalanine, 4-methyl- phenylalanine, 2-Nitro-phenylalanine, 3-Nitro-phenylalanine, 4-Nitro-phenylalanine, 4-pentafluoro-phenylalanine, phenylglycine (Phg), 4-amino-phenylalanine, 4- methoxy-phenylalanine, 5-hydroxytrptophan, 3, 5-diiodo-tyrosine. 4-benzoyl- phenylalanine, 5-hydroxy-trptophan, 3, 5-diiodo-tyrosine, 4-benzoyl-phenylalanine (Bpa), cyclohexylglycine (Chg), and 2-thienyl-alanine (Thi).

3. The composition comprising a fibroblast activation protein alpha (FAI’)-targeted peptide according to claim 1 or claim 2. having the following sequence of residues:- AA1 is a residue of Thr or Ser,-AA2 is a residue of Pro or homoproline,- AA3 is a residue of Trp or another amino acid having a side chain including an optionally substituted aryl or heteroaryl group,-AA4 is a residue of Glu,-AA5 is a residue of Gln, Glu, Ile, His, Asp, Trp, Lys, Arg, Ser, Thr or Asn, -AA6 is a residue of Trp, Phe, Tyr, Ser or Thr, and-AA7 is a residue of Trp, Phe or Tyr.

4. The composition comprising a fibroblast activation protein alpha (FAP)-targeted peptide according to any preceding claim, having the following sequence of residues:- AA1 is a residue of Thr,-AA2 is a residue of Pro,-AA3 is a residue of Trp, Phe, Tyr, or His,-AA4 is a residue of Glu,- AA5 is a residue of Gln, Glu, Ile, His, Asp, Arg, Lys, Ser, Thr or Asn,-AAe is a residue of Trp, Phe, or Tyr, and-AA7 is a residue of Trp, Phe, or Tyr.

5. The composition comprising a fibroblast activation protein alpha (FAP)-targeted peptide according to any one of claims 1 to 3, having the following sequence of residues:- AAi is a residue of Thr.-AA2 is a residue of Pro,-AA3 is a residue of Trp or other amino acid having a side chain including an optionally substituted aryl or heteroaryl group,-AA4 is a residue of Glu,-AA5 is a residue of Gin,-AAe is a residue of Trp, and-AA7 is a residue of Trp.

6. The composition comprising a fibroblast activation protein alpha (FAP)-targeted peptide according to any of the preceding claims, having the following sequence of residues:- AAi is a residue of Thr,“AA2 is a residue of Pro,-AA3 is a residue of Trp, Phe, Tyr, or His,-AA4 is a residue of Glu,-AA5 is a residue of Gln,-AA6 is a residue of Trp, and-AA? is a residue of Trp.

7. The composition comprising a fibroblast activation protein alpha (FAP)-targeted peptide according to claims 1 to 4 having the following sequence of residues:- AAi is a residue of Thr,-AA2 is a residue of Pro,-AA3 is a residue of Trp,-AA4 is a residue of Glu,“AAj is a residue of Gin, Glu, Ala, Leu, He, Vai, Phe, Trp, Tyr, Lys, Arg, His, Asp, Ser, Thr, Asn, or Gly,-AA6 is a residue of Trp, and-AA7 is a residue of Trp.

8. The composition comprising a fibroblast activation protein alpha (FAP)-targeted peptide according to claims 1 to 4, having the following sequence of residues:- AA1 is a residue of Thr,-AA2 is a residue of Pro,-AA3 is a residue of Trp,-AA4 is a residue of Glu,-AA5 is a residue of Gln,-AA6 is a residue of Trp, Phe, or Tyr, and-AA? is a residue of Trp.

9. The composition comprising a fibroblast activation protein alpha (FAP)-targeted peptide according to claims 1 to 4 having the following sequence of residues:- AA1 is a residue of Thr,--AA2 is a residue of Pro,-AA3 is a residue of Trp.-AA4 is a residue of Glu,- AA5 is a residue of Gln,-AAe is a residue of Trp, and-AA7 is a residue of Trp, Phe or Tyr.

10. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate according to any preceding claim, wherein R8, R9 and M together comprise a chain of 6 to 18 ring atoms connecting AA1 to AA7.

11. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate according to any preceding claim, wherein R8, R9 and M together comprise a chain of 8 to 16 ring atoms connecting AA1 to AA7.

12. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate according to any preceding claim, wherein R8, R9 and M together comprise a chain of 10 to 14 ring atoms connecting AA1 to AA7.

13. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate according to any preceding claim, wherein R8 and R9 comprise moieties that are each independently selected from the group consisting of amino acid residues or derivatives thereof, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted aralkylene or optionally substituted heteroaralkylene.

14. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of claim 13, wherein:R8 and R9 are each a derivative of an amino acid,R9 is *-C(O)CH2(NHR7)R77-**, wherein * indicates the point of attachment of the carbonyl group (-C(O)-) to AA1, ** indicates the point of attachment of the amino acid residue to M, and R77 comprises the side chain of the amino acid or is a bond,R8 is+-R66(C(O)R6)CH2NH-++, wherein+indicates the point of attachment of the amino acid residue to M,++indicates the point of attachment of the amine group (-NH-) to AA7 and R66 comprises the side chain of the amino acid or is a bond,R6 is L in embodiments where Y-L is bound to R8, or is -NR20R21, -OR22, an amino acid residue, or other C-terminal modification of R8 in embodiments where Y-L is bound to M, where R20 and R21 are independently hydrogen or optionally substituted C1-C6 alkyl, and R22is hydrogen or optionally substituted C1-C6 alkyl, andR7 is hydrogen, optionally substituted C1-C10 alkyl or heteroalkyl, an optionally substituted C1-C10 acyl or heteroacyl group either of which may be straight or branched and may contain one or more additional acyl groups, hydroxyl groups, carboxyl groups, amide group, amine groups or imine groups or other N-terminal modification of R9, including an amino acid residue and / or acylated amino acid residue.

15. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of claim 14, wherein R7 comprises an optionally substituted C1-C10 acyl or heteroacyl group, which may be straight or branched and may contain one or more additional acyl groups, hydroxyl groups, carboxyl groups, amide group, amine groups or imine groups at an end furthest from the N-terminus of R9.

16. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of claim 14, wherein R7 is selected from the following group:

17. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one of claims 13 to 16, wherein R8 and R9 comprise moieties that are independently selected from the group consisting of residues of cysteine, lysine, aspartic acid, glutamic acid, penicillamine, 2-amino-3-mercaptobutanoic acid, 3-mercaptopropionic acid, 2,3-diaminopropionic acid, and cysteamine, or derivatives thereof.

18. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one of the preceding claims wherein the cyclization moiety, M, comprises a cyclic or acyclic moiety that includes 2 to 8 ring atoms connecting R9 to R8 selected from the group consisting of optionally substituted carbon, optionally substituted nitrogen, oxygen and sulfur.

19. The composition comprising a fibroblast activation protein alpha (FAP)-targeting conjugate of any of claims 13-18 wherein one of R8 and R9 comprises a residue of lysine or derivative thereof, and the other of R8 and R9 comprises a residue of aspartic acid or lactic acid or derivative thereof, and wherein M is a bond that forms a lactam bridge between R8 and R9.

20. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any of claims 13-19 wherein R7 and R9 comprise cysteine residues or derivatives thereof, and wherein the cyclization moiety M is bonded to the cysteine residues through the cysteine side chains.21 The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one of the preceding claims, wherein the conjugate comprises any of the following Formulas 5a-5d, or 6a-6dFormula 5aFormula 5cFormula 6bFormula 6cwherein R5 is selected from the group consisting of optionally substituted aryl and heteroaryl. Rn is a side chain of an amino acid residue selected from the group consisting of glutamine, glycine, alanine, isoleucine, leucine, valine, lysine, arginine, aspartic acid, glutamic acid, serine, threonine, asparagine, phenylalanine, tryptophan, tyrosine, or histidine, R12 is a side chain of an amino acid residue selected from the group consisting of tryptophan, phenylalanine, tyrosine, serine, threonine, methionine, glycine, histidine, and aspartic acid and R13 is a side chain of an amino acid residue selected from the group consisting of tryptophan, methionine, phenylalanine, glycine, glutamine, serine and tyrosine.

22. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one of the preceding claims, wherein M is an optionally substituted carbocyclic alkylene or optionally substituted heterocylic alkylene corresponding to Formula 7Formula 7wherein each t is independently 1-2, n is 0 to 2, each RE is independently halogen, hydroxy, thiol, amino, or Ci-Ce alkyl and ring E is an optionally substituted, 5 to 10-membered carbocycle or heterocycle.

23. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of claim 22, wherein ring E is selected from the group consisting of pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, furan, thiophene, benzene, pyridine, pyran, pyrimidine, pyridazine, pyrazine, piperazine, thiazine, oxazine, indole, isoindole, quinoline, isoquinoline, purine, naphthalene, purine, and chroman.

24. The composition comprising a fibroblast activation protein alpha (FAP)- targeted conjugate of any one of claims 22-23, wherein M corresponds to Formula 7 and -R9-M-R8-corresponds to Formula 8 below:Formula 8wherein the wavy lines, indicate the point of attachment of Rs to AA7 and R9 to AAi and wherein each t is independently 1-2, n is 0 to 2, each RE is independently halogen, hydroxy, thiol, amino, or Ci-Ce alkyl and ring E is an optionally substituted, 5 to 10-membered carbocycle or heterocycle.

25. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one of claims 22-24, wherein each of Rs and R9 comprise residues of an amino acid or derivative thereof, each t is 1, E is an aromatic or heteroaromatic ring comprising 5-10 ring atoms, n is 0-3, and each RE is independently, halogen, hydroxy, thiol, amino, or Ci-Ce alkyl.

26. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of claim 25, wherein E is any of benzene, naphthylene, or a 5-membered heteroaromatic ring.

27. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one of claims 22-26 having the following structure:wherein AAi to AA?, Re, R7, Ree, R77, t, n, E and RE are as described above, and wherein at least one of Re or at least one RE comprises L-Y.

28. The fibroblast activation protein alpha (FAP)-targeted conjugate of any one of the preceding claims, wherein the conjugate comprises a structure according to any of Formulas 10a-10d below:Formula 10aFormula 10bFormula 10cwherein Rs is selected from the group consisting of optionally substituted aryl and heteroaryl, Rn is a side chain of an amino acid residue selected from the group consisting of glutamine, glycine, alanine, isoleucine, leucine, valine, lysine, arginine, aspartic acid, glutamic acid, serine, threonine, asparagine, phenylalanine, tryptophan, tyrosine, or histidine, R12 is a side chain of an amino acid residue selected from the group consisting of tryptophan, phenylalanine, tyrosine, serine, threonine, methionine, glycine, histidine, and aspartic acid, and R13 is a side chain of an amino acid residue selected from the group consisting of tryptophan, methionine, phenylalanine, glycine, glutamine, serine and tyrosine, R- is hydrogen, optionally substituted Ci-Cio alkyl or heteroalkyl, an optionally substituted Ci-Cio acyl or heteroacyl group either of which may be straight or branched and may contain one or more additional acyl groups, hydroxyl groups, carboxyl groups, amide group, amine groups or imine groups or other N-terminal modification of R9, including an amino acid residue and / or acylated amino acid residue, t is 0-2, E is a 5 to 10-membered carbocycle or heterocycle, n is 0-2 and each RE is independently halogen, hydroxy, thiol, amino, or Ci-Ce alkyl.

29. The fibroblast activation protein alpha (FAP)-targeted conjugate of any one of the preceding claims, wherein the conjugate comprises a structure according to any of Formulas 11a-11d below:Formula 11bFormula 11cFormula lidwherein Rs is selected from the group consisting of optionally substituted aryl and heteroaryl. Rn is a side chain of an amino acid residue selected from the group consisting of glutamine, glycine, alanine, isoleucine, leucine, valine, lysine, arginine, aspartic acid, glutamic acid, serine, threonine, asparagine, phenylalanine, tryptophan, tyrosine, or histidine, R12 is a side chain of an amino acid residue of tryptophan, phenylalanine, tyrosine, serine, threonine, methionine, glycine, histidine, aspartic acid, R13 is a side chain of an ammo acid residue selected from the group consisting tryptophan, methionine, phenylalanine, glycine, glutamine, serine and tyrosine, Re is -NR20R21, or -OR22, an amino acid residue, or other C-terminal modification, where R20 and R21 are independently hydrogen or optionally substituted Ci-Ce alkyl, and R22 is hydrogen or optionally substituted Ci-Ce alkyl, R7 is hydrogen, optionally substituted C1-C10 alkyl or heteroalkyl, an optionally substituted C1-C10 acyl or heteroacyl group either of which may be straight or branched and may contain one or more additional acyl groups, hydroxyl groups, carboxyl groups, amide group, amine groups or imine groups or other N-terminal modification of R9, including an amino acid residue and / or acylated amino acid residue, t is 0-2, E is a 5 to 10-membered carbocycle or heterocycle, n is 0-2 and each RE is independently halogen, hydroxy, thiol, amino, or Ci-Ce alkyl.

30. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one of the preceding claims, wherein M comprises the structure according to Formula 12, having substituent in the ortho, meta, or para position with respect to each other:Formula 12wherein n is 0-2 and each RE is independently halogen, hydroxy, thiol, amino, or Ci-Ce alkyl.

31. The composition comprising a fibroblast activation protein alpha (FAI’)-targeted conjugate of any one of the preceding claims, wherein the chelator (Y) comprises the following structureOR!where each Ri is independently hydrogen or an alkyl group,R.2 is -ORi, -NH2 or a bond connecting the chelator to the linker, L, or directly bonds to the binding peptide, in a case where L is a bond,R3 and R4 are independently hydrogen or a bond connecting the chelator to the linker, L, or directly bonds to the binding peptide, in a case where L is a bond, provided (i) at least one of R3 and Rus hydrogen, and (ii) each of R3 and Rus hydrogen when R2 is a bond connecting the chelator, to the linker, L, or directly bonds to the binding peptide, in a case where L is a bond.

32. The composition comprising a fibroblast activation protein alpha (FAP)- targeted conjugate of any one of claims I to 30, wherem the chelator (Y) comprises the following structurewhere each Ri is independently hydrogen or an alkyl group,R.2 is -ORi, -NH2 or a bond connecting the chelator to the linker, L, or connecting to the binding peptide, in a case where L is a bond,R3 and R4 are independently hydrogen or a bond connecting the chelator to the linker, L, or connecting to the binding peptide, in a case where L is a bond, provided (i) at least one of Rs and Rus hydrogen, and (ii) each ofRs and Rus hydrogen when R2 is a bond connecting the NOTA chelator, to the linker, L, or connecting to the binding peptide, in a case where L is a bond.

33. The composition comprising a fibroblast activation protein alpha (FAP)-iargeted conjugate of any one of claims 1 to 30. wherein the chelator (Y) is any selected from the group consisting of AAZTA, BAT, BAT-TM, Crown, Cyclen, DO2A. CB-DO2A, DO3A. H3HP-DO3A, Oxo-DO3A, p-NH2-Bn-Oxo-DO3A, PSC, DOTA, DOTAGpy, DOTA-PA, DOTA-GA. DOTA-4AMP, DOTA-2py, DOTA-lpy, p-SCN-Bn-DOTA, CHX-A”-EDT. MeO-DOTA-NCS EDTA, DOTAMAP, DOTAGA, DOTAGA-anhydride, DOTMA, DOTASA, DOTAM, DOTP, CB-Cyclam, TE2 A, CB-TE2A, CB-TE2P, DM-TE2A, MM- TE2A. NOTA, NOTP, HEHA, HEHA-NCS, p-SCN-Bn-HEHA, DTP A, CHX-A"-DTP, p-. H.2-BD.-CHX-A"-DTPA, p-SCN-DTPA. p-SCN-Bz-Mx-DTPA. 1B4M-DTP A, p-SCN- BnlB-DTPA, p-SCN-Bml B4M-DTPA, p-SC IG MX- A’7- DT ’PA, PEPA, p-SCN-Bn- PEPA, TETPA, DOTPA, DOTMP, DOTPM, t-Bu-calix|4]arene-tetracarboxylic acid, macropa, macropa-NCS, macropid, H3L1, H3L4, Ebazapa. Hsdecapa, bi spa2, Hrpypa, H-ioctapa, HsCHXoctapa, p-SCN-Bn-Hioctapa, p-SCN-Bn-H4OCtapa, TTHA, p-NCh-Bn- neunpa, I-hoctox, I-fcmacropa, H2bispa2, Thphospa, Hsphospa, p-SCN-Bn-Hgphospa, TETA, p- NO 2-Bn-TETA. TRAP, TP A. HBED, SHBED, HBED-CC, (HBED-CC)TFP, DMS A, DMPS, DHLA. lipoic acid, TGA, BAL, Bis-thioseminarabazones, p-SCN-NOTA, nNOTA,NODAGA, CB-TE1A1P, 3P-C-NETA-NCS, 3p-C-DEPA, 3P-C-DEPA-NCS, TCMC, PCTA, NODIA-Me, TACN, pycuplAlB, pycup2A, THP, DEDPA, H2DEDPA, p-SCN-Bn-H Di DPA. p-SCN-Bn-TCMC, motexafm, NT A, NOC, 3p-C-NETA, p-NH2-Bn-TE3A, SarAr, DiAmSar, SarAr-NCS, AmBaSar, BaBaSar. TACN-TM, CP256, C-NE3TA, C- NE3TA-NCS, NODASA, NETA-monoamide, C-NETA, NOPO, BPCA. p-SCN-Bn-DFO, DI O-ChX -Mai, DFO, DFO-IAC, DFO-BAC, DiP-LICAM, EC. SBAD, BAPEN.TACHPYR, NEC-SP, Lpy, LI, L2, L3, EuK-106, DTA, CyEDTA, EDTMP, DTPMP, DTPA, CyDTP, Cy2DTPA, DTPA-MA, DTPA-BA, 2,2',2"-(10-(2-amino-2-oxoethyl)-l,4,7,10-tetraazacyclododecane-l,4,7-triyl)triacetic acid, (2,2',2"-(10-(2-amino-2-oxoethyl)-l,4,7,10-tetraazacyclododecane-l,4,7-triyl)triaethanoic acid), and BOP A.34 The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one of claims 1 to 30, wirerein the chelator (Y) is any selected from the group consisting of 2,2',2'',2'"-(l,4,7,10-Tetraazacyclododecane-l,4,7,10-tetrayl)tetraacetic acid (DOTA), l,4,7-triazacyclononane-l,4,7-triacetic acid (NOTA), or 1,4,7,10-Tetraazacyclododecane-7-acetamide -1,4,10-triacetic acid or 2,2',2"-(10-(2-amino-2-oxoethyl)-l,4,7,10-tetraazacyclododecane-l,4,7-triyl)triacetic acid or (2,2',2"-(10-(2-amino-2-oxoethyl)-l,4,7,10-tetraazacyclododecane-l,4,7-triyl)triaethanoic acid) (lead specific chelator, or PSC).

35. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one of the preceding claims, wherein L comprises a linker that comprises any one or more of an amino acid residue, a polyethylene glycol group having from 1 to 10 repeat groups, a piperidine group, a benzyl isothiocyanate group, a pyrazine group, and the residue of compound having the formula NH? — (CH?)n-(C=O)OH, wherein n is 1 to 10.

36. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one of the preceding claims, wherein the linker comprises any one or combination of 2 or more residues of lysine, serine, phenylalanine, cysteamine, 6-aminohexanoic acid, benzyl-isothiocyanate, and an amino-polyethylene glycol-acid having from 1 to 4 polyethylene glycol groups.

37. The composition comprising a fibroblast activation protein alpha (F API-targeted conjugate of any one of the preceding claims, wherein L comprises the residue of a modified polyethylene glycol group comprising the formula NH2-(CH2-CH2-O)n-(CH2)m-C(=O)OH, where n = 1-4 and m = 1-2.

38. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one of the preceding claims, wherein the conjugate is radiolabeled with a radionuclide comprising any selected from the group consisting of21Pb.47Cu,'i4Cu,89Zr,90Y.!09Pd,luAg,!49Pm,i5?Sm,566HO,99" Tc,67Ga,6SGaJiiIri.90Y,177I. ALJ1S6R.e,iS8Re,i97Aiii98Au,i99Au?05Rh,165FIo,161Tb,149Prn,44Sc,47S c,7aAs,71As,72As,73As,74As,76As,77As,212Pb,212Bi,213Bi,228Ac,i i7'”Sn,67Ga,20!rH,,23I,i3!I?60Gd,!4SNd,89Sr,2nAt,4JSc,44Sc,51Mn.S4Cu,67Ga,68Ga.saY,89Zr,99," Tc, W,76B,77Br,11‘In,1231.1251,152Tb,>3Pb,596Pb,197Pb,198Pb,199Pb,200Pb,201Pb,202Pb,205Pb,209Pb,210Pb,211Pb,213Pb,214Pb,215Pb, and216Pb39. The fibroblast activation protein alpha (FAP)-targeted conjugate of any one of the preceding claims, wherein the binding peptide comprises a structure according to any of the following formulas:wherein the chelator, and optionally linker, are connected at the location of one of the wavy lines in the above structures.

40. The fibroblast activation protein alpha (FAP)-targeted conjugate of any one of the preceding claims, wherein the conjugate is radiolabeled with a radionuclide that is used for medical imaging and / or therapy of the cancerous tumors.

41. The fibroblast activation protein alpha (FAP)-targeted conjugate of any one of the preceding claims, comprising any of the following formulas:VMT-FAP-2-26: (Ac-S-[C(oXdB)TPFEQWWC]-Lys(NH2)-PEG2-PSC)VMT-FAP-2-55 (Ac-S-[C(mXtB(CA-PEG2-PSC))TPWEQWWC]-NH2)VMT-FAP-2-57 (But-[C(mXtB(CA-PEG2-PSC))TPWEQWWC]-NH2)42. The composition comprising a fibroblast activation protein alpha (F. AP)-targeted conjugate of any one of the preceding claims, wherein the FAP -targeting conjugate further comprises an albumin-binding moiety.

43. The composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one of the preceding claims, wherein Y comprises a cytotoxic drug.

44. A method of targeting a fibroblast activation protein alpha (FAP) comprising administering a composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate according to any one of claims 1-43, wherein the conjugate is radiolabeled.

45. A method of imaging and / or diagnosing a subject having a disorder that is a result of or associated with upregulated FAP expression, the method comprising administering to the subject a composition comprising a fibroblast activation protein alpha (F AP)- targeted conjugate of any one of claims 1-43, wherein the conjugate is radiolabeled, and imaging the subject.

46. A method of treating a subject having a disorder that is a result of or associated with upregulated FAP expression, the method comprising administering to the subject a composition comprising a fibroblast activation protein alpha (F API-targeted conjugate of any one of claims 1-43, wherein the conjugate is radiolabeled.47 A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one claims 1-43, wherein the conjugate is radiolabeled.

48. The method according to claim 47, wherein the cancer is any selected from the group consisting of agastric cancer, brain cancer, myeloma, melanoma, sarcoma, salivary gland cancer, esophageal cancer, cholangiocarcinoma, breast cancer, lung cancer, prostate cancer.pancreatic cancer, thymus cancer, head and neck cancer, ovarian cancer, desmoid tumor, chordoma, colorectal cancer, anal cancer, neuroendocrine tumor, small intestine cancer, medullary' thyroid cancer, cervical cancer, endometrial cancer, hepatocellular cancer, gastric cancer, adenoid cystic cancer, pheochromocytoma, differentiated thyroid cancer, insulinoma, kidney cancer, and skin cancer.

49. A method of treating a disorder in a subject in need thereof, the method comprising administering to the subject a composition comprising a fibroblast activation protein alpha (FAP)-targeted conjugate of any one of the preceding claims 1-43, wherein the conjugate is radiolabeled and wherein the disorder is any selected from the group consisting of a wound healing disorder, fibrosis, arthritis, atherosclerotic plaques, autoimmune diseases, metabolic diseases, and ischemic heart tissue after myocardial infarction.

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