Radiolabeled compounds for in vivo imaging of the gastrin-releasing peptide receptor (GRPR) and treatment of GRPR-associated disorders

Abstract

Formula I, A or B (R rad n6 -[Linker]-R L -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -ψ-Xaa 9 -NH2) is provided. 1 is D-Phe, Cpa, D-Cpa, Nal, D-Nal, 2-Nal, or D-2-Nal; 2 is Asn, Gln, Hse, Cit, or His. 3 is Trp, Bta, Trp(Me), Trp(7-Me), Trp(6-Me), Trp(5-Me), Trp(4-Me), Trp(2-Me), Trp(7-F), Trp(6-F), Trp(5-F), Trp(4-F), Trp(5-OH), or αMe-Trp. 4 is Ala or Ser. 5 is Val, Cpg, or Tle. 6 is Gly, NMe-Gly, or D-Ala. 7 is His or NMe-His. 8 is Leu or Phe. 9 -NH2 is a C-terminal amidated amino acid residue selected from Pro, 4-oxa-L-Pro, Me2Thz, or Thz. ψ is Xaa 8 Xaa 9 R represents a peptide bond or reduced peptide bond to be bonded to rad n6 is 1 to 5 radiolabeling groups. Also provided is the use of such compounds as imaging agents or therapeutic agents.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 323,831, filed March 25, 2022, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0002] The present invention relates to radiolabeled compounds for the in vivo imaging or treatment of diseases or conditions characterized by expression of the Gastrin Releasing Peptide Receptor. [Background technology]

[0003] The gastrin releasing peptide receptor (GRPR) is a G protein-coupled receptor of the bombesin (BBN) receptor family (Roesler & Schwartsmann. 2012. Front Endocrinol (Lausanne) 3:159; Bitar & Zhu. 1993. Gastroenterology. 105:1672-1680; Weber. 2009. Curr Opin Endocrinol Diabetes Obes. 16:66-71). Together with its endogenous ligand, gastrin releasing peptide (GRP), GRPR is involved in synaptic plasticity, emotional and feeding behavior, hormone secretion, smooth muscle contraction, and cell proliferation (ibid.). Under normal conditions, GRPR expression is restricted to the central nervous system, pancreas, adrenal cortex, and gastrointestinal tract (Jensen, et al. 2008. Pharmacol Rev. 60:1-42). GRPR is also involved in tumor progression, and overexpression of GRPR has been reported in many cancer subtypes, including lung, head and neck, colon, kidney, ovarian, breast, and prostate cancers (Cornelio, et al. 2007. Ann Oncol. 18:1457-1466). This ectopic expression in cancer makes it an attractive target for personalized therapy.

[0004] BBN is a 14-amino acid GRPR-binding peptide (Lin, et al.2004.Bioconjugate Chemistry.Vol 15.American Chemical Society pages 1416-1423;Inkster,et al.2013 Bioorganic Med Chem Lett.23:3920-3926;Mansi,et al.2016 J Nucl Med.57:67S-72S;Bodei,et al. al.2007. 177 Lu-AMBA Bombesin analogue in hormone refractory prostate cancer patients:a phase I escalation study with single-cycle administrations.In:JOINT EANM-EORTC Symposium;Sah,et al.2015 J Nucl Med.56:372-378;Zang,et al.2018 Clin Nucl Med.43:663-669;Nock,et al.2017 J Nucl Med.58:75-80; Maina, et al.2016 Eur J Nucl Med Mol Imaging 43:964-973). BBN derivatives have been radiolabeled for imaging with single photon emission computed tomography (SPECT), positron emission tomography (PET), and for therapy with beta and alpha emitters (Maina, et al. PET Clin. 2017;12:297-309; Lin, et al. 2004. Bioconjugate Chemistry. Vol 15. American Chemical Society pages 1416-1423; Inkster, et al. 2013 Bioorganic Med Chem Lett. 23:3920-3926). In most cases, the radiolabeling group is added to the N-terminus of the structure directly or via a linker, and modifications at the C-terminus determine the agonist / antagonist properties. When targeting the GRPR, antagonists are preferred, as agonists have been shown to induce gastrointestinal adverse events (Bodei, et al. 2007.177 Lu-AMBA Bombesin analogue in hormone refractory prostate cancer patients: a phase I escalation study with single-cycle administrations. In: JOINT EANM-EORTC Symposium). Examples of GRPR antagonists being evaluated in clinical trials include: 68 Ga-RM2, 68 Ga-SB3, 68 Ga-NeoBOMB1, 68 Ga-RM26, 18 F-BAY-864367, and 64 Cu-CB-TE2A-AR06(Mansi,et al.2016 J Nucl Med.57:67S-72S;Sah,et al.2015 J Nucl Med.56:372-378;Zang,et al.2018 Clin Nucl Med.43:663-669;Nock,et al.2017 J Nucl Med.58:75-80;Maina,et al.2016 Eur J Nucl Med Mol Imaging 43:964-973;Kahkonen,et al.Clin Cancer Res.2013;19:5434-5443,Kahkonen,et al.Clin Cancer Res.2013;19:5434-5443;Baum,et al.2007 Journal of Nuclear Medicine 48,79P-79P).

[0005] High pancreatic uptake is the main limitation of currently reported GRPR-targeted radioligands. 68 High uptake of Ga-labeled AMBA in the pancreas was observed with a maximum of 54.9 SUV (SUV: standard uptake value) (Baum, et al. 2007 Journal of Nuclear Medicine 48, 79P-79P). 68Ga-labeled RM2 was also reported to show high uptake in the pancreas (Kurth, et al. 2020. European journal of nuclear medicine and molecular imaging 47, 123-135; Minamimoto, et al. 2016 J Nucl Med. 57: 557-562). Radiolabeled NeoBOMB1 was also reported to show high pancreatic uptake in both PC-3 tumor-bearing mice and prostate cancer patients (Nock, et al. 2017 J Nucl Med. 58: 75-80).

[0006] Another limitation of most reported GRPR-targeting ligands is their in vivo metabolic instability (Bakker, et al. 2018 Molecular imaging and biology 20, 973-983; Rousseau, et al. 2020 Journal of Labelled Compounds and Radiopharmaceuticals 63, 56-64) due to enzymatic degradation by neutral endopeptidase (NEP) (Nock, et al. 2014 J Nucl Med. 55: 121-127). 12 -Leu 13 , Trp 8 -Ala 9 , and Gln 7 -Trp 8 is reported to be the major cleavage site within the AMBA sequence, and Trp 8 -Ala 9 , Ala 9 -Val 10 , and Gln 7 -Trp 8 was considered to be the cleavage site of RM2 (Kahkonen, et al. 2013 Clin Cancer Res. 19:5434-5443; Linder et al. 2009 Bioconjugate chemistry 20,1171-1178).

[0007] There remains an unmet need in the art for improved tracers for non-invasive in vivo imaging of GRPR. Such tracers are useful for diagnosing disorders associated with abnormal / ectopic expression of GRPR, including but not limited to cancer (e.g., prostate cancer). There also remains an unmet need for improved radiotherapeutic agents for the treatment of diseases / disorders associated with abnormal / ectopic expression of GRPR, including but not limited to cancer (e.g., prostate cancer). In particular, there is a need for GRPR-targeted radioligands (for imaging and / or therapy) that have low pancreatic uptake and good stability in vivo.

[0008] No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention. Summary of the Invention

[0009] In one aspect, the disclosure provides peptide compounds of formula I (defined below). Such compounds may have lower pancreatic uptake than prior art bombesin analogues and superior stability in vivo for imaging and / or radiotherapy. [Brief description of the drawings]

[0010] The features of the present invention will become apparent from the following description taken in conjunction with the accompanying drawings.

[0011] [Figure 1] Figure 1 shows representative maximum intensity projection PET images of 68Ga-LW01025, 68Ga-LW01029, 68Ga-LW01107, 68Ga-LW01108, 68Ga-LW01110, 68Ga-LW01142, 68Ga-LW01158, and 68Ga-LW01102 in mice bearing PC-3 tumor xenografts. Images were acquired 1 hour after injection.

[0012] [Diagram 2]FIG. 2 shows representative radio-HPLC chromatograms of 68Ga-LW01025 extracted from mouse urine and plasma samples.

[0013] [Diagram 3] FIG. 3 shows representative radio-HPLC chromatograms from the analysis of the intact fraction of 68Ga-LW01029 in mouse plasma (A) and urine (B) samples taken 15 min after injection.

[0014] [Figure 4] FIG. 4 shows representative radio-HPLC chromatograms of 68Ga-LW01107 extracted from mouse urine and plasma samples.

[0015] [Diagram 5] FIG. 5 shows representative radio-HPLC chromatograms of 68Ga-LW01108 extracted from mouse urine and plasma samples.

[0016] [Figure 6] FIG. 6 shows representative radio-HPLC chromatograms of 68Ga-LW01110 extracted from mouse urine and plasma samples.

[0017] [Figure 7] FIG. 7 shows representative radio-HPLC chromatograms of 68Ga-LW01142 extracted from mouse urine and plasma samples.

[0018] [Figure 8] FIG. 8 shows representative radio-HPLC chromatograms of 68Ga-LW01102 extracted from mouse urine and plasma samples.

[0019] [Figure 9A]Figures 9A-C show representative data for 68Ga-LW01045, including representative maximum intensity projection PET images of 68Ga-LW01045 in mice bearing PC-3 tumor xenografts (Figure 9A), representative displacement curves of [125I-Tyr4]bombesin by Ga-LW01045 generated using GRPR-expressing PC-3 cells (Figure 9B), and radio-HPLC chromatograms of 68Ga-LW01045 extracted from mouse urine and plasma samples (Figure 9C). [Figure 9B] Same as above. [Figure 9C] Same as above.

[0020] [Figure 10A] Figures 10A-B show representative data for 68Ga-LW01059, including maximum intensity projection PET images of 68Ga-LW01059 in mice bearing PC-3 tumor xenografts (Figure 10A) and the displacement curve of [125I-Tyr4]bombesin by Ga-LW01059 generated using GRPR-expressing PC-3 cells (Figure 10B). [Figure 10B] Same as above.

[0021] [Figure 11A] 11A-11C show representative data for 68Ga-LW01090, including maximum intensity projection PET images of 68Ga-LW01090 in mice bearing PC-3 tumor xenografts (FIG. 11A), the displacement curve of [125I-Tyr4]bombesin by Ga-LW01090 generated using GRPR-expressing PC-3 cells (FIG. 11B), and radio-HPLC chromatograms of 68Ga-LW01090 extracted from mouse urine and plasma samples (FIG. 11C). [Figure 11B] Same as above. [Figure 11C] Same as above.

[0022] [Figure 12A]12A-B show representative data for 68Ga-LW01117, including maximum intensity projection PET images of 68Ga-LW01117 in mice bearing PC-3 tumor xenografts (FIG. 12A), and a representative displacement curve of [125I-Tyr4]bombesin with Ga-LW01117 generated using GRPR-expressing PC-3 cells (FIG. 12B). [Figure 12B] Same as above.

[0023] [Figure 13] FIG. 13 shows representative maximum intensity projection PET images of 68Ga-LW02045 in mice bearing PC-3 tumor xenografts. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] As used herein, the words "comprising," "having," "including," and "containing," as well as grammatical variations thereof, are inclusive and open-ended and do not exclude additional unrecited elements and / or features / components that are defined as being part of the specified features / components, even if the features / components consist or consist essentially of the specified features / components. When used herein in the context of a compound, composition, use, or method, the term "consisting essentially of" means that additional elements and / or method steps may be present, but these additions do not substantially affect the manner in which the recited compound, composition, method, or use functions. When used herein in the context of a compound, composition, use, or method feature, the term "consisting of" 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, 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 those embodiments are specifically mentioned). Uses or methods described herein as including certain elements and / or steps may in certain embodiments consist essentially of those elements and / or steps, and in other embodiments consist of those elements and / or steps (regardless of whether those embodiments are specifically referred to).

[0025] Reference to an element with the indefinite article "a" does not exclude the possibility that more than one element is present, unless the context clearly requires that only one element is present. The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. When used herein in conjunction with the term "comprising," the use of the words "a" or "an" can mean "one," but is also consistent with the meanings of "one or more," "at least one," and "one or more than one."

[0026] In this disclosure, the recitation of numerical ranges by endpoints includes all numbers subsumed within that range, including all whole numbers, integers, and, where appropriate, all intermediate fractions (e.g., 1 to 5 can include 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5, etc.).

[0027] Unless otherwise specified, terms such as "certain particular embodiment," "various embodiments," "an embodiment," and similar terms include the particular feature described for that embodiment, either alone or in combination with any other embodiment described herein, whether other embodiments are referenced directly or indirectly, and whether the feature or embodiment is described in the context of a method, product, use, composition, compound, etc.

[0028] As used herein, the terms "treat," "treatment," "therapeutic," and the like include amelioration of symptoms, reduction in disease progression, improved prognosis, and reduction in recurrence.

[0029] As used herein, the term "diagnostic agent" includes an "imaging agent." Thus, a "diagnostic radionuclide" includes a radionuclide suitable for use in an imaging agent.

[0030] The term "subject" refers to an animal (e.g., a mammal or a non-mammal). The subject may be a human or a non-human primate. The subject may be a laboratory mammal (e.g., a mouse, rat, rabbit, hamster, etc.). The subject may be a farm animal (e.g., a horse, sheep, cow, pig, camelid, etc.) or a domestic animal (e.g., a dog, cat, etc.). In some embodiments, the subject is a human.

[0031] The compounds disclosed herein may also include their free base forms, solvates, salts, or pharma- ceutically acceptable salts.Unless otherwise specified or indicated, the compounds claimed and described herein are intended to include all racemic mixtures and all individual enantiomers or combinations thereof, whether or not expressly represented herein.

[0032] The compounds disclosed herein may be shown with one or more charged groups, with ionizable groups in an uncharged (e.g., protonated) state, or without specifying a formal charge. As will be understood by those skilled in the art, the ionization state of a particular group in a compound (e.g., but not limited to, COOH) depends, among other things, on the pKa of that group and the pH of its location. By way of example and not limitation, it will be understood that a carboxylic acid group (i.e., COOH) is typically deprotonated (and negatively charged) at neutral pH and up to physiological pH values, unless the protonation state is stabilized.

[0033] As used herein, the terms "salt" and "solvate" have their usual meaning in chemistry. Thus, when a compound is a salt or solvate, it is associated with a suitable counterion. Methods of preparing salts or exchanging counterions are well known in the art. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g., but not limited to, Na, Ca, Mg, or K hydroxides, carbonates, bicarbonates, etc.) or by reacting the 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. The counterion may be changed by ion exchange techniques, such as, for example, ion exchange chromatography. All zwitterions, salts, solvates, and counterions are intended unless a particular form is specifically indicated.

[0034] In certain embodiments, the salt or counterion may be pharma- ceutically acceptable for administration to a subject. As used herein, "pharma- ceutically acceptable" means suitable for in vivo use in a subject, including but not necessarily limited to therapeutic use, including diagnostic use. More generally, with respect to any pharmaceutical composition disclosed herein, non-limiting examples of suitable excipients include any suitable buffer, stabilizer, salt, antioxidant, complexing agent, isotonicity agent, cryoprotectant, lyoprotectant, suspending agent, emulsifying agent, antimicrobial agent, preservative, chelating agent, binder, surfactant, wetting agent, non-aqueous vehicle such as fixed oil, or sustained or controlled release polymer. 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.

[0035] As used herein, "C nThe phrase "where n is an integer (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.) or n is defined as an integer range (e.g., 1-20, 1-18, 2-15, 3-20, etc.)" refers to the number of carbons in a compound, R group, L group, or substituent, or the number of carbons and heteroatoms in a compound, R group, L group, or substituent. An integer range includes all integers within that range, for example, the range 1-20 includes the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. Unless otherwise defined, heteroatoms may include any, some, or all of the possible heteroatoms. For example, in some embodiments, the heteroatoms may be selected from N, O, S, P, and Se. In some embodiments, the heteroatoms are selected from N, S, or O. Such embodiments are non-limiting. "Cy-Cz," where y and z are integers (e.g., C3-C 15 An alternative expression of "C n " (where n is an integer range from y to z).

[0036] The terms "alkyl", "alkylenyl", "alkenylenyl", and "alkynylenyl" have their usual meanings in organic chemistry. For example, "alkenylenyl" has at least one carbon-carbon double bond and may have any number of carbon-carbon single bonds. Similarly, "alkynylenyl" has at least one carbon-carbon triple bond and may have any number of carbon-carbon single bonds. The terms "alkylenyl, alkenylenyl, and / or alkynylenyl" and "alkylenyl, alkenylenyl, or alkynylenyl" are intended to be equivalent and each include a hydrocarbon chain that may have any reasonable number of carbon-carbon single bonds, double bonds, and triple bonds, or combinations thereof. These hydrocarbon chains may be linear, branched, cyclic, or any combination of linear and branched, linear and cyclic, cyclic and branched, branched and cyclic, or linear, branched, and cyclic. Cyclic hydrocarbons may be non-aromatic, partially aromatic, or aromatic. Unless otherwise specified, the term "cyclic" includes single rings, multiple non-fused rings, fused rings, bridged rings, and combinations thereof.

[0037] The phrase "any carbon... is optionally and independently replaced by N, S, or O" and other similar phrases refer to a defined hydrocarbon (e.g., "alkyl", "alkylenyl", "alkenylenyl", or "alkynylenyl") that includes zero, one, two or more heteroatoms, or any reasonable combination of two or more heteroatoms selected from N, S, and O. Thus, the above phrases expand the defined hydrocarbon to additionally include heteroalkyl, heteroalkylenyl, heteroalkenylenyl, and heteroalkynylenyl, etc. One of ordinary skill in the art will appreciate that various combinations of different heteroatoms may be used. The phrase "any carbon bonded to two other carbons is optionally and independently replaced by N, S, or O" and other similar phrases refer to any carbon in the defined hydrocarbon that is bonded to two other carbons (e.g., -C- C-C- (underlined carbon) also means that the bonds may be heteroatoms, whether those bonds are single, double, or triple bonds, but excludes heteroatoms bonded to other heteroatoms (e.g., excluding -CNS-, -SSN-, -NSC-, etc.).

[0038] Various R groups (e.g., R 1 , R 2 , R 3 etc.) and L groups (e.g., L 1 , L 2 , L 3 etc.) are defined in the present disclosure. L groups generally include linkages (e.g., -S-, -NH-C(O)-, -C(O)-NH-, -N(alkyl)-C(O)-, -C(O)-N(alkyl)-, -NH-C(O)-NH-, -NH-C(S)-NH-, [ka] )

[0039] If not specified, the size of the R or L group is that which would be considered reasonable by one of ordinary skill in the art. By way of example and not limitation, if not specified, the size of the alkyl group may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 108, 109, 110, 111, , 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or more than 100 carbon lengths. Further, without being limited, if not specified, the size of the heteroalkyl may be any of the following, according to common general knowledge to one of ordinary skill in the art: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 109, 108, 109, 109, 109, 110, 1 The carbon and heteroatom length may be 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or greater than 100. In connection with the expressions "alkyl, alkenyl, or alkynyl" and similar expressions, "alkyl" will be understood to be a saturated alkyl and "alkenyl" and "alkynyl" will be understood to be unsaturated.

[0040] As used herein, in the context of alkyl / heteroalkyl groups of a compound, the term "linear" may be used as commonly understood by one of ordinary skill in the art and generally refers to a chemical entity that includes a backbone or main chain that is not divided into two or more continuous chains. Non-limiting examples of linear alkyls include methyl, ethyl, n-propyl, and n-butyl.

[0041] As used herein, the term "branched" may be used as commonly understood by those of skill in the art and generally refers to a chemical entity that includes a backbone or main chain that is divided into two or more continuous chains. The portion of the backbone or main chain that is divided in two or more directions may be linear, cyclic, or any combination thereof. Non-limiting examples of branched alkyl groups include tert-butyl and isopropyl.

[0042] The term "alkylenyl" refers to the divalent analog of an alkyl group. In connection with the expressions "alkylenyl, alkenylenyl, and / or alkynylenyl" and similar expressions, "alkylenyl" will be understood to be saturated alkylenyl, and "alkenylenyl" and "alkynylenyl" will be understood to be unsaturated. The term "heteroalkylenyl" refers to the divalent analog of a heteroalkyl group. The term "heteroalkenylenyl" refers to the divalent analog of a heteroalkenyl group. The term "heteroalkynylenyl" refers to the divalent analog of a heteroalkynyl group.

[0043] As used herein, the term "saturated" when referring to a chemical entity may be used as commonly understood by one of ordinary skill in the art and generally refers to a chemical entity that contains only single bonds and may contain linear, branched, and / or cyclic groups. Saturated C1-C 20Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, sec-pentyl, t-pentyl, n-hexyl, i-hexyl, 1,2-dimethylpropyl, 2-ethylpropyl, 1-methyl-2-ethylpropyl, l-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1,2-triethylpropyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 2-ethylbutyl, 1 , 3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, sec-hexyl, t-hexyl, n-heptyl, i-heptyl, sec-heptyl, t-heptyl, n-octyl, i-octyl, sec-octyl, t-octyl, n-nonyl, i-nonyl, sec-nonyl, t-nonyl, n-decyl, i-decyl, sec-decyl, t-decyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, cyclooctanyl, cyclononanyl, cyclodecanyl, and the like. Thus, unless otherwise specified, C1-C 20 Alkylenyl includes, but is not limited to, all divalent analogs of the above saturated alkyl groups.

[0044] As used herein, the term "unsaturated" when referring to a chemical entity may be used as commonly understood by one of ordinary skill in the art and generally refers to a chemical entity that contains at least one double or triple bond and may contain linear, branched, and / or cyclic groups. 20 Non-limiting examples of alkenyl groups include vinyl, allyl, isopropenyl, 1-propen-2-yl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 2-buten-1-yl, 2-buten-2-yl, octenyl, decenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononanenyl, cyclodecanenyl, and the like. Thus, unless otherwise specified, C1-C 20Alkenylenyl includes, but is not limited to, all divalent analogs of the above alkenyl groups. 20 Non-limiting examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. Thus, unless otherwise specified, C1-C 20 Alkynylenyl includes, but is not limited to, all divalent analogs of the above alkynyl groups.

[0045] Non-limiting examples of non-aromatic cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Non-limiting examples of non-aromatic heterocyclic groups include aziridinyl, azetidinyl, diazetidinyl, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, imidazolinyl, pyrazolidinyl, imidazolidinyl, phthalimidyl, succinimidyl, oxiranyl, tetrahydropyranyl, oxetanyl, dioxanyl, thietanyl, thiepinyl, morpholinyl, oxathiolanyl, etc.

[0046] Unless further specified, "aryl" groups include both aromatic monocyclic and fused rings containing at least one aromatic ring. 20 Non-limiting examples of aryl groups include phenyl (Ph), pentalenyl, indenyl, naphthyl, and azulenyl.Non-limiting examples of aromatic heterocyclic groups of similar size include pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, acridinyl, indolyl, isoindolyl, indolizinyl, purinyl, carbazolyl, indazolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, phenanthridinyl, phenazinyl, phenanthrolinyl, perimidinyl, furyl, dibenzofuryl, xanthenyl, benzofuryl, thiophenyl, thianthrenyl, benzothiophenyl, phosphorinyl, phosphinolinyl, phosphindolyl, thiazolyl, oxazolyl, isoxazolyl, and the like.

[0047] As used herein, the term "substituted" is used as would be commonly understood by one of ordinary skill in the art and generally refers to a compound or chemical entity having one chemical group replaced with a different chemical group. Unless otherwise specified, a substituted alkyl, alkylenyl, alkenylenyl, or alkynylenyl has one or more hydrogen atoms independently replaced with a non-hydrogen atom. For example, chloromethyl is a non-limiting example of a substituted alkyl, and more specifically, an example of a substituted methyl. Aminoethyl is another non-limiting example of a substituted alkyl, and more specifically, an example of a substituted ethyl. Unless otherwise specified, a substituted compound or group (e.g., an R group or an L group) may be substituted with any chemical group reasonable to one of ordinary skill in the art. By way of example and not limitation, a hydrogen bonded to a carbon or heteroatom (e.g., N) may be substituted with a halide (e.g., F, I, Br, Cl), amine, amide, oxo, hydroxyl, thiol, phosphate, phosphonate, sulfate, SO2H, SO3H, alkyl, heteroalkyl, aryl, heteroaryl, ketone, carboxaldehyde, carboxylate, carboxamide, nitrile, monohalomethyl, dihalomethyl, or trihalomethyl. In some embodiments, each carbon may be independently substituted with an oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphoric acid, or may be unsubstituted. In some embodiments, the amide substituent is -C(O)-NH2.

[0048] As used herein, the term "unsubstituted" is used as would be commonly understood by one of ordinary skill in the art. Non-limiting examples of unsubstituted alkyl include methyl, ethyl, tert-butyl, pentyl, etc. The term "optionally substituted" is used interchangeably with the term "unsubstituted or substituted." The term "optionally substituted" means that each position may or may not be substituted, and if substituted, each substituent may be the same or different.

[0049] In the structures provided herein, hydrogen may or may not be shown. In some embodiments, hydrogen (whether shown or implied) is replaced by protium (i.e., 1 H), and deuterium (i.e., 2 H) 1 H and 2 It may be in combination with H. 1 H 2 Methods for exchanging with H are well known in the art. In the case of solvent exchangeable hydrogen, 1 H and 2 Exchange with H occurs readily in the presence of a suitable deuterium source without a catalyst. The use of acids, bases, or metal catalysts, coupled with elevated temperature and pressure conditions, can facilitate the exchange of non-exchangeable hydrogen atoms, generally resulting in the exchange of all hydrogen atoms in the molecule. 1 From H 2 This results in an exchange for H.

[0050] The term "Xaa" refers to an amino acid residue in a peptide chain or otherwise part of a compound. An amino acid has both an amino group and a carboxylic acid group, either or both of which may be used for covalent attachment. When attached to the remainder of the compound, the amino and / or carboxylic acid groups may be converted to an amide or other structure, for example, when the carboxylic acid group of a first amino acid is attached to the amino group of a second amino acid (i.e., a peptide bond). Thus, Xaa can be represented by the formula -N(R a )R b C(O)-(wherein, R a and R b is an R group. a is typically hydrogen or alkyl (e.g., methyl), or R a and R bmay form a cyclic structure. The amino acid residues of the peptide may contain typical peptide (amide) bonds and may further contain bonds between a side chain functional group and a side chain or main chain functional group of another amino acid. For example, the side chain carboxylic acid of one amino acid residue (e.g., Asp, Glu, etc.) in the peptide may be bonded to the amine of another amino acid residue (e.g., Dap, Dab, Orn, Lys) in the peptide. Further details are provided below. Unless otherwise indicated, "Xaa" may be any amino acid, including proteinogenic or non-proteinogenic amino acids. Non-limiting examples of non-proteinogenic amino acids are provided in Table 1, including, but not limited to, D-amino acids (including, but not limited to, any D-form of the following amino acids): ornithine (Orn), 3-(1-naphthyl)alanine (Nal), 3-(2-naphthyl)alanine (2-Nal), α-aminobutyric acid, norvaline, norleucine (Nle), homonorleucine, beta-(1,2,3-triazol-4-yl)-L-alanine, 1,2,4-triazol-3-alanine, Phe(4-F), Phe(4-Cl), Phe(4-Br), Phe(4-I), Phe(4-NH2), Phe(4-NO2), homoarginine (hArg), 2-amino-4-guanidinobutyric acid (Agb), 2-amino-3-guanidinopropionic acid (Agb), 2-amino-4-guanidinopropionic ...4-guanidinopropionic acid (Agb), 2-amino-4-guanidinopropionic acid (Agb), 2-amino-4-guanid Agp), B-alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 7-aminoheptanoic acid, 8-aminooctanoic acid, 9-aminononanoic acid, 10-aminodecanoic acid, 2-aminooctanoic acid, 2-amino-3-(anthracen-2-yl)propanoic acid, 2-amino-3-(anthracen-9-yl)propanoic acid, 2-amino-3-(pyren-1-yl)propanoic acid, Trp(5-Br), Trp(5-OCH3), Trp(6-F), Trp(5-OH) or Trp(CHO), 2-aminoadipic acid (2-Aad), 3-aminoadipic acid (3-Aad), propargylglycine (Pra), homopropargylglycine (Hpg), beta-homopropargylglycine (Bpg), 2,3-diaminopropionic acid (Dap), 2,4-Diaminobutyric acid (Dab), azidolysine (Lys(N3)), azido-ornithine (Orn(N3)), 2-amino-4-azidobutanoic acid Dab(N3), Dap(N3), 2-(5'-azidopentyl)alanine, 2-(6'-azidohexyl)alanine, 4-amino-1-carboxymethyl-piperidine (Pip), 4-(2-aminoethyl)-1-carboxymethyl-piperazine (Acp), tranexamic acid, tert-leucine (Tle), 4-chlorophenylalanine (Cpa), thiazoline-4-carboxylic acid (Thz), αMe-Trp, p-aminomethylaniline-diglycolic acid (pABzA-DIG), 4-amino-1-carboxymethyl-piperidine (Pip), NH2(CH2)2O( CH2)2C(O)OH, NH2(CH2)2[O(CH2)2]2C(O)OH(dPEG2), NH2(CH2)2[O(CH2)2]3C(O)OH, NH2(CH2)2[O(CH2)2]4C(O)OH, NH2(CH2)2[O(CH2)2]5C(O)OH, NH2(CH2)2[O(CH2)2]6C(O)OH, oxazolidine-4-carboxylate Examples of amino acids include carboxylic acid (4-oxa-L-Pro), β-(3-benzothienyl)alanine (Bta), citrulline (Cit), Trp(Me), Trp(7-Me), Trp(6-Me), Trp(5-Me), Trp(4-Me), Trp(2-Me), Trp(7-F), Trp(5-F), Trp(4-F) or cyclopentylglycine (Cpa). When not specified as an L-amino acid or a D-amino acid, an amino acid should be understood to be an L-amino acid.

[0051] [Table 1-1] [Table 1-2]

[0052] Definition L of the chemical formula (e.g., Formula I) 1 or R alb ) through the bond or at the end of the bond [ka] The symbols are intended to define the groups on one side of the wavy line without modifying the definition of the structure on the other side of the line. When an R or L group is attached on more than one side, any atoms shown outside the wavy line are intended to clarify the orientation of the defined group. Thus, only the atoms between the two wavy lines constitute the definition of the R or L group. If no atoms are shown outside the wavy lines (e.g., L 1 ), or in the case of a chemical group shown without a wavy line but with bonds on multiple sides (such as, for example, -C(O)NH-), the chemical group should be read from left to right, consistent with the orientation in the formula to which the group relates, e.g., the formula -R a -R b -R c -, R as -C(O)NH- b The definition of -R a -NHC(O)-R c -R instead of - a -C(O)NH-R c will be incorporated into the formula as -.

[0053] In various aspects, a peptide compound is disclosed, the compound having the structure of Formula I, or a salt or solvate of Formula I, defined as follows: R rad n6 -[Linker]-R L -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -ψ-Xaa 9 -NH2 (I) During the ceremony, Xaa 1is an N-terminal amino acid residue selected from D-Phe, Cpa (4-chlorophenylalanine), D-Cpa, Nal (3-(1-naphthyl)alanine), D-Nal, 2-Nal (3-(2-naphthyl)alanine), or D-2-Nal; Xaa 2 is Asn, Gln, homoserine (Hse), citrulline (Cit), or His; Xaa 3 is Trp, β-(3-benzothienyl)alanine (Bta), Trp(Me), Trp(7-Me), Trp(6-Me), Trp(5-Me), Trp(4-Me), Trp(2-Me), Trp(7-F), Trp(6-F), Trp(5-F), Trp(4-F), Trp(5-OH), or αMe-Trp; Xaa 4 is Ala or Ser, Xaa 5 is Val, Cpg (cyclopentylglycine), or tert-leucine (Tle); Xaa 6 is Gly, NMe-Gly, or D-Ala, Xaa 7 is His or NMe-His, Xaa 8 is Leu, D-Pro, or Phe; Xaa 9 -NH2 is a C-terminal amidated amino acid residue selected from Pro, Phe, 4-oxa-L-Pro (oxazolidine-4-carboxylic acid), Me2Thz (5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid), or Thz (thiazoline-4-carboxylic acid); ψ is Xaa 8 and Xaa 9 is a peptide bond or reduced peptide bond between Xaa 2 , Xaa 3 , Xaa 5 , and Xaa 7 are Gln, Trp, Val, and His, respectively, and ψ is a reduced peptide bond, R Lis -C(O)-, -NH-C(O)-, or -NH-C(S)-, The linker, -L 1 R 1 -and / or- (L 1 )2R 1 - a linear or branched chain of n1 units, n1 is 1 to 20; Each R 1 are independently linear, branched, and / or cyclic C n2 alkylenyl, alkenylenyl, and / or alkynylenyl, where each n2 is independently 1 to 20, and any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted with oxo, hydroxyl, sulfhydryl, -SeH, halogen, guanidino, amine, amide, urea, carboxylic acid, sulfonic acid, sulfinic acid, or phosphate; L 1 is attached to a carbon, where each L 1 are independently -S-, -N(R 2 )C(O)-, -C(O)N(R 2 )-, -NH-C(O)-NH-, -NH-C(S)-NH-, [ka] and R 2 is H, methyl, or ethyl; Albumin binder (R alb ) is the linker L 1 and an albumin binder optionally bound to -(CH2) n3 -CH3, wherein n3 is 8 to 20; -(CH2) n4 -C(O)OH, where n4 is 8 to 20; [ka] In the formula, n5 is 1 to 4; R 3a is H or methyl, R3b is I, Br, F, Cl, H, OH, OCH3, NH2, NO2 or C1-C6 alkyl, or [ka] n6 is 1 to 5; Each R rad is the linker L 1 wherein each radiolabeling group is independently a radiometal chelator, an aryl or heteroaryl substituted with a radioactive halogen, a prosthetic group containing a trifluoroborate, a prosthetic group containing a silicon-fluorine-acceptor moiety, or a prosthetic group containing a fluorophosphate, a fluorosulfate, a sulfonyl fluoride, or a combination thereof.

[0054] In another embodiment, the peptide compound may be a compound having the structure of Formula A, or a salt or solvate of Formula A, as follows: rad n6 -[Linker]-R L -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -ψ-Xaa 9 -NH2 (formula A), During the ceremony, Xaa 1 is an N-terminal amino acid residue selected from D-Phe, 4-chlorophenylalanine (Cpa), D-Cpa, 3-(1-naphthyl)alanine (Nal), D-Tpi, D-Nal, 3-(2-naphthyl)alanine (2-Nal), or D-2-Nal; Xaa 2 is Asn, Gln, homoserine (Hse), citrulline (Cit), or His; Xaa 3is Trp, β-(3-benzothienyl)alanine (Bta), Trp(Me), Trp(7-Me), Trp(6-Me), Trp(5-Me), Trp(4-Me), Trp(2-Me), Trp(7-F), Trp(6-F), Trp(5-F), Trp(4-F), Trp(5-OH), Tpi, 7-Aza, or αMe-Trp; Xaa 4 is Ala or Ser, Xaa 5 is Val, 2,3-dehydro-Val, Cpg (cyclopentylglycine), cyclopropylglycine, cyclobutylglycine, or tert-leucine (Tle); Xaa 6 is Gly, NMe-Gly, or D-Ala, Xaa 7 is His or NMe-His, Xaa 8 is Leu, D-Pro, or Phe; Xaa 9 -NH2 is a C-terminal amidated amino acid residue selected from Pro, Phe, oxazolidine-4-carboxylic acid (4-oxa-L-Pro), Me2Thz (5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid), or thiazoline-4-carboxylic acid (Thz); ψ is Xaa 8 Xaa 9 represents a peptide bond or reduced peptide bond that is bonded to Xaa 2 , Xaa 3 , Xaa 5 , and Xaa 7 are Gln, Trp, Val, and His, respectively, except for compounds where ψ is a reduced peptide bond. L is -C(O)-, -NH-C(O)-, or -NH-C(S)-, The linker, -L 1 R 1 -and / or- (L 1 )2R 1 - a linear or branched chain of n1 units, n1 is 1 to 20, and each R 1are independently linear, branched, and / or cyclic C n2 alkylenyl, alkenylenyl, and / or alkynylenyl, where each n2 is independently 1 to 20, and any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted with oxo, hydroxyl, sulfhydryl, -SeH, halogen, guanidino, amine, amide, urea, carboxylic acid, sulfonic acid, sulfinic acid, or phosphate; L 1 is attached to a carbon, where each L 1 are independently -S-, -N(R 2 )C(O)-, -C(O)N(R 2 )-, -NH-C(O)-NH-, -NH-C(S)-NH-, [ka] and R 2 is H, methyl, or ethyl, and the albumin binder (R alb ) is the linker L 1 and the albumin binder is optionally linked to -(CH2) n3 -CH3, where n3 is 8 to 20, -(CH2) n4 -C(O)OH, where n4 is 8 to 20; [ka] In the formula, n5 is 1 to 4; R 3a is H or methyl, R 3b is I, Br, F, Cl, H, OH, OCH3, NH2, NO2 or C1-C6 alkyl, or [ka] n6 is 1 to 5; Each R rad is the linker L 1wherein each radiolabeling group is independently a radiometal chelator, an aryl or heteroaryl substituted with a radioactive halogen, a prosthetic group containing a trifluoroborate, a prosthetic group containing a silicon-fluorine-acceptor moiety, or a prosthetic group containing a fluorophosphate, a fluorosulfate, a sulfonyl fluoride, or a combination thereof.

[0055] In another embodiment, the present invention relates to a method for the treatment of 1 is an N-terminal amino acid residue selected from D-Phe, 4-chlorophenylalanine (Cpa), D-Cpa, 3-(1-naphthyl)alanine (Nal), D-Nal, 3-(2-naphthyl)alanine (2-Nal), or D-2-Nal; 3 is Trp, β-(3-benzothienyl)alanine (Bta), Trp(Me), Trp(7-Me), Trp(6-Me), Trp(5-Me), Trp(4-Me), Trp(2-Me), Trp(7-F), Trp(6-F), Trp(5-F), Trp(4-F), Trp(5-OH), or αMe-Trp; 5 may include a peptide compound that is Val, Cpg (cyclopentylglycine), or tert-leucine (Tle).

[0056] In another particular embodiment, Xaa 1 is an N-terminal amino acid residue selected from D-Phe, or D-2-Nal. 2 In another particular embodiment, Xaa is Gln or His. 5 In another particular embodiment, Xaa is Val, or tert-leucine (Tle). 6 In another particular embodiment, Xaa is Gly or NMe-Gly. 9 -NH2 is a C-terminal amidated amino acid residue selected from Pro or thiazoline-4-carboxylic acid (Thz). 1 is an N-terminal amino acid residue selected from D-Phe or D-2-Nal; 2is Gln or His, and Xaa 4 is Ala and Xaa 5 is Val or tert-leucine (Tle), and Xaa 6 is Gly or NMe-Gly, and Xaa 8 is Leu and Xaa 9 -NH2 is a C-terminal amidated amino acid residue selected from Pro or thiazoline-4-carboxylic acid (Thz).

[0057] In another particular embodiment, Xaa 3 is β-(3-benzothienyl)alanine (Bta), Trp(Me), Trp(7-Me), Trp(6-Me), Trp(5-Me), Trp(4-Me), Trp(2-Me), Trp(7-F), Trp(6-F), Trp(5-F), Trp(4-F), Trp(5-OH), Tpi, 7-Aza, or αMe-Trp. In another particular embodiment, ψ is a peptide bond. In another particular embodiment, Xaa is a 9 In another particular embodiment, Xaa is Thz. 2 In another particular embodiment, Xaa is His. 3 In another particular embodiment, Xaa is Trp. 5 In another particular embodiment, Xaa is Tle. 7 is NMe-His.

[0058] In another particular embodiment of the peptide compounds described herein, ψ is a peptide bond and Xaa 9 is Thz and Xaa 2 is His and Xaa 3 is Trp and Xaa 5 is Tle and Xaa 7 is NMe-His.

[0059] In another embodiment, Xaa 3 In another embodiment, Xaa is αMe-Trp. 6 In another embodiment, Xaa is Gly. 8 is Leu.

[0060] In another embodiment, Xaa 1 , Xaa 2 , Xaa 3 , Xaa 4 , Xaa 5 , Xaa 6 , Xaa 7 , Xaa 8 , or Xaa 9 At least one of the following is methylated:

[0061] In another embodiment, the peptide compound of the invention may have the structure of Formula B, or is a salt or solvate of Formula B, where Formula B is as follows: R rad n6 -[Linker]-R L -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -ψ-Xaa 9 -NH2 (Formula B), where: Xaa 1 is an N-terminal amino acid residue selected from D-Phe, 4-chlorophenylalanine (Cpa), D-Cpa, 3-(1-naphthyl)alanine (Nal), D-Tpi, D-Nal, 3-(2-naphthyl)alanine (2-Nal), or D-2-Nal; Xaa 2 is Asn, Gln, homoserine (Hse), citrulline (Cit), or His; Xaa 3 is Trp, β-(3-benzothienyl)alanine (Bta), Trp(Me), Trp(7-Me), Trp(6-Me), Trp(5-Me), Trp(4-Me), Trp(2-Me), Trp(7-F), Trp(6-F), Trp(5-F), Trp(4-F), Trp(5-OH), Tpi, 7-Aza, or αMe-Trp; Xaa 4 is Ala or Ser, Xaa5 is Val, 2,3-dehydro-Val, Cpg (cyclopentylglycine), cyclopropylglycine, cyclobutylglycine, or tert-leucine (Tle); Xaa 6 is Gly, NMe-Gly, or D-Ala, Xaa 7 is His or NMe-His, Xaa 8 is Leu, D-Pro, or Phe; Xaa 9 -NH2 is a C-terminal amidated amino acid residue selected from Pro, oxazolidine-4-carboxylic acid (4-oxa-L-Pro), Me2Thz (5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid), or thiazoline-4-carboxylic acid (Thz); ψ is Xaa 8 Xaa 9 represents a peptide bond or reduced peptide bond that is bonded to R L is -C(O)-, -NH-C(O)-, or -NH-C(S)-, The linker, -L 1 R 1 -and / or- (L 1 )2R 1 - a linear or branched chain of n1 units, n1 is 1 to 20; Each R 1 are independently linear, branched, and / or cyclic C n2 alkylenyl, alkenylenyl, and / or alkynylenyl, where each n2 is independently 1 to 20, and any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted with oxo, hydroxyl, sulfhydryl, -SeH, halogen, guanidino, amine, amide, urea, carboxylic acid, sulfonic acid, sulfinic acid, or phosphate; L 1 is attached to a carbon, where each L 1 are independently -S-, -N(R 2)C(O)-, -C(O)N(R 2 )-, -NH-C(O)-NH-, -NH-C(S)-NH-, [ka] and R 2 is H, methyl, or ethyl; Albumin binder (R alb ) is the linker L 1 and an albumin binder optionally bound to -(CH2) n3 -CH3, wherein n3 is 8 to 20; -(CH2) n4 -C(O)OH, where n4 is 8 to 20; [ka] In the formula, n5 is 1 to 4; R 3a is H or methyl, R 3b is I, Br, F, Cl, H, OH, OCH3, NH2, NO2 or C1-C6 alkyl, or [ka] n6 is 1 to 5; Each R rad is the linker L 1 wherein each radiolabeling group is independently a radiometal chelator, an aryl or heteroaryl substituted with a radioactive halogen, a prosthetic group containing a trifluoroborate, a prosthetic group containing a silicon-fluorine-acceptor moiety, or a prosthetic group containing a fluorophosphate, a fluorosulfate, a sulfonyl fluoride, or a combination thereof.

[0062] In certain embodiments, the compound of formula I, A, or B may include an albumin binder R alb Does not include.

[0063] In certain embodiments, Xaa 1 , Xaa 2 , Xaa 3 , Xaa 4 , Xaa 5 , Xaa 6 , Xaa 7 , Xaa 8 , or Xaa 9 In another particular embodiment, ψ is methylated at least one of Xaa 8 Xaa 9 In another particular embodiment, Xaa is a reduced peptide bond that is linked to 1 is D-Phe, and / or Xaa 6 is Gly, and / or Xaa 8 is Leu, and / or Xaa 9 In another particular embodiment, Xaa is Pro, Tz, or 4-oxa-L-Pro. 6 is Gly or N-methyl-Gly. 9 In another particular embodiment, Xaa is Thz. 9 In another embodiment, Xaa is Pro. 1 is D-phe, and Xaa 2 is Gln, and Xaa 3 is Trp and Xaa 4 is Ala and Xaa 5 is Val and Xaa 6 Xaa 6 is Gly or N-methyl-Gly, and Xaa 7 is His and Xaa 8 is Leu and Xaa 9 is Thz and ψ is Xaa 8 Xaa 9 In another particular embodiment, Xaa is a reduced peptide bond that is linked to 6 is N-methyl-Gly.

[0064] In another particular embodiment, the peptide compound is any compound of formula I, A, or B, excluding the compounds described in PCT Application Publication No. WO2009 / 109332, which is incorporated by reference in its entirety. In a particular embodiment, the peptide compound is any compound of formula B, excluding the compounds described in PCT Application Publication No. WO2009 / 109332, which is incorporated by reference in its entirety. In another particular embodiment, the peptide compound is any compound of formula I, A, or B, excluding the compounds described in PCT Application Publication No. WO2021 / 068051, which is incorporated by reference in its entirety. In a particular embodiment, the peptide compound is any compound of formula B, excluding the compounds described in PCT Application Publication No. WO2021 / 068051, which is incorporated by reference in its entirety.

[0065] In certain embodiments, the peptide compound is any compound described in PCT Application Publication No. WO2021 / 068051, the entirety of which is incorporated herein by reference.

[0066] In certain embodiments, the peptide compound is any compound of formula B, excluding the compounds described in Wang, L et al., Molecules, 2022 27, 3777, the entire contents of which are incorporated herein by reference.

[0067] In certain embodiments, the peptide compound is any compound described in Wang, L et al., Molecules, 2022 27, 3777, the entire contents of which are incorporated herein by reference.

[0068] In another particular embodiment, the peptide compound of formula I, A, or B is R rad n6 -[Linker]-R L - or R rad n6、 or [linker] or R L - Exclude.

[0069] In another particular embodiment of the peptide compounds described herein, the radiometal, radionuclide-bound metal, or radionuclide-bound metal-containing prosthetic group is 68 Ga, 61 Cu, 64 Cu, 67 Ga, 99m Tc, 110m In, 111 In, 44 Sc, 86 Y, 89 Zr, 90 Nb, 152 Tb, 155 Tb, [ 18 F]AlF, 131 I, 123 I, 124 I, and 203 Pb, 72 As.

[0070] In another particular embodiment of the peptide compounds described herein, the radiometal, radionuclide-bound metal, or radionuclide-bound metal-containing prosthetic group is 165 Er, 212 Bi, 211 At, 166 Ho, 149 Pm, 159 Gd, 105 Rh, 109 Pd, 198 Au, 199 Au, 175 Yb, 142 Pr, 177 Lu, 111 In, 213 Bi, 47 Sc, 90 Y, 225 Ac, 117m Sn, 153 Sm, 149 Tb, 161 Tb, 224 Ra, 223 Ra, 212 Pb, 227 Th, 223 Ra, 77 As, 186 Re, 188 Re, 67 Cu, or 64 Cu.

[0071] In another particular embodiment, the compound or peptide compound may be included in a pharmaceutical composition. In a particular embodiment, the pharmaceutical composition may include one or more compounds from Formula I, A, or B and a pharma- ceutically acceptable carrier. In another particular embodiment, the peptide compound may be bound to or include a radioactive metal. In a particular embodiment, the radioactive metal is 165 Er, 212 Bi, 211 At, 166 Ho, 149 Pm, 159 Gd, 105 Rh, 109 Pd, 198 Au, 199 Au, 175 Yb, 142 Pr, 177 Lu, 111 In, 213 Bi, 47 Sc, 90 Y, 225 Ac, 117m Sn, 153 Sm, 149 Tb, 161 Tb, 224 Ra, 223 Ra, 212 Pb, 227 Th, 223 Ra, 77 As, 186 Re, 188 Re, 67 Cu, or 64 Cu.

[0072] In another embodiment, the invention may include the use of the peptide compounds described herein for imaging methods. In certain embodiments, the method may include imaging a gastrin releasing peptide receptor (GRPR) in a subject, the method comprising administering to the subject a peptide compound of any one of formulas I, A or B, and imaging a tissue of the subject. In certain embodiments, the method may include a method of treating cancer in a subject, comprising administering to a subject in need thereof a peptide compound of any one of formulas I, A or B and a pharma- ceutically acceptable excipient.

[0073] In another particular embodiment, the method may include treating a GRPR-expressing condition or disease. In particular embodiments, the GRPR-expressing condition or disease may be a psychiatric disorder, a neurological disorder, an inflammatory disease, prostate cancer, lung cancer, head and neck cancer, colon cancer, kidney cancer, ovarian cancer, liver cancer, pancreatic cancer, breast cancer, glioma, or neuroblastoma. In some embodiments, the cancer is prostate cancer.

[0074] As described herein, the peptide moiety -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -ψ-Xaa 9 -NH2 is the GRPR targeting portion of the compound, i.e., it is capable of specifically binding to the GRPR and potentially producing an antagonist effect.

[0075] In some embodiments, Xaa 1 In another embodiment, Xaa is D-Phe. 1 In another embodiment, Xaa is Cpa. 1 In another embodiment, Xaa is D-Cpa. 1 In another embodiment, Xaa is Nal. 1 In another embodiment, Xaa is D-Nal. 1In another embodiment, Xaa is 2-Nal. 1 is D-2-Nal. 1 D-Phe at position Xaa has been reported to retain binding affinity for GRPR (see, e.g., Lau, et al., 2019, ACS Omega 4:1470-1478). 1 It has been reported that D-Cpa, Tpi, D-Tpi, and D-Nal at the positions L and L-positions retain strong binding affinity to the GRPR (see, e.g., Tables 1 and 3 in Cai et al., 1994 Proc. Natl. Acad. Sci. USA 91:12664-12668; RC-3965-II disclosed in Reile et al., 1995 International Journal of Oncology 7:749-754). Since both L-Tpi and D-Tpi retain binding affinity, the L-isomers of D-Nal and D-Cpa will also retain strong binding affinity to the GRPR.

[0076] In some embodiments, Xaa 2 In another embodiment, Xaa is Asn. 2 In another embodiment, Xaa is Gln. 2 In another embodiment, Xaa is Hse. 2 In another embodiment, Xaa is Cit. 2 is His. 2 Gln at position Xaa is found in wild-type BBN. 2 The His at position Xaa is found in wild-type GRP. 2 It has been reported that Hse and Cit at positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,

[0077] In some embodiments, Xaa 3 In another embodiment, Xaa is Trp. 3 In another embodiment, Xaa is Bta. 3 In another embodiment, Xaa is αMe-Trp.3 In another embodiment, Xaa is Trp(Me). 3 In another embodiment, Xaa is Trp(7-Me). 3 In another embodiment, Xaa is Trp(6-Me). 3 In another embodiment, Xaa is Trp(5-Me). 3 In another embodiment, Xaa is Trp(4-Me). 3 In another embodiment, Xaa is Trp(2-Me). 3 In another embodiment, Xaa is Trp(7-F). 3 In another embodiment, Xaa is Trp(6-F). 3 In another embodiment, Xaa is Trp(5-F). 3 In another embodiment, Xaa is Trp(4-F). 3 is Trp(5-OH). 3 Trp at position Xaa is found in wild-type BBN and GRP. 3 Positions Bta and αMe-Trp have been reported to retain binding affinity for GRPR (see Gunther, et al., 2021, Journal of Nuclear Medicine 62(Suppl 1)1474; Gunther, et al., J Nucl Med. 2022, jnumed.121.263323, DOI: https: / / doi.org / 10.2967 / jnumed.121.263323).

[0078] In some embodiments, Xaa 4 In another embodiment, Xaa is Ala. 4 is Ser.

[0079] In some embodiments, Xaa 5 In another embodiment, Xaa is Val. 5 In another embodiment, Xaa is Cpg. 5 is Tle. 5 Val at position 11 is found in wild-type BBN and GRP.

[0080] In some embodiments, Xaa 6 In another embodiment, Xaa is Gly. 6 In another embodiment, Xaa is N-methyl-Gly. 6 is D-Ala. 6 It has been reported that N-methyl-Gly and D-Ala at positions 1, 2, and 3 retain strong binding affinity for GRPR (see, e.g., Table 4 in Horwell et al., 1996 Int. J. Peptide Protein Res. 48:522-531; Table 3 in Lin et al., 1995 European Journal of Pharmacology 284:55-69).

[0081] In some embodiments, Xaa 7 In another embodiment, Xaa is His. 7 is NMe-His. 7 His at position Xaa7 is found in wild-type BBN and GRP. NMe-His at position Xaa7 has been reported to retain binding affinity for GRPR (see, e.g., Table 4 in Horwell et al., 1996 Int. J. Peptide Protein Res. 48:522-531).

[0082] In some embodiments, Xaa 8 In another embodiment, Xaa is Leu. 8 In another embodiment, Xaa is D-Pro. 8 is Phe. 8 Leu at position Xaa is found in wild-type BBN and GRP. 8 D-Pro at position Xaa has been reported to retain binding affinity for GRPR (see, e.g., Leban, et al., 1994, J. Med. Chem. 37:439-445). 8The Phe at this position is supported by Phe at this position in ranatensin and ritorin, which have very strong binding affinity for GRPR (Heimbrook et al., 1991 J. Med. Chem. 34:2102-2107; Lin et al., 1995 European Journal of Pharmacology 294:55-69).

[0083] In some embodiments, Xaa 9 is Pro (i.e., Xaa 9 -NH2 is a C-terminal amidated Pro). 9 is Phe (i.e., Xaa 9 -NH2 is a C-terminal amidated Phe). 9 is 4-oxa-L-Pro (i.e., Xaa 9- NH2 is C-terminal amidated 4-oxa-L-Pro). 9 is Me2Thz (i.e., Xaa 9 -NH2 is C-terminal amidated Me2Thz). 9 is Thz (i.e., Xaa 9 -NH2 is the C-terminal amidated Thz). 9 Pro at position Xaa has been reported to retain binding affinity for GRPR (see, e.g., Lau, et al., 2019, ACS Omega 4:1470-1478; WO / 2021 / 068051). 9 Phe at position Xaa has been reported to retain binding affinity for GRPR (see, e.g., Leban, et al., 1994, J. Med. Chem. 37:439-445). 9 Position Thz has been reported to retain binding affinity for GRPR (see, e.g., Cai, et al., 1994 Proc Natl Acad Sci USA 91:12664-12668).

[0084] In some embodiments, "ψ" is Xaa 8 and Xaa 9 In another embodiment, "ψ" represents a peptide bond linking Xaa 8 and Xaa 9 represents a reduced peptide bond linking 8 and Xaa 9 The main chain amide (e.g., -C(O)NH-) formed between [ka] This means that it is replaced by

[0085] In some embodiments, -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -ψ-Xaa 9 -NH2 is -D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-Thz-NH2.

[0086] In some embodiments, -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -ψ-Xaa 9 -NH2 is -D-2-Nal-Gln-Trp-Ala-Val-Gly-His-Leu-Thz-NH2.

[0087] In some embodiments, -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8-ψ-Xaa 9 -NH2 is -D-Phe-Gln-Trp-Ala-Val-Gly-NMe-His-Leu-Thz-NH2.

[0088] In some embodiments, -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -ψ-Xaa 9 -NH2 is -D-Phe-Gln-Trp-Ala-Tle-Gly-His-Leu-Thz-NH2.

[0089] In some embodiments, -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -ψ-Xaa 9 -NH2 is -Phe-Gln-Trp-Ala-Tle-Gly-NMe-His-Leu-Thz-NH2.

[0090] In some embodiments, -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -ψ-Xaa 9 -NH2 is -D-Phe-His-Trp-Ala-Val-Gly-His-LeuψThz-NH2.

[0091] In some embodiments, -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa6 -Xaa 7 -Xaa 8 -ψ-Xaa 9 -NH2 is -D-Phe-His-Trp-Ala-Tle-Gly-NMe-His-Leu-Thz-NH2.

[0092] In some embodiments, -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -ψ-Xaa 9 -NH2 is -D-Phe-Gln-Trp-Ala-Tle-Gly-His-LeuψThz-NH2.

[0093] R L The linker is Xaa 1 In some embodiments, R L is -C(O)-. In other embodiments, R L is -NH-C(O)-. In yet another embodiment, R L is -NH-C(S)-,

[0094] The linker allows for attachment of 1 to 5 radiolabeled groups, and optionally an albumin binder, to the compound.

[0095] A non-limiting example of a suitable linker is a peptide linker. More commonly, the linker is -L 1 R 1 -and / or- (L 1 )2R 1 -L 1 R 1 -or- (L 1 )2R 1-), where n1 is 1-20. In alternative embodiments, n1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, n1 is 1-7. In some embodiments, n1 is 1. In other embodiments, n1 is 2. In other embodiments, n1 is 3. In other embodiments, n1 is 4. In other embodiments, n1 is 5. In other embodiments, n1 is 6. In other embodiments, n1 is 7.

[0096] In some embodiments, n6 is 1 and n1 is 1.

[0097] In some embodiments, n6 is 1, n1 is 1, and L 1 is -C(O)NH-.

[0098] In some embodiments, n6 is 1, n1 is 1, and L 1 is -C(O)NH-, and R L is -C(O)-.

[0099] In some embodiments, n6 is 1, n1 is 1, and L 1 is -C(O)NH- and R L is -C(O)-, and R 1 is linear C 1-5 Alkylenyl or -(CH2)2-[O(CH2)2] 1-6 -(CH2) 0-2 It is.

[0100] In some embodiments, R rad n6 -[Linker]- is constructed as shown in Formula II. [ka] In the formula, L 1 and R 1 is as defined in the definition of the linker of formula I; R rad / alb is Rrad or R alb It is one of 0 to 1. rad / alb is R alb It is.

[0101] Each R 1 (Formula I or Formula II) may independently be linear, branched, and / or cyclic C n2 alkylenyl, alkenylenyl, and / or alkynylenyl, where each n2 is independently 1 to 20, any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and the carbons are optionally independently substituted. In some embodiments, each n2 is independently 1 to 15 or 1 to 10. In alternative embodiments, each n2 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, each R 1 is independent, C n2 In some embodiments, R is an alkylenyl, where any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and the carbons are optionally independently substituted. 1 are each independently a linear C 1-5 Alkylenyl or -(CH2)2-[O(CH2)2] 1-6 -(CH2) 0-2 - and in some of these embodiments, n1 is 1 to 7. In some embodiments, each R 1 are independent of each other, -C(R aa ) H-, wherein each R aa is independently a side chain of a proteinogenic amino acid or an alpha amino acid of Table 1. In some embodiments, each R 1 are independently a proteinogenic amino acid or an amino acid from Table 1 with the backbone amino and carboxylic acid groups of the amino acid omitted.

[0102] Each L 1 (Formula I or Formula II) is a linking group. In some embodiments, at least one L 1 is -S-. In some embodiments, at least one L 1is -N(R 2 )C(O)—, and in certain of these embodiments, at least one R 2 is hydrogen. In some embodiments, at least one L 1 is -C(O)N(R 2 )-, and in some of these embodiments, at least one R 2 is hydrogen. In some embodiments, at least one L 1 is -NH-C(O)-NH-. In some embodiments, at least one L 1 is -NH-C(S)-NH-. In some embodiments, at least one L 1 teeth, [ka] In some embodiments, at least one L 1 teeth, [ka] In some embodiments, at least one L 1 teeth, [ka] In some embodiments, at least one L 1 teeth, [ka] It is.

[0103] In some embodiments, the linker has the structure shown in formula II, where each R 1 are independently linear C 1-5 Alkylenyl or -(CH2)2-[O(CH2)2] 1-6 -(CH2) 0-2 -It is.

[0104] In some embodiments, n6 is 1 and the linker is L 1 R 1 and R L With the form -C(O)-Xaa 11 -, wherein Xaa 11 is a proteinogenic amino acid residue or an amino acid residue selected from Table 1. In some embodiments, Xaa 11 In another embodiment, Xaa is pABzA-DIG. 11 In another embodiment, Xaa is Pip. 11 In another embodiment, Xaa is dPEG2. 11 is an Acp.

[0105] In some embodiments, the linker is R L together form a peptide linker, in which the peptide (amide) bonds are independently optionally methylated, and optionally one or more amide bonds are replaced with 1,2,3-triazole bonds (the product of the reaction between an azide and an alkyne). In some embodiments, the peptide linker is a linear peptide linker, optionally replacing one or more amide bonds with 1,2,3-triazole bonds. In some embodiments, the peptide linker is a branched peptide linker, in which the amino acid residues may be linked via a combination of backbone amide (peptide) bonds and "side chain" to "backbone" bonds, or "side chain" to "side chain" bonds. For example, the branched peptides may be linked by one or more of a backbone (backbone) peptide (amide) bond, a "backbone" to side chain amide bond (between the amino group and the carboxylic acid group), and optionally one or more amide bonds are replaced with 1,2,3-triazole bonds. In some such embodiments, the peptide linker is a linear peptide linker, optionally replacing one or more amide bonds with 1,2,3-triazole bonds. 10 ) 1-20 wherein each Xaa 10 are independently proteinogenic or non-proteinogenic amino acid residues (e.g., selected from Table 1) linked together as a linear or branched peptide linker. 10 ) 1-20is a linear peptide linker. In some embodiments, (Xaa 10 ) 1-20 is a branched peptide linker. rad is an amide bond or another L 1 It is attached to the peptide linker via a linking group, and in some embodiments, Rrad is attached to the peptide linker via an amide bond.

[0106] In some embodiments, each Xaa 10 are independent, -N(R a )R b C(O)—, where R a may be H or methyl, R b may be an alkylenyl, heterolakylenyl, alkenylenyl, heteroalkenylenyl, alkynylenyl, or heteroalkynylenyl of 1 to 30 atoms, including linear, branched, and / or cyclic (aromatic or nonaromatic, and monocyclic, polycyclic, or fused ring) structures, or N, R a , and R b may together form a heteroalkylenyl or heteroalkenylenyl having 5 to 7 atoms.

[0107] In some embodiments, (Xaa 10 ) 1-20 consists of a single amino acid or residue. 10 ) 1-20 is a dipeptide, and each Xaa 10 may be the same or different. In some embodiments, (Xaa 10 ) 1-20 is a tripeptide, and each Xaa 10 may be the same or different, or a combination thereof. In some embodiments, (Xaa 10 ) 1-20 consists of four amino acid residues linked by peptide bonds, with each Xaa 10 may be the same or different, or a combination thereof. In some embodiments, each Xaa10 are independently selected from proteinogenic amino acids and non-proteinogenic amino acids listed in Table 1, and each peptide backbone amino group of the peptide linker is independently optionally methylated. In some embodiments, all peptide backbone amino groups of the peptide linker are methylated. In other embodiments, only one peptide backbone amino group of the peptide linker is methylated. In other embodiments, only two peptide backbone amino groups of the peptide linker are methylated. In other embodiments, no peptide backbone amino groups of the peptide linker are methylated.

[0108] In some embodiments, n6 is 1. In other embodiments, n6 is 2. In other embodiments, n6 is 3. In other embodiments, n6 is 4. In other embodiments, n6 is 5.

[0109] In some embodiments, the linker is R alb Does not include.

[0110] In some embodiments, the linker is a linker L 1 R bonded to alb Includes.

[0111] In some embodiments, R alb is -(CH2) n3 wherein n3 is 8 to 20. In alternative embodiments, n3 is 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0112] In some embodiments, R alb is -(CH2) n4 -C(O)OH, where n4 is 8 to 20. In alternative embodiments, n4 is 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0113] In some embodiments, R alb teeth [ka] n5 is 1 to 4, and R 3a is H or methyl, R 3b is I, Br, F, Cl, H, OH, OCH, NH, NO, or C-C alkyl. In alternative embodiments, n is 1, 2, 3, or 4. In certain embodiments, R 3a is H. In certain embodiments, R 3a is methyl. In certain embodiments, R 3b is I, Br, F, or Cl, optionally in the para position. In certain embodiments, R 3b is H. In certain embodiments, R 3b is OH, optionally in the para position. In certain embodiments, R 3b is OCH3, optionally in the para position. In certain embodiments, R 3b is NH, optionally in the para position. In certain embodiments, R 3b is NO2, optionally in the para position. In certain embodiments, R 3b is C1-C6 alkyl, optionally in the para position. In certain embodiments, R 3a is H and R 3b is OCH or NO. In some embodiments, R 3a is methyl, R 3b is isobutyl, optionally para-isobutyl.

[0114] In some embodiments, R alb teeth, [ka] It is.

[0115] In some embodiments, at least one R radis or comprises a radiometal chelator. The radiometal chelator may be any chelator suitable for binding to a radiometal, a radionuclide-bound metal, or a radionuclide-bound metal-containing prosthetic group, and is attached to the linker by forming an amide bond (between an amino group and a carboxylic acid group) or a 1,2,3-triazole (reaction between an azide and an alkyne), or by reaction between a maleimide and a thiol group. Many suitable radiometal chelators are known and are summarized, for example, in Price and Orvig, Chem. Soc. Rev., 2014, 43, 260-290. In some embodiments, each radiometal chelator is independently selected from the group consisting of, but not limited to, DOTA and DOTA derivatives, DTPA and DTPA analogs selected from DOTAGA, NOTA, NODAGA, NODASA, CB-DO2A, 3p-C-DEPA, TCMC, DO3A, CHX-A″-DTPA, and 1B4M-DTPA, sarcofagin and sarcofagin derivatives selected from TETA, NOPO, Me-3,2-HOPO, CB-TE1A1P, CB-TE2P, MM-TE2A, DM-TE2A, SarAr, SarAr-NCS, diamSar, AmBaSar, and BaBaSar, TRAP, AAZTA, DATA, and DATA derivatives, H2-macropa or its derivatives. Derivatives, H2dedpa, H4octapa, H4py4pa, H4Pypa, H2azapa, H5decapa, and other picolinic acid derivatives, CP256, PCTA, C-NETA, C-NE3TA, HBED, SHBED, BCPA, CP256, YM103, desferrioxamine (DFO) and DFO derivatives, H6phospa, trithiol chelate, mercaptoacetyl, hydrazinonicotinamide, dimeric captosuccinic acid, 1,2-ethylenediylbis-L-cysteine ​​diethyl ester, methylene diphosphonate, hexamethylpropyleneamine oxime, and hexakis(methoxyisobutylisonitrile). In some embodiments, at least one radioactive metal chelator is DOTA or a DOTA derivative.

[0116] Illustrative non-limiting examples of radiometal chelators, and exemplary radionuclides that can be chelated by these chelators, are shown in Table 2. In alternative embodiments, at least one R rad is a radiometal chelator selected from those listed above or in Table 2. However, it should be noted that one of skill in the art could substitute another chelator for any of the chelators listed herein.

[0117] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

[0118] In some embodiments, each radiometal chelator is independently selected from Table 2, and each chelator is optionally bound by a radiometal. In some embodiments, each radiometal chelator is bound by one of the corresponding radionuclides shown in Table 2.

[0119] In some embodiments, at least one R rad is DOTA or a derivative thereof linked via an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, at least one R radis CB-DO2A or a derivative thereof linked via an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, at least one R rad is TCMC or a derivative thereof linked through an amide (e.g., formed from one of the -CONH groups shown in Table 2). In some embodiments, at least one R rad is 3p-C-DEPA or a derivative thereof linked via an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, at least one R rad is p-NH2-Bn-oxo-DO3A or a derivative thereof linked via an amide (e.g., formed from one of the carboxyl groups shown in Table 2). rad is TETA or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, at least one R rad is CB-TE2A or a derivative thereof linked via an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, at least one R rad is Diamsar or a derivative thereof linked through an amide (e.g., formed from one of the amino groups shown in Table 2). rad is NOTA or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, at least one R rad is NETA or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, at least one R rad is a HxTSE or derivative thereof linked via an amide (e.g., formed from one of the amino groups shown in Table 2). In some embodiments, at least one R radis P2N2Ph2 or a derivative thereof linked via an amide (e.g., formed from one of the amino groups shown in Table 2). rad is DTPA or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, at least one R rad is CHX-A00-DTPA or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). rad is H2dedpa or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). rad is H2azapa or a derivative thereof linked via an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, at least one R rad is H4octapa or a derivative thereof linked via an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, at least one R rad is H6phospa or a derivative thereof linked via an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, at least one R rad is H4CHXoctapa or a derivative thereof linked via an amide (e.g., formed from one of the carboxyl groups shown in Table 2). rad is H5decapa or a derivative thereof linked via an amide (e.g., formed from one of the carboxyl groups shown in Table 2). rad is H4neunpa-p-Bn-NO2 or a derivative thereof linked via an amide (e.g., formed from one of the carboxyl groups shown in Table 2). radis SHBED or a derivative thereof linked via an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, at least one R rad is BPCA or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). rad is PCTA or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, at least one R rad is an H2-macropa linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2), or a derivative thereof. In some embodiments, at least one R rad is a crown or derivative thereof linked via an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, at least one R rad is HYNIC or a derivative thereof linked through an amide (e.g., formed from a carboxyl group as shown in Table 2). In some embodiments, at least one R rad is N4 or a derivative thereof linked through an amide (e.g., formed from a carboxyl group as shown in Table 2). rad is HBED-CC or a derivative thereof linked via an amide (eg, formed from one of the carboxyl groups shown in Table 2).

[0120] In some embodiments, the radiometal chelator (or one of the radiometal chelators) is a derivative of a radiometal chelator shown in Table 2. Derivatives may include, for example, (1) modification of a functional group of the chelator (e.g., a carboxyl group, an amino group, etc.), or (2) attachment of a new functional group (e.g., attachment of an R group to the ethylene carbon located between the two nitrogen atoms, where the R group is a functional group fused to a spacer). In some embodiments, the carboxyl functional group shown in Table 2 is replaced with azidopropylethylacetamide (e.g., azido-mono-amide-DOTA), butynylacetamide (e.g., butyne-DOTA), thioethylacetamide (e.g., DO3A-thiol), maleimidoethylacetamide (e.g., maleimido-mono-amide-DOTA), or N-hydroxysuccinimide ester (e.g., DOTA-NHS-ester). When linked, these derivative chelators can be linked via an amide (formed from the remaining carboxyl group) or via a -C(O)-NH-(CH2) 2-3 -(triazole) or -C(O)-NH-(CH2) 2-3 In other embodiments, a backbone carbon in the chelator ring (e.g., in an ethylene located between two backbone nitrogen atoms) is fused to an R group bearing a functional group, optionally the R group being -(CH2) 1-3 -(phenyl)-N=C=S or -(CH2) 1-3 -(phenyl)-N=C=O, optionally 1,4-isothiocyanatobenzyl, such as p-SCN-Bn-DOTA (S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid), p-SCN-Bn-NOTA (2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid), etc. When linked, these derivatives can form urea bonds (formed from isocyanates) or thiourea bonds (formed from isothiocyanates).

[0121] In some embodiments, the radiometal chelator is conjugated to a radioactive metal, a radionuclide-bound metal, or a radionuclide-bound metal-containing prosthetic group, and the radioactive metal, radionuclide-bound metal, or radionuclide-bound metal-containing prosthetic group is chelated to a radionuclide chelator complex. 68 Ga, 61 Cu, 64 Cu, 67 Cu, 67 Ga, 111 In, 44 Sc, 86 Y, 89 Zr, 90 Nb, 177 Lu, 117m Sn, 165 Er, 90 Y, 227 Th, 225 Ac, 213 Bi, 212 Bi, 72 As, 77 As, 211 At, 203 Pb, 212 Pb, 47 Sc, 166 Ho, 188 Re, 186 Re, 149 Pm, 159 Gd, 105 Rh, 109 Pd, 198 Au, 199 Au, 175 Yb, 142 Pr, 114m In, 94m Tc, 99m Tc, 149 Tb, 152 Tb, 155 Tb, 161 Tb, or [ 18 In another embodiment, the radiometal, radionuclide-bound metal, or radionuclide-bound metal-containing prosthetic group is 68 Ga, 61 Cu, 64 Cu, 67 Cu, 67 Ga, 111In, 44 Sc, 86 Y, 177 Lu, 90 Y, 225 Ac, 213 Bi, or 212 In some embodiments, the chelator is a chelator of Table 2 and the chelated radionuclide is a radionuclide shown in Table 2 as the binder of the chelator.

[0122] In some embodiments, the chelator is 177 Lu, 111 In, 213 Bi, 68 Ga, 67 Ga, 203 Pb, 212 Pb, 44 Sc, 47 Sc, 90 Y, 86 Y, 225 Ac, 117m Sn, 153 Sm, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 165 Er, 213 Bi, 224 Ra, 212 Bi, 212 Pb, 225 Ac, 227 Th, 223 Ra, 47 Sc, 64 Cu, or 67 DOTA or its derivatives conjugated with Cu; 225 H2-macropa conjugated with Ac, 227 Me-3,2-HOPO conjugated with Th, 225 Ac, 227 Th, or 177 H4py4pa conjugated with Lu, 177 H4pypa conjugated with Lu, 68 NODAGA conjugated with Ga, 111 DTPA conjugated with In, or 89DFO conjugated with Zr.

[0123] In some embodiments, the chelator is selected from the group consisting of TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), SarAr (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexazabicyclo[6.6.6]-eicosane-1,8-diamine), NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), TRAP (1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid), HBED (N,N0-biphenyl). The picolinic acid derivatives are: bis(2-hydroxybenzyl)-ethylenediamine-N,N-diacetic acid), 2,3-HOPO (3-hydroxypyridin-2-one), PCTA (3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid), DFO (desferrioxamine), DTPA (diethylenetriaminepentaacetic acid), OCTAPA (N,N-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N-diacetic acid), or another picolinic acid derivative.

[0124] In some embodiments, R rad Examples of such amines include mercaptoacetyl, hydrazinonicotinamide, dimeric captosuccinic acid, 1,2-ethylenediylbis-L-cysteine ​​diethyl ester, methylene diphosphonate, hexamethylpropyleneamine oxime, and hexakis(methoxyisobutylisonitrile). 99m Tc, 94m Tc, 186 Re, or 188 In some embodiments, R radis a chelating agent, the chelating agent being mercaptoacetyl, hydrazinonicotinamide, dimeric captosuccinic acid, 1,2-ethylenediylbis-L-cysteine ​​diethyl ester, methylene diphosphonate, hexamethylpropyleneamine oxime, or hexakis(methoxyisobutylisonitrile). In some of these embodiments, the chelating agent is bound by a radionuclide. In some such embodiments, the radionuclide is 99m Tc, 94m Tc, 186 Re, or 188 Re.

[0125] In some embodiments, R rad 1,4,7-triazacyclononane-1,4-diacetate (NODA) 18 F-Aluminum fluoride ([ 18 In some embodiments, the chelator is NODA. In some embodiments, the chelator is [ 18 F]AlF.

[0126] In some embodiments, R rad teeth, 72 As or 77 In some embodiments, the chelator is a trithiol chelate. In some embodiments, the chelator is 72 In some embodiments, the chelator is 77 It is conjugated to As.

[0127] In certain embodiments, at least one R rad teeth, 18 F / 19 In some of these embodiments, R is a trifluoroborate (BF)-containing prosthetic group that allows for exchange radiolabeling of F. rad is BF3-R 5 -R 4 -, wherein R4 is -(CH2) 1-5 , optionally methylene, and BF 5 - forms the following: [ka] In the formula, R 5a and R 5b are each independently a C1-C5 straight chain or branched alkyl group or a structure listed in Table 3 (below) or Table 4 (below). For Tables 3 and 4, each R group in each pyridine substituted with -OR, -SR, -NR-, -NHR, or -NR2 is independently a C1-C5 straight chain or branched alkyl. In some embodiments, at least one BF3-R 5 -teeth [ka] wherein R 5a and R 5b are each independently a C1-C5 straight chain or branched alkyl group. In some embodiments, BF3-R 5 At least one of the - groups is selected from those listed in Table 3. In some embodiments, BF-R 5 At least one of the - groups is selected from those listed in Table 4. The trifluoroborate-containing prosthetic group is 18 F. In some embodiments, one fluorine in the BF3 form is 18 F. In some embodiments, all three fluorines in BF3 are 18 F. In some embodiments, all three fluorines in BF3 are 19 It's F.

[0128] [Table 3-1] [Table 3-2]

[0129] [Table 4-1] [Table 4-2]

[0130] In some embodiments, BF3-R 5 - is independent, [ka] wherein each R (if present) in the pyridine substituted -OR, -SR, -NR-, -NHR, or -NR2 is independently a straight chain or branched C1-C5 alkyl. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments, R is propyl. In some embodiments, R is isopropyl. In some embodiments, R is n-butyl. Trifluoroborate-containing prosthetic groups include: 18 In some embodiments, BF3-R 5 -One of the fluorines is 18 F. In some embodiments, BF3-R 5 -All three fluorines in 18 F. In some embodiments, BF3-R 5 -All three fluorines in 19 It's F.

[0131] In some embodiments, BF3-R 5 -teeth, [ka] [ka] wherein each R (when present) in the pyridine substituted -OR, -SR, -NR-, -NHR, or -NR2 is independently a straight chain or branched C1-C5 alkyl. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments, R is propyl. In some embodiments, R is isopropyl. In some embodiments, R is n-butyl. In some embodiments, BF3-R 5 -teeth, [ka] In some embodiments, BF3-R 5 -All three fluorines in 18 F. In some embodiments, BF3-R 5 -One of the fluorines is 18 F. In some embodiments, BF3-R 5 -All three fluorines in 19 It's F.

[0132] In some embodiments, at least one BF3-R 5 - or optionally each BF3-R 5 - is independent [ka] where R 5a and R 5b are each independently a C1-C5 straight chain or branched alkyl group. In some embodiments, R 5a is methyl. In some embodiments, R 5a is ethyl. In some embodiments, R 5a is propyl. In some embodiments, R 5a is isopropyl. In some embodiments, R 5a is butyl. In some embodiments, R 5a is n-butyl. In some embodiments, R 5ais pentyl. In some embodiments, R 5b is methyl. In some embodiments, R 5b is ethyl. In some embodiments, R 5b is propyl. In some embodiments, R 5b is isopropyl. In some embodiments, R 5b is butyl. In some embodiments, R 5b is n-butyl. In some embodiments, R 5b is pentyl. In some embodiments, R 5a and R 5b are both methyl. The trifluoroborate-containing prosthetic group is 18 In some embodiments, BF3-R 5 -One of the fluorines is 18 F. In some embodiments, BF3-R 5 -All three fluorines in 18 F. In some embodiments, BF3-R 5 -All three fluorines in 19 It's F.

[0133] In certain embodiments, the compounds are conjugated to a radionuclide for positron emission tomography (PET) or single photon emission computed tomography (SPECT) imaging of GRPR-expressing tumors, and the compounds are conjugated to a radionuclide that is a positron emitter or a gamma emitter. Without limitation, positron or gamma emitting radionuclides include: 68 Ga, 67 Ga, 61 Cu, 64 Cu, 67 Ga, 99m Tc, 110m In, 111 In, 44 Sc, 86 Y, 89 Zr, 90 Nb, 152 Tb, 155 Tb, 18 F, 131 I, 123 I,124 I, 203 Pb and 72 As.

[0134] In certain embodiments, the compounds are conjugated to radionuclides for use in therapy, including: 165 Er, 212 Bi, 211 At, 166 Ho, 149 Pm, 159 Gd, 105 Rh, 109 Pd, 198 Au, 199 Au, 175 Yb, 142 Pr, 177 Lu, 111 In, 213 Bi, 47 Sc, 90 Y, 225 Ac, 117m Sn, 153 Sm, 149 Tb, 161 Tb, 165 Er, 213 Bi, 224 Ra, 223 Ra, 212 Bi, 212 Pb, 225 Ac, 227 Th, 223 Ra, 47 Sc, 77 As, 186 Re, 188 Re, 64 Cu or 67 These include radioactive isotopes such as Cu.

[0135] In some embodiments, n6 is 1, and the linker and R L together form a p-aminomethylaniline-diglycolic acid (pABzA-DIG) linker, a 4-amino-(1-carboxymethyl)piperidine (Pip) linker, a 9-amino-4,7-dioxanoic acid (dPEG2) linker, or a 4-(2-aminoethyl)-1-carboxymethyl-piperazine (Acp) linker. In some embodiments, the linker and RL Together, [ka] Form.

[0136] In some embodiments, the compound is LW01025, optionally conjugated with a radioactive metal. In some embodiments, the compound is LW01029, optionally conjugated with a radioactive metal. In some embodiments, the compound is LW01107, optionally conjugated with a radioactive metal. In some embodiments, the compound is LW01108, optionally conjugated with a radioactive metal. In some embodiments, the compound is LW01110, optionally conjugated with a radioactive metal. In some embodiments, the compound is LW01102, optionally conjugated with a radioactive metal. In some embodiments, the compound is LW01142, optionally conjugated with a radioactive metal. In some embodiments, the compound is LW01158, optionally conjugated with a radioactive metal. In some embodiments, the compound is LW01186, optionally conjugated with a radioactive metal.

[0137] In some embodiments, the compound is LW02002, optionally conjugated with a radioactive metal. In some embodiments, the compound is LW02021, optionally conjugated with a radioactive metal. In some embodiments, the compound is LW02023, optionally conjugated with a radioactive metal. In some embodiments, the compound is LW02025, optionally conjugated with a radioactive metal.

[0138] In some embodiments, the compound is LW01045, optionally conjugated with a radioactive metal. In some embodiments, the compound is LW01059, optionally conjugated with a radioactive metal. In some embodiments, the compound is LW01061, optionally conjugated with a radioactive metal. In some embodiments, the compound is LW01090, optionally conjugated with a radioactive metal. In some embodiments, the compound is LW01117, optionally conjugated with a radioactive metal.

[0139] In some embodiments, the compound is LW01025(DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-Thz-NH2); LW01029(DOTA-Pip-D-2-Nal-Gln-Trp-Ala-Val-Gly-His-Leu-Thz-NH2); LW01107(DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-NMe-His-Leu-Thz-NH2), LW01108(DOTA-Pip-D-Phe-Gln-Trp-Ala-Tle-Gly-His-Leu-Thz-NH2), LW01110(DOTA-Pip-D-Phe-Gln-Trp-Ala-Tle-Gly-NMe-His-Leu-Thz-NH2), LW01142(DOTA-Pip-D-Phe-His-Trp-Ala-Tle-Gly-NMe-His-Leu-Thz-NH2), LW01102(DOTA-Pip-D-Phe-His-Trp-Ala-Val-Gly-His-Leu ψThz-NH2), LW01158(DOTA-Pip-D-Phe-Gln-Trp-Ala-Tle-Gly-His-Leu ψThz-NH2), LW01080(D-Phe-Gln-Trp-Ala-Tle-Gly-His-Leu-Thz-NH2), LW01085(D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-Thz-NH2)、 LW01088(D-Phe-Gln-Trp-Ala-Val-Gly-NMe-His-Leu-Thz-NH2)、 LW01136(D-Phe-Gln-Trp(Me)-Ala-Val-Gly-His-Leu-Thz-NH2)、 LW01186(DOTA-Pip-D-Phe-Gln-αMe-Trp-Ala-Tle-Gly-His-LeuψThz-NH2)、 LW02002(DOTA-Pip-D-Phe-Gln-Trp-Ala-Tle-N-Me-Gly-His-Leu ψThz-NH2)、 LW02021(DOTA-Pip-D-Phe-Gln-7-F-Trp-Ala-Val-Gly-His-Leu-Thz-NH2); LW01142(DOTA-Pip-D-Phe-His-Trp-Ala-Tle-Gly-NMe-His-Leu-Thz-NH2)、 LW02023(DOTA-Pip-D-Phe-Gln-5-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH2)、 LW02025(DOTA-Pip-D-Phe-Gln-2-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH2)、 LW02045(DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-N-MeGly-His-Leu ψPro-NH2)、 LW02042(DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Phe-Thz-NH2)、 LW02011(D-Phe-Gln-Trp-Ala-2,3-デヒドロ-Val-Gly-His-Leu-Thz-NH2)、 LW02016(D-Phe-Gln-Trp-Ala-L-シクロプロピリシン(cyclopropylycine)-Gly-His-Leu-Thz-NH2)、 LW02019 (D-Phe-Gln-Trp-Ala-Cyclobutaneacetic acid-Gly-His-Leu-Thz-NH2), LW01166 (D-Phe-Gln-5-F-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01171 (D-Phe-Gln-6-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01173 (D-Phe-Gln-5-OH-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01175 (D-Phe-Gln-6-F-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01177 (D-Phe-Gln-7-F-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01180 (D-Phe-Gln-4-F-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01182 (D-Phe-Gln-5-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01183 (D-Phe-Gln-4-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01191 (D-Phe-Gln-D-Tpi-Ala-Val-Gly-His-Leu-Thz-NH2); LW02007 (D-Phe-Gln-7-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW02009 (D-Phe-Gln-2-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW02013 (D-Phe-Gln-7-Aza-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), or LW02015 (D-Phe-Gln-Bta-Ala-Val-Gly-His-Leu-Thz-NH2), and the ψ of these compounds is a reduced peptide bond.

[0140] In another embodiment, the compound is LW01080*(DOTA-Pip-D-Phe-Gln-Trp-Ala-Tle-Gly-His-Leu-Thz-NH2), LW01085*(DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01088*(DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-NMe-His-Leu-Thz-NH2), LW01136*(DOTA-Pip-D-Phe-Gln-Trp(Me)-Ala-Val-Gly-His-Leu-Thz-NH2), LW02011*(DOTA-Pip-D-Phe-Gln-Trp-Ala-2,3-dehydro-Val-Gly-His-Leu-Thz-NH2), LW02016* (DOTA-Pip-D-Phe-Gln-Trp-Ala-L-Cyclopropylidin-Gly-His-Leu-Thz-NH2), LW02019* (DOTA-Pip-D-Phe-Gln-Trp-Ala-cyclobutaneacetic acid-Gly-His-Leu-Thz-NH2), LW01166*(DOTA-Pip-D-Phe-Gln-5-F-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01171*(DOTA-Pip-D-Phe-Gln-6-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01173*(DOTA-Pip-D-Phe-Gln-5-OH-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01175*(DOTA-Pip-D-Phe-Gln-6-F-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01177*(DOTA-Pip-D-Phe-Gln-7-F-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01180*(DOTA-Pip-D-Phe-Gln-4-F-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01182*(DOTA-Pip-D-Phe-Gln-5-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01183(DOTA-Pip-D-Phe-Gln-4-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01191*(DOTA-Pip-D-Phe-Gln-D-Tpi-Ala-Val-Gly-His-Leu-Thz-NH2), LW02007*(DOTA-Pip-D-Phe-Gln-7-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW02009*(DOTA-Pip-D-Phe-Gln-2-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH2); LW02013*(DOTA-Pip-D-Phe-Gln-7-Aza-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), or LW02015* (DOTA-Pip-D-Phe-Gln-Bta-Ala-Val-Gly-His-Leu-Thz-NH2), and ψ in these compounds is a reduced peptide bond.

[0141] In another embodiment, the compound is LW01045(DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-ψ-Thz-NH2), LW01059(DOTA-Pip-D-2-NaI-Gln-Trp-Ala-Val-Gly-His-Leu-ψ-Thz-NH2), LW01061(DOTA-Pip-D-Tpi-Gln-Trp-Ala-Val-Gly-His-Leu-ψ-Thz-NH2), LW01090(DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-NMe-Gly-His-Leu-ψ-Thz-NH2), or LW01117 (DOTA-cysteic acid-Pip-D-2-NaI-Gln-Trp-Ala-Val-Gly-His-Leu-ψ-Thz-NH2), where ψ in these compounds is a reduced peptide bond.

[0142] In another particular embodiment, the LW0 compounds listed above and described herein may be included in a pharmaceutical composition. In a particular embodiment, the pharmaceutical composition may include the LW0 compounds listed above and described herein, or one or more compounds from formula I, A, or B, and a pharma- ceutically acceptable carrier. In another particular embodiment, the compound may be bound to or include a radioactive metal. In a particular embodiment, the radioactive metal is: 165 Er, 212 Bi, 211 At, 166 Ho, 149 Pm, 159 Gd, 105 Rh, 109 Pd, 198 Au, 199 Au, 175 Yb, 142 Pr, 177 Lu, 111 In, 213 Bi, 47 Sc, 90 Y, 225 Ac, 117m Sn, 153 Sm, 149 Tb, 161 Tb, 224 Ra, 223 Ra, 212 Pb, 227 Th, 223 Ra, 77 As, 186 Re, 188 Re, 67 Cu, or 64 Cu.

[0143] In certain embodiments, the LW0 compounds listed above and described herein may be used in imaging methods. In certain embodiments, the method may include imaging gastrin releasing peptide receptor (GRPR) in a subject, the method includes administering to the subject a peptide compound including the LW0 compounds listed above and described herein, and / or any compound of formula I, A, or B, and imaging the tissue of the subject. In certain embodiments, the method may include a method of treating cancer in a subject, the method includes administering to a subject in need thereof a peptide compound including the LW0 compounds listed above and described herein, and / or any compound of formula I, A, or B.

[0144] In another particular embodiment, the method may include treating a GRPR-expressing condition or disease. In particular embodiments, the GRPR-expressing condition or disease may be a psychiatric disorder, a neurological disorder, an inflammatory disease, prostate cancer, lung cancer, head and neck cancer, colon cancer, kidney cancer, ovarian cancer, liver cancer, pancreatic cancer, breast cancer, glioma, or neuroblastoma. In some embodiments, the cancer is prostate cancer.

[0145] In some embodiments, the compounds described herein may be optionally conjugated with a radiometal and used in the methods described herein.

[0146] In an alternative embodiment, the radiometal is 177 Lu, 111 In, 213 Bi, 68 Ga, 67 Ga, 203 Pb, 212 Pb, 44 Sc, 47 Sc, 90 Y, 86 Y, 225 Ac, 117m Sn, 153 Sm, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 165Er, 213 Bi, 224 Ra, 212 Bi, 212 Pb, 225 Ac, 227 Th, 223 Ra, 47 Sc, 64 Cu, or 67 In some embodiments, the radiometal is 68 In some embodiments, the radiometal is 64 In some embodiments, the radiometal is 67 In some embodiments, the radiometal is 67 In some embodiments, the radiometal is 111 In some embodiments, the radiometal is 177 In some embodiments, the radiometal is 90 In some embodiments, the radiometal is 225 It is Ac.

[0147] A radiolabeling group (i.e., R rad When the compound (A) comprises or is conjugated to a diagnostic radionuclide, the use of certain embodiments of the compounds disclosed herein for the preparation of a radiolabeled tracer for imaging GRPR-expressing tissue in a subject is disclosed. A method of imaging GRPR-expressing tissue in a subject is also disclosed, the method comprising administering to the subject a composition comprising a compound described herein and a pharma- ceutically acceptable excipient, and imaging the tissue of the subject, for example, using PET or SPECT. When the tissue is a diseased tissue (e.g., a GRPR-expressing cancer), a GRPR-targeted therapy may be selected to treat the subject.

[0148] A radiolabeling group (i.e., R radDisclosed are certain embodiments of the compounds (or pharmaceutical compositions thereof) for the treatment of a GRPR-expressing condition or disease (such as, for example, cancer) in a subject, when the compound (or pharmaceutical composition thereof) comprises or is conjugated to a therapeutic radionuclide. Accordingly, provided are uses of the compounds disclosed herein in the preparation of a medicament for treating a GRPR-expressing condition or disease in a subject. Also provided are methods of treating a GRPR-expressing disease in a subject, comprising administering to the subject a composition comprising the compound and a pharma- ceutically acceptable excipient. For example, but not limited to, the disease may be a GRPR-expressing cancer. In certain embodiments, the LW0 compounds listed above and described herein may comprise or be conjugated to a radiometal. In certain embodiments, the method may comprise imaging a gastrin-releasing peptide receptor (GRPR) in a subject, comprising administering to the subject a peptide compound comprising the LW0 compounds listed above and described herein comprising a radiometal, and / or any compound of formula I, A, or B comprising a radiometal, and imaging a tissue of the subject. In certain embodiments, the method may include a method of treating cancer in a subject, the method comprising administering to a subject in need thereof a peptide compound, including an LW0 compound as listed above and described herein, comprising a radioactive metal, and / or any compound of Formula I, A, or B comprising a radioactive metal.

[0149] Aberrant or ectopic GRPR expression has been detected in a variety of conditions and diseases, including psychiatric / neurological disorders, inflammatory diseases, and cancer (Cornelio, et al. Ann Oncol. 2007, 18:1457-1466; Bajo et al. Proc Natl Acad Sci US A. 2002, 99:3836-3841; Koppan et al. Cancer. 1998, 83:1335-1343; Shirahige et al. Biomed Pharmacother. 1994 48:465-472; Cai et al. Int J Oncol. 1995, 6:1165-1172; Jungwirth, Eur J Cancer Part A. 1997, 33:1141-1148; Gonzalez et al., J Pharmacol Exp Ther. 200, 331(1): 265-276; Dalm et al. PLoS One. 2017, 12(1): e0170536; Guo et al., Curr Opin Endocrinol Diabetes Obes. 2015, 22(1): 3-8; Ischia et al., BJU Int. 201, 113 Suppl 2: 40-47; Ramos-Alvarez et al. Peptide 2015, 72: 128-144). Thus, the GRPR expression condition or disease can be, but is not limited to, a psychiatric disorder, a neurological disorder, an inflammatory disease, prostate cancer, lung cancer, head and neck cancer, colon cancer, kidney cancer, ovarian cancer, liver cancer, pancreatic cancer, breast cancer, glioma, or neuroblastoma. In some embodiments, the cancer is prostate cancer.

[0150] The compounds presented herein incorporate peptides that may be synthesized by any of a variety of methods established in the art, including, but not limited to, solution-phase and solid-phase peptide synthesis using methods employing 9-fluorenylmethoxycarbonyl (Fmoc) and / or t-butyloxycarbonyl (Boc) chemistry, and / or other synthetic approaches.

[0151] Solid phase peptide synthesis methods and techniques are well established in the art. For example, a peptide can be synthesized by sequentially incorporating the desired amino acid residues one by one. In such methods, peptide synthesis typically begins with coupling the C-terminal amino acid of the peptide of interest to a suitable resin. Prior to this, the reactive side chain and alpha amino group of the amino acid are protected from reaction by suitable protecting groups, allowing only the alpha carboxyl group to react with functional groups such as amine groups, hydroxyl groups, or halogenated alkyl groups on the solid support. After coupling the C-terminal amino acid to the support, the protecting groups on the side chain and / or alpha amino group of the amino acid are selectively removed to allow coupling of the next amino acid of interest. This process is repeated until the desired peptide is fully synthesized, at which point it can be cleaved from the support and purified. A non-limiting example of an instrument for solid phase peptide synthesis is the Aapptec Endeavor 90 peptide synthesizer.

[0152] To allow for the coupling of additional amino acids, the Fmoc protecting group may be removed from the amino acid on the solid support under mildly basic conditions, such as piperidine (20-50% v / v) in DMF. The amino acid to be added must also be activated for coupling (e.g., with an alpha carboxylate). Non-limiting examples of activating reagents include, but are not limited to, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP). Racemization is minimized by using triazoles such as 1-hydroxy-benzotriazole (HOBt) and 1-hydroxy-7-aza-benzotriazole (HOAt). The coupling may be carried out in the presence of a suitable base, such as N,N-diisopropylethylamine (DIPEA / DIEA).

[0153] Apart from the formation of a typical peptide bond to extend a peptide, the peptide can be extended in a branched manner by coupling to a side chain functional group (e.g., a carboxylic acid or amino group) either side chain to side chain or side chain to backbone amino or carboxylate. Coupling to amino acid side chains may be performed by any known method and may be performed on-resin or off-resin. Non-limiting examples include forming amides between an amino acid side chain containing a carboxyl group (e.g., Asp, D-Asp, Glu, D-Glu, etc.) and either an amino acid side chain containing an amino group (e.g., Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, etc.) or the peptide N-terminus; forming amides between an amino acid side chain containing an amino group (e.g., Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, etc.) and either an amino acid side chain containing a carboxyl group (e.g., Asp, D-Asp, Glu, D-Glu, etc.) or the peptide C-terminus; and forming 1,2,3-triazoles via click chemistry between an amino acid side chain containing an azide group (e.g., Lys(N3), D-Lys(N3), etc.) and either an amino acid side chain containing an alkyne group (e.g., Pra, D-Pra, etc.). While the protecting groups on the appropriate functional groups must be selectively removed prior to amide bond formation, the reaction between alkyne and azide groups via the click reaction to form 1,2,3-triazoles does not require selective deprotection. Non-limiting examples of selectively removable protecting groups include 2-phenylisopropyl ester (O-2-PhiPr) (e.g., on Asp / Glu), as well as 4-methyltrityl (Mtt), allyloxycarbonyl (alloc), 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene))ethyl (Dde), and 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl (ivDde) ​​(e.g., on Lys / Orn / Dab / Dap). The O-2-PhiPr and Mtt protecting groups can be selectively deprotected under mildly acidic conditions, such as 2.5% trifluoroacetic acid (TFA) in DCM.The Alloc protecting group can be selectively deprotected using tetrakis(triphenylphosphine)palladium(0) and phenylsilane in DCM. The Dde and ivDde protecting groups can be selectively deprotected using 2-5% hydrazine in DMF. The deprotected side chains of Asp / Glu (L or D form) and Lys / Orn / Dab / Dap (L or D form) can then be coupled, for example, by using the coupling reaction conditions described above. The above provides a means for the inclusion of multiple BF3 groups.

[0154] The peptide backbone amide may be N-methylated (i.e., alpha aminomethylated) or N-alkylated. This may be accomplished by directly using Fmoc-N-methylated (or Fmoc-N-alkylated) amino acids during peptide synthesis. Alternatively, N-methylation under Mitsunobu conditions may be performed. First, the free primary amine group is protected using 4-nitrobenzenesulfonyl chloride (Ns-Cl) and 2,4,6-trimethylpyridine (collidine) in NMP. N-methylation (or N-alkylation) may then be achieved in the presence of triphenylphosphine, diisopropyl azodicarboxylate (DIAD), and methanol. N-deprotection may then be performed using mercaptoethanol and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in NMP. HATU, HOAt, and DIEA may be used to couple the protected amino acid to the N-methylated (or N-alkylated) alpha amino group.

[0155] Thioether (-S-) bond formation (e.g., L 1) can be accomplished either on the solid phase or in solution phase. For example, the formation of a thioether (-S-) bond can be achieved by coupling a thiol-containing compound (such as a thiol group on a cysteine ​​side chain) with an alkyl halide (such as 3-(Fmoc-amino)propyl bromide) in the presence of a base (such as N,N-diisopropylethylamine) in a suitable solvent (such as N,N-dimethylformamide). When the reaction is carried out in solution phase, the reactants used are preferably in equivalent molar ratios (1:1) and the desired product can be purified by flash column chromatography or high performance liquid chromatography (HPLC). When the reaction is carried out on the solid phase, i.e., one reactant is bound to the solid phase, the other reactant is usually used in excess (3 or more equivalents of the reactant bound to the solid phase). After the reaction, excess unreacted reactants and reagents can be removed by sequentially washing the solid phase (resin) using a combination of solvents such as, for example, N,N-dimethylformamide, methanol, and dichloromethane.

[0156] Formation of a bond between a thiol group and a maleimide group (e.g., L 1 ) can be carried out using the conditions described above for the formation of thioether (-S-) bonds, simply by replacing the alkyl halide with a maleimide-containing compound. Similarly, this reaction can be carried out on solid phase or in solution phase. When the reaction is carried out in solution phase, the reactants used are preferably in equivalent molar ratios (1:1), and the desired product can be purified by flash column chromatography or high performance liquid chromatography (HPLC). When the reaction is carried out on solid phase, i.e., one reactant is bound to a solid phase, the other reactant is usually used in excess (3 or more equivalents of the reactant bound to the solid phase). After the reaction, excess unreacted reactants and reagents can be removed by sequentially washing the solid phase (resin) using a combination of solvents such as, for example, N,N-dimethylformamide, methanol, and dichloromethane.

[0157] Urea or thiourea linkages can be created by reacting an amine group with isocyanate or isothiocyanate, respectively, which are common functional groups on radiometal chelators. An isothiocyanate functional group can be added to a radiometal chelator by reacting an amino group on the chelator with thiophosgene [i.e., C(S)Cl2]. Similarly, an isocyanate functional group can be added to a radiometal chelator by reacting an amino group on the chelator with phosgene [i.e., C(O)Cl2].

[0158] A non-peptide moiety (e.g., a radiolabel group and / or an albumin binder) can be coupled to the peptide N-terminus while the peptide is attached to the solid support. This is facilitated if the non-peptide moiety contains an activated carboxylate (and optionally a protecting group), allowing the coupling to be performed on the resin. By way of example and not limitation, a bifunctional chelator such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) tris(tert-butyl ester) can be activated in the presence of N-hydroxysuccinimide (NHS) and N,N'-dicyclohexylcarbodiimide (DCC) and coupled to the peptide. Alternatively, the non-peptide moiety may be incorporated into the compound via a copper-catalyzed click reaction under either solution- or solid-phase conditions. The copper-catalyzed click reaction is well established in the art. For example, 2-azidoacetic acid is first activated and coupled to the peptide by NHS and DCC. The alkyne-containing non-peptide moiety can then be coupled to the peptide by the addition of Cu. 2+ and sodium ascorbate in the presence of water and organic solvents, such as acetonitrile (ACN) and DMF solutions. Non-peptide moieties may also be added in the solution phase, which is routinely done.

[0159] The synthesis of radioactive metal chelators is well known, and many chelators are commercially available (e.g., from Sigma-Aldrich™ / Milipore Sigma™, etc.). Protocols for conjugation of radioactive metals to chelators are also well known (e.g., see the Examples below).

[0160] Compound BF3-R 5 -R 4 Synthesis of the -components can be accomplished according to previously reported procedures (Liu et al. Angew Chem Int Ed 2014 53:11876-11880; Liu et al. J Nucl Med 2015 55:1499-1505; Liu et al. Nat Protoc 2015 10:1423-1432; Kuo et al. J Nucl Med,2019 60:1160-1166, each of which is incorporated by reference in its entirety). In general, BF3-containing motifs can be coupled to linkers via click chemistry by forming a 1,2,3-triazole ring between a BF3-containing azide (or alkynyl) group and an alkynyl (or azide) group on the linker, or by forming an amide bond between a BF3-containing carboxylate and an amino group on the linker. To make BF3-containing azides, alkynes, or carboxylates, first prepare a boronic ester-containing azide, alkyne, or carboxylate, followed by converting the boronic ester to BF3 in a mixture of HCl, DMF, and KHF2. In the case of alkyl BF3, the boronic ester-containing azide, alkyne, or carboxylate can be prepared by coupling a boronic ester-containing alkyl halide (such as iodomethylboronic acid pinacol ester) with an amine-containing azide, alkyne, or carboxylate (such as N,N-dimethylpropargylamine). In the case of aryl BF3, the boronic ester can be prepared via Suzuki coupling using an aryl halide (iodine or bromide) and bis(pinacolato)diboron.

[0161] 18F- 19 F isotope exchange reactions of BF3-containing compounds 18 F-fluorination can be achieved according to a previously published procedure (Liu et al. Nat Protoc 2015 10:1423-1432, incorporated by reference in its entirety). Typically, about 100 nmol of BF3-containing compound is dissolved in a mixture of 15 μl of pyridazine-HCl buffer (pH=2.0-2.5, 1 M), 15 μl of DMF, and 1 μl of 7.5 mM KHF2 aqueous solution. 18 F-fluoride solution (60 μl in saline) is added to the reaction mixture and the resulting solution is heated for 20 min at 80° C. At the end of the reaction, the desired product can be purified by solid phase extraction or by inverse high performance liquid chromatography (HPLC) using a mixture of water and acetonitrile as the mobile phase.

[0162] Once the peptide is fully synthesized on the solid support, the desired peptide may be cleaved from the solid support using a suitable reagent such as TFA, triisopropylsilane (TIS), and water. Side chain protecting groups such as Boc, pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), trityl (Trt), and tert-butyl (tBu) are simultaneously removed (i.e., deprotected). The crude peptide may be collected from the solution by precipitating the crude peptide and adding cold ether, followed by centrifugation. Purification and characterization of the peptide may be performed by standard separation techniques, such as high performance liquid chromatography (HPLC), based on the size, charge, and polarity of the peptide. The identity of the purified peptide may be confirmed by mass spectrometry or other similar approaches. The invention described herein is further illustrated by the following embodiments.

[0163] EMBODIMENTS OF THE PRESENT DISCLOSURE

[0164] Embodiment 1. A peptide compound, wherein the compound has the structure of Formula I, or is a salt or solvate of Formula I: R rad n6 -[Linker]-R L-Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -ψ-Xaa 9 -NH2 (I) During the ceremony, Xaa 1 is an N-terminal amino acid residue selected from D-Phe, 4-chlorophenylalanine (Cpa), D-Cpa, 3-(1-naphthyl)alanine (Nal), D-Nal, 3-(2-naphthyl)alanine (2-Nal), or D-2-Nal; Xaa 2 is Asn, Gln, homoserine (Hse), citrulline (Cit), or His; Xaa 3 is Trp, β-(3-benzothienyl)alanine (Bta), Trp(Me), Trp(7-Me), Trp(6-Me), Trp(5-Me), Trp(4-Me), Trp(2-Me), Trp(7-F), Trp(6-F), Trp(5-F), Trp(4-F), Trp(5-OH), or αMe-Trp; Xaa 4 is Ala or Ser, Xaa 5 is Val, Cpg (cyclopentylglycine), or tert-leucine (Tle); Xaa 6 is Gly, NMe-Gly, or D-Ala, Xaa 7 is His or NMe-His, Xaa 8 is Leu, D-Pro, or Phe; Xaa 9 -NH2 is a C-terminal amidated amino acid residue selected from Pro, Phe, oxazolidine-4-carboxylic acid (4-oxa-L-Pro), Me2Thz (5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid), or thiazoline-4-carboxylic acid (Thz); ψ is Xaa 8 Xaa 9 represents a peptide bond or reduced peptide bond that is bonded to Xaa 2 , Xaa 3 , Xaa 5 , and Xaa 7 are Gln, Trp, Val, and His, respectively, and ψ is a reduced peptide bond, R L is -C(O)-, -NH-C(O)-, or -NH-C(S)-, The linker, -L 1 R 1 -and / or- (L 1 )2R 1 - a linear or branched chain of n1 units, n1 is 1 to 20; Each R 1 are independently linear, branched, and / or cyclic C n2 alkylenyl, alkenylenyl, and / or alkynylenyl, where each n2 is independently 1 to 20, any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted with oxo, hydroxyl, sulfhydryl, -SeH, halogen, guanidino, amine, amide, urea, carboxylic acid, sulfonic acid, sulfinic acid, or phosphate; L 1 is attached to a carbon, where each L 1 are independently -S-, -N(R 2 )C(O)-, -C(O)N(R 2 )-, -NH-C(O)-NH-, -NH-C(S)-NH-, [ka] and R 2 is H, methyl, or ethyl; Albumin binder (R alb ) is the linker L 1 and an albumin binder optionally bound to -(CH2) n3 -CH3, wherein n3 is 8 to 20; -(CH2) n4 -C(O)OH, where n4 is 8 to 20; [ka] In the formula, n5 is 1 to 4; R 3a is H or methyl, R 3b is I, Br, F, Cl, H, OH, OCH3, NH2, NO2 or C1-C6 alkyl, or [ka] n6 is 1 to 5; Each R rad is the linker L 1 wherein each radiolabeling group is independently a radiometal chelator, an aryl or heteroaryl substituted with a radioactive halogen, a prosthetic group containing a trifluoroborate, a prosthetic group containing a silicon-fluorine-acceptor moiety, or a prosthetic group containing a fluorophosphate, a fluorosulfate, a sulfonyl fluoride, or a combination thereof.

[0165] Embodiment 2. The peptide compound of embodiment 1, wherein ψ is a peptide bond.

[0166] Embodiment 3. Xaa 3 3. The peptide compound according to embodiment 1 or 2, wherein is αMe-Trp.

[0167] Embodiment 4. Xaa 5 The peptide compound according to any one of embodiments 1 to 3, wherein is Tle.

[0168] Embodiment 5. Xaa 7 is NMe-His.

[0169] Embodiment 6. Xaa 1 is D-Phe or D-2-Nal.

[0170] Embodiment 7. Xaa 2 is Gln or His.

[0171] Embodiment 8. Xaa 3 is Trp.

[0172] Embodiment 9. Xaa 6 is Gly.

[0173] Embodiment 10. Xaa 8 The peptide compound according to any one of embodiments 1 to 9, wherein is Leu.

[0174] Embodiment 11. Xaa 9 The peptide compound according to any one of embodiments 1 to 10, wherein

[0175] Embodiment 12. At least one R radis a radioactive metal chelator, optionally comprising DOTA and derivatives, DTPA and DTPA analogs optionally selected from DOTAGA, NOTA, NODAGA, NODASA, CB-DO2A, 3p-C-DEPA, TCMC, DO3A, CHX-A″-DTPA and 1B4M-DTPA, sarcofazine and sarcofazine derivatives optionally selected from TETA, NOPO, Me-3,2-HOPO, CB-TE1A1P, CB-TE2P, MM-TE2A, DM-TE2A, SarAr, SarAr-NCS, diamSar, AmBaSar, and BaBaSar, TRAP, AAZTA, DATA and DATA derivatives, H2-macropa or derivatives thereof, H2dedpa, H4octapa, H4p 12. The peptide compound according to any one of the preceding embodiments, selected from the group consisting of y4pa, H4Pypa, H2azapa, H5decapa and other picolinic acid derivatives, CP256, PCTA, C-NETA, C-NE3TA, HBED, SHBED, BCPA, CP256, YM103, desferrioxamine (DFO) and DFO derivatives, H6phospa, trithiol chelate, mercaptoacetyl, hydrazinonicotinamide, dimeric captosuccinic acid, 1,2-ethylenediylbis-L-cysteine ​​diethyl ester, methylene diphosphonate, hexamethylpropyleneamine oxime, hexakis(methoxyisobutylisonitrile), H4py4pa-phenyl-NCS, and crown.

[0176] Embodiment 13. The radiometal chelator is bound by a radiometal, a radionuclide-bound metal, or a radionuclide-bound metal-containing prosthetic group, which optionally 68 Ga, 61 Cu, 64 Cu, 67 Cu, 67 Ga, 111 In, 44 Sc, 86 Y, 89 Zr, 90 Nb, 177 Lu, 117m Sn, 165 Er, 90 Y, 227 Th, 225Ac, 213 Bi, 212 Bi, 72 As, 77 As, 211 At, 203 Pb, 212 Pb, 47 Sc, 166 Ho, 188 Re, 186 Re, 149 Pm, 159 Gd, 105 Rh, 109 Pd, 198 Au, 199 Au, 175 Yb, 142 Pr, 114m In, 94m Tc, 99m Tc, 149 Tb, 152 Tb, 155 Tb, 161 Tb, and [ 18 13. The peptide compound of embodiment 12, wherein the compound is selected from the group consisting of: F]AlF.

[0177] Embodiment 14. At least one R rad However, the prosthetic group BF3-R 5 -R 4 -, wherein R 4 But -(CH2) 1-5 - and optionally methylene, BF3-R 5 -but, [ka] wherein R 5a and R 5b each independently represents a C1-C5 linear or branched alkyl group; [ka] R in each pyridine substituted -OR, -SR, -NR-, -NHR or -NR2 is independently a branched or straight chain C1-C5 alkyl, and optionally BF3-R 5 -R 4-The fluorine in 18 14. The peptide compound according to any one of embodiments 1 to 13, comprising F.

[0178] In the embodiment 15.n6 is 2 and R rad n6 is the first R rad and the second R rad The first R rad is a radiometal chelator as defined in embodiment 12, optionally bound by a radiometal, a radionuclide-bound metal, or a radionuclide-bound metal-containing prosthetic group as defined in embodiment 13, and a second R rad 12. The peptide compound according to any one of embodiments 1 to 11, wherein is a trifluoroborate-containing prosthetic group as defined in embodiment 14, or a radioactive fluoride-substituted aryl or heteroaryl.

[0179] Embodiment 16. Linker and R L together form a linear or branched peptide linker (Xaa 10 ) 1-20 Forming each Xaa 10 are independently a proteinogenic or non-proteinogenic amino acid residue, each peptide backbone amino group is independently optionally methylated, and each non-proteinogenic amino acid residue is independently selected from Table 1.

[0180] Embodiment 17. n6 is 1 and the linker and R L together form a p-aminomethylaniline-diglycolic acid (pABzA-DIG) linker, a 4-amino-(1-carboxymethyl)piperidine (Pip) linker, a 9-amino-4,7-dioxanoic acid (dPEG2) linker, or a 4-(2-aminoethyl)-1-carboxymethyl-piperazine (Acp) linker, and optionally a linker and R L Let's get together [ka] 12. The peptide compound according to any one of embodiments 1 to 11, which forms: EXAMPLES

[0181] The present invention is further illustrated in the following examples.

[0182] Example 1

[0183] Common methods

[0184] Chemicals were obtained from commercial sources and used without further purification. All peptides were synthesized on an AAPPTec (Louisville, KY) Endeavor 90 peptide synthesizer. Radiolabeled precursors, non-radioactive Ga-complex standards, and 68 Purification and quality control of the Ga-labeled peptides were performed on an Agilent (Santa Clara, CA) HPLC system equipped with a model 1200 quaternary pump, a model 1200 UV absorbance detector (set at 220 nm), and a Bioscan (Washington, DC) NaI scintillation detector. The Agilent ChemStation software was used to control the operation of the Agilent HPLC system. The HPLC columns used were a semi-preparative (Luna C18, 5 μm particle size, 100 Å pore size, 250×10 mm) and an analytical (Luna C18, 5 μm particle size, 100 Å pore size, 250×4.6 mm) column from Phenomenex (Torrance, CA). The collected HPLC eluate containing the desired peptide was lyophilized using a Labconco (Kansas City, MO) FreeZone 4.5 Plus freeze dryer. Mass spectrometry was performed using a Waters (Milford, MA) ACQUITY QDa mass spectrometer equipped with a 2489 UV / Vis detector and an e2695 separations module. C18 Sep-Pak cartridges (1 cm 3 , 50 mg) was obtained from Waters (Milford, Mass.). 68Ga was eluted from the generator at iThemba Laboratories (Somerset West, South Africa) and purified using a DGA resin column from Eichrom Technologies LLC (Lisle, IL). 68 Radioactivity of Ga-labeled peptides was measured using a CRC-25R / W dose calibrator from Capintec (Ramsey, NJ). PET / CT imaging was performed using a microPET / CT scanner from Siemens Inveon (Knoxville, TN). Radioactivity in mouse tissues collected from biodistribution studies was counted using a Wizard2 2480 automatic gamma counter from PerkinElmer (Waltham, MA).

[0185] Synthesis of Fmoc-LeuψThz-OH(4), where ψ is a reduced peptide bond

[0186] Compound 4 was synthesized according to the reaction steps depicted in Scheme 1 shown below. [ka]

[0187] Synthesis of Boc-Thz-OtBu1: Thiazolidine-4-carboxylic acid (2.66 g, 20 mmol), di-tert-butyl dicarbonate (4.37 g, 20 mmol), and sodium bicarbonate (2.52 g, 30 mmol) were stirred in water (40 mL) and 1,4-dioxane (40 mL) at room temperature overnight. The reaction mixture was washed with ether (100 mL x 2) and the aqueous layer was collected. The collected aqueous fraction was adjusted to pH 3 using concentrated hydrochloric acid, then extracted with ethyl acetate (100 mL x 2), dried over magnesium sulfate, filtered, and evaporated to give a white solid. The resulting white solid was dissolved in 30 mL of dichloromethane along with tert-butyl 2,2,2-trichloroacetimidate (8.74 g, 40 mmol) and the mixture was stirred at room temperature for 48 hours. The mixture was filtered, and the filtrate was concentrated in vacuo and purified by flash column chromatography eluting with 1:5 ethyl acetate / hexanes to give compound 1 (4.36 g, 75% yield) as a colorless oil.

[0188] Synthesis of Thz-OtBu HCl salt (2) Compound 1 (4.31 g) was dissolved in a mixture of 4 M HCl in ethyl acetate (56.3 mL) and 1,4-dioxane (18.8 mL) and stirred at room temperature for 4 h. The precipitate was collected by filtration to give 2 (1.78 g, 53% yield) as a white solid.

[0189] Synthesis of Fmoc-LeuψThz-OtBu (3), wherein ψ is a reduced peptide bond. Solution 1: Fmoc-leucinol (3.79 g, 11.1 mmol) was converted to the aldehyde by treatment with Dess-Martin periodinane (5.87 g, 13.8 mol) in dichloromethane (70 mL) under ice / water bath for 4 h. The reaction mixture was then mixed with saturated aqueous NaHCO3 (130 mL) and sodium thiosulfate (13.0 g) and stirred for 30 min before being extracted with dichloromethane (130 mL). The organic layer was collected, dried over anhydrous magnesium sulfate and concentrated in vacuo to a volume of approximately 20 mL.

[0190] Solution 2: Compound 2 was dissolved in saturated aqueous NaHCO3 (35 mL) and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give a colorless oil. The oil was mixed with acetic acid (400 μL, 7.0 mmol) in dichloromethane (30 mL).

[0191] Solutions 1 and 2 were mixed and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (5.41 g, 25.5 mmol) was added to the mixture and stirred for 20 h. Saturated aqueous NaHCO3 (100 mL) was added and stirred for 10 min. The mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, dried over anhydrous MgSO4, and purified by flash column chromatography eluting with 1:3 ether / hexane to give 3 as a white solid (2.13 g, 63% yield).

[0192] ψ is a reduced peptide bond Synthesis of Fmoc-LeuψThz-OH (4): Compound 3 was dissolved in a mixture of dichloromethane (25 mL) and trifluoroacetic acid (75 mL) and stirred at room temperature for 3 h. After concentration in vacuum, the residue was dissolved in ethyl acetate (80 mL) and mixed with 4M HCl in 1,4-dioxanedioxane (3 mL). After stirring for 10 min, the volatile solvents were removed in vacuum. Diethyl ether (250 mL) was added to the residue and the mixture was stirred for 30 min. The white solid formed was collected by filtration to give 1.38 g of 4 (70% yield). ESI-MS: 4C 25 H 30 Calculated value for N2O4S [M+H] + 455.59;actual value 455.42.

[0193] Synthesis of LW01025 and LW01029

[0194] The chemical structures of LW01025 and LW01029 are shown below. [ka]

[0195] LW01025 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-Thz-NH2) and LW01029 (DOTA-Pip-D-2-Nal-Gln-Trp-Ala-Val-Gly-His-Leu-Thz-NH2) were synthesized using a standard Fmoc solid-phase synthesis strategy starting from Fmoc-Rink Amide MBHA resin. Fmoc-Thz-OH (Fmoc-L-thiazolidine-4-carboxylic acid), Fmoc-Leu-OH, Fmoc-His(Trt)-OH, Fmoc-Gly-OH, Fmoc-Val-OH, Fmoc-Ala-OH, Fmoc-Trp(Boc)-OH, Fmoc-Gln(Trt)-OH, Fmoc-D-Phe-OH (LW01025) / Fmoc-D-2-Nal-OH (W01029), Fmoc-4-amino-(1-carboxymethyl)piperidine, and DOTA( t Bu)3 was sequentially coupled to Fmoc-Rink amide-MBHA resin. After cleavage with TFA / TIS / water / DODT / thioanisole / phenol 81.5:1:5:2.5:5:5 and precipitation with diethyl ether, the crude LW01025 product was purified by HPLC (C18 semi-preparative column, flow rate: 4.5 mL / min, 23% ACN and 0.1% TFA in water, retention time = 11.3 min) to give a white powder (30% yield). ESI-MS: LW01025 C 74 H 108 N 20 O 18 Calculated value for S [M+2H] 2+ 799.4; found 799.6. For LW01029, the crude was purified by HPLC (C18 semi-preparative column, flow rate: 4.5 mL / min, 25% ACN and 0.1% TFA in water, retention time = 13.0 min) and lyophilized to give a white powder (38% yield). ESI-MS: LW01029 C 78 H 110 N 20 O 18 Calculated value for S [M+2H] 2+ 824.41;actual value 824.92.

[0196] Synthesis of LW01107, LW01108, LW01110, and LW01142

[0197] The chemical structures of LW01107, LW01108, LW01110, and LW01142 are shown below. [ka]

[0198] LW01107 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-NMe-His-Leu-Thz-NH2), LW01108 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Tle-Gly-His-Leu-Thz-NH2), LW01110 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Tle-Gly-NMe-His-Leu-Thz-NH2), and LW01142 (DOTA-Pip-D-Phe-His-Trp-Ala-Tle-Gly-NMe-His-Leu-Thz-NH2) were synthesized using standard Fmoc solid-phase synthesis. Fmoc-protected amino acids, Fmoc-4-amino-(1-carboxymethyl)piperidine, and DOTA( t Bu)3 was sequentially coupled to Fmoc-Rink amide-MBHA resin. After cleavage with TFA / TIS / water / DODT / thioanisole / phenol 81.5:1:5:2.5:5:5 and precipitation with diethyl ether, the crude product was purified by HPLC (C18 semi-preparative column, flow rate: 4.5 mL / min) and lyophilized to give a white powder.

[0199] For LW01107, the HPLC conditions were 23% ACN and 0.1% TFA in water (retention time = 14.2 min), yield: 19%. ESI-MS: LW01107 C 75 H 110 N 20 O 18 Calculated value for S [M+2H] 2+806.41; Found 806.80. For LW01108, the HPLC conditions were 24% ACN and 0.1% TFA in water (retention time = 10.9 min), yield: 26%. ESI-MS: LW01108 C 75 H 110 N 20 O 18 Calculated value for S [M+2H] 2+ 806.41; Found 807.00. For LW01110, the HPLC conditions were 24% ACN and 0.1% TFA in water (retention time = 14.9 min), yield: 11%. ESI-MS: LW01110 C 76 H 112 N 20 O 18 Calculated value for S [M+2H] 2+ 813.41; Found 813.66. For LW01142, the HPLC conditions were 25% ACN and 0.1% TFA in water (retention time = 12.4 min), yield: 17%. ESI-MS: LW01142 C 77 H 111 N 21 O 17 Calculated value for S [M+2H] 2+ 817.92;actual value 817.88.

[0200] Synthesis of LW01102 and LW01158

[0201] The chemical structures of LW01102 and LW01158 are shown below. [ka]

[0202] LW01102 (DOTA-Pip-D-Phe-His-Trp-Ala-Val-Gly-His-Leu ψThz-NH2) and LW01158 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Tle-Gly-His-Leu ψThz-NH2), During the ceremonywhere ψ is a reduced peptide bond, was synthesized using a standard Fmoc solid-phase synthesis strategy starting from Sieber resin. Fmoc-LeuψThz-OH (4), Fmoc-protected amino acids, Fmoc-4-amino-(1-carboxymethyl)-piperidine, and DOTA ( t Bu)3 was sequentially coupled to the resin. After cleavage with TFA / TIS / water / DODT / thioanisole / phenol 81.5:1:5:2.5:5:5) and precipitation with diethyl ether, the crude product was purified by HPLC (C18 semi-preparative column, flow rate: 4.5 mL / min) and lyophilized to give a white powder.

[0203] For LW01102, the HPLC conditions were 23.5% ACN and 0.1% TFA in water (retention time = 14.9 min), yield: 35%. ESI-MS: LW01102 C 75 H 109 N 21 O 16 Calculated value for S [M+2H] 2+ 796.91; Found 796.51. For LW01158, the HPLC conditions were 26% ACN and 0.1% TFA in water (retention time = 14.1 min), yield: 32%. ESI-MS: LW01158 C 75 H 112 N 20 O 17 Calculated value for S [M+2H] 2+ 779.42;actual value 779.46.

[0204] Example 2

[0205] Synthesis of LW01186, LW02002, LW02021, LW02023, and LW02025

[0206] The chemical structures of LW01186, LW02002, LW02021, LW02023, and LW02025 are as follows: [ka]

[0207] LW01186 (DOTA-Pip-D-Phe-Gln-αMe-Trp-Ala-Tle-Gly-His-LeuψThz-NH2) and LW02002 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Tle-N-Me-Gly-His-LeuψThz-NH2), During the ceremony The compound Fmoc-LeuψThz-OH (4), where ψ is a reduced peptide bond, was synthesized using an Fmoc solid-phase synthesis strategy starting from Sieber resin. As described above in Example 1, the compound Fmoc-LeuψThz-OH (4), an Fmoc-protected amino acid, Fmoc-4-amino-(1-carboxymethyl)-piperidine, and DOTA ( t Bu)3 was sequentially coupled to the resin. After cleavage with TFA / TIS / water / DODT / thioanisole / phenol 81.5:1:5:2.5:5:5) and precipitation with diethyl ether, the crude product was purified by HPLC (C18 semi-preparative column, flow rate: 4.5 mL / min) and lyophilized to give a white powder.

[0208] LW02021 (DOTA-Pip-D-Phe-Gln-7-F-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW02023 (DOTA-Pip-D-Phe-Gln-5-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), and LW02025 (DOTA-Pip-D-Phe-Gln-2-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH2) were synthesized using an Fmoc solid-phase synthesis strategy starting from Fmoc-Rink MBHA resin. Fmoc-protected amino acids, Fmoc-4-amino-(1-carboxymethyl)-piperidine, and DOTA( t Bu)3 was sequentially coupled to the resin. After cleavage with TFA / TIS / water / DODT / thioanisole / phenol 81.5:1:5:2.5:5:5) and precipitation with diethyl ether, the crude product was purified by HPLC (C18 semi-preparative column, flow rate: 4.5 mL / min) and lyophilized to give a white powder. The HPLC conditions and results are shown in Table 5 below.

[0209] [Table 5]

[0210] Synthesis of LW01080, LW01085, LW01088, and LW01136

[0211] The chemical structures of LW01080, LW01085, LW01088, and LW01136 are shown below. [ka]

[0212] LW01080 (D-Phe-Gln-Trp-Ala-Tle-Gly-His-Leu-Thz-NH2), LW01085 (D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01088 (D-Phe-Gln-Trp-Ala-Val-Gly-NMe-His-Leu-Thz-NH2), and LW01136 (D-Phe-Gln-Trp(Me)-Ala-Val-Gly-His-Leu-Thz-NH2) were synthesized using standard Fmoc solid phase synthesis. The Fmoc-protected amino acids were sequentially coupled to Fmoc-Rink amide-MBHA resin. After cleavage with TFA / TIS / water / DODT / thioanisole / phenol 81.5:1:5:2.5:5:5 and precipitation with diethyl ether, the crude product was purified by HPLC (C18 semi-preparative column, flow rate: 4.5 mL / min) and lyophilized to give a white powder.

[0213] For LW01080, the HPLC conditions were 26% ACN and 0.1% TFA in water (retention time = 9.02 min), yield: 26%. ESI-MS: LW01080 C 52 H 72 N 14 O 10 Calculated value for S [M+H] +1085.54; Found 1085.99. For LW01085, the HPLC conditions were 23% ACN and 0.1% TFA in water (retention time = 16.0 min), yield: 41%. ESI-MS: LW01085 C 51 H 70 N 14 O 10 Calculated value for S [M+H] 1+ 1071.52; Found 1071.77. For LW01088, the HPLC conditions were 23% ACN and 0.1% TFA in water (retention time = 17.4 min), yield: 29%. ESI-MS: LW01088 C 52 H 72 N 14 O 10 Calculated value for S [M+H] + 1085.54; Found 1085.69. For LW01136, the HPLC conditions were 27% ACN and 0.1% TFA in water (retention time = 13.4 min), yield: 30%. ESI-MS: LW01136 C 52 H 72 N 14 O 10 Calculated value for S [M+H] + 1085.54;actual value 1085.79.

[0214] Example 3

[0215] Synthesis of LW02011, LW02016, LW02019, LW01166, LW01171, LW01173, LW01175, LW01177, LW01180, LW01182, LW01183, LW01191, LW02007, LW02009, LW02013, and LW02015

[0216] The chemical structures of LW02011, LW02016, LW02019, LW01166, LW01171, LW01173, LW01175, LW01177, LW01180, LW01182, LW01183, LW01191, LW02007, LW02009, LW02013, and LW02015 are as follows:

change

change

[0217] LW02011 (D-Phe-Gln-Trp-Ala-2,3-dehydro-Val-Gly-His-Leu-Thz-NH2), LW02016 (D-Phe-Gln-Trp-Ala-L-cyclopropylglycine-Gly-His-Leu-Thz-NH2), LW02019 (D-Phe-Gln-Trp-Ala-cyclobutylglycine-Gly-His-Leu-Thz-NH2), LW01166 (D-Phe-Gln-5-F-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), H2), LW01171(D-Phe-Gln-6-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01173(D-Phe-Gln-5-OH-Trp-Ala-Val-Gly-His-Leu-Thz-NH2) , LW01175(D-Phe-Gln-6-F-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01177(D-Phe-Gln-7-F-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01 180(D-Phe-Gln-4-F-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01182(D-Phe-Gln-5-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01183( D-Phe-Gln-4-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW01191(D-Phe-Gln-D-Tpi-Ala-Val-Gly-His-Leu-Thz-NH2), LW02007(D-Phe- Gln-7-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW02009 (D-Phe-Gln-2-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), LW02013 (D-Phe-Gln-7-Aza-Trp-Ala-Val-Gly-His-Leu-Thz-NH2), and LW02015 (D-Phe-Gln-Bta-Ala-Val-Gly-His-Leu-Thz-NH2) were synthesized using standard Fmoc solid phase synthesis. The Fmoc-protected amino acids were sequentially coupled to Fmoc-Rink amide-MBHA resin.After cleavage with TFA / TIS / water / DODT / thioanisole / phenol 81.5:1:5:2.5:5:5 and precipitation with diethyl ether, the crude product was purified by HPLC (C18 semi-preparative column, flow rate: 4.5 mL / min) and lyophilized to give a white powder. The HPLC conditions are shown in Table 6 below.

[0218] [Table 6]

[0219] Example 4

[0220] Synthesis of non-radioactive Ga complex standards: LW01025, LW01029, LW01107, LW01108, LW01110, LW01102, LW01142, LW01158, LW01186, LW02002, LW02021, LW02023, and LW02025.

[0221] LW01025 (2.82 mg), LW01029 (2.12 mg), LW01107 (2.20 mg), LW01108 (2.42 mg), LW01110 (2.03 mg), LW01102 (2.17 mg), LW01142 (1.81 mg), and LW01158 (2.54 mg) were each dissolved in 0.5 mL of NaOAc buffer (0.1 N, pH 4.53) and GaCl3 (5 equivalents, 0.2 M) was added. Approximately 2 mg of LW01186, LW02002, LW02021, LW02023, and LW02025 were each dissolved in 0.5 mL of NaOAc buffer (0.1 N, pH 4.53), and GaCl3 (5 equivalents, 0.2 M) was added. o C for 15 min, then purified by HPLC (C18 semi-preparative column) and lyophilized to give a white powder. The HPLC conditions are shown in Table 7 below.

[0222] [Table 7]

[0223] Example 5

[0224] Synthesis of non-radioactive Lu complex standards of LW01090, LW01110, and LW01142 Approximately 2 mg of LW01090, LW01110, or LW01142 was dissolved in 0.5 mL of NaOAc buffer (0.1 N, pH 4.48), and LuCl3 (10 equivalents, 0.1 M) was added. The reaction mixture was stirred for 80 o C for 30 min, then purified by HPLC (C18 semi-preparative column) and lyophilized to give a white powder. The HPLC conditions are shown in Table 8 below.

[0225] [Table 8]

[0226] Example 6

[0227] 68 Synthesis of Ga-labeled peptides

[0228] Purification in 0.5mL of water 68 Ga was added to a 4-mL glass vial pre-filled with 0.7 mL of HEPES buffer (2 M, pH 5.0) and 10 μL of precursor solution (1 mM). The radiolabeling reaction was carried out under microwave heating for 1 min and then purified by HPLC using a semi-preparative column. The elution fractions containing the radiolabeled product were collected, diluted with water (50 mL) and passed through a C18 Sep-Pak cartridge that had been pre-washed with ethanol (10 mL) and water (10 mL). After washing the C18 Sep-Pak cartridge with water (10 mL), 68 The Ga-labeled product was eluted from the cartridge with ethanol (0.4 mL) and diluted with saline for imaging and biodistribution. Quality control was performed using an analytical column. The tracer was obtained with a radiochemical purity of >95%.

[0229] In vitro competitive binding assay

[0230] PC-3 cells were seeded onto 24-well poly-D-lysine plates at 2 × 10 5 Cells were seeded at 1000 x g / well. Growth medium was replaced with 400 μL of reaction medium (RPMI 1640 containing 2 mg / mL BSA, 4.8 mg / mL HEPES, 1 U / mL penicillin G, and 1 μg / mL streptomycin). Cells were incubated at 37°C for 30-60 minutes. Peptides provided in Table 9 below were added at 50 μL of decreasing concentrations (10 μM to 1 pM) and 50 μL of 0.011 nM [ 125 I-Tyr 4 ] Bombesin was added to the wells. Cells were incubated at 27°C for 1 hour with moderate agitation, washed twice with ice-cold PBS, harvested by trypsinization, and measured for radioactivity in a gamma counter. Data were analyzed using nonlinear regression (one binding site model for competitive assays) with GraphPad Prism 8.

[0231] [Table 9]

[0232] PET / CT imaging and ex vivo biodistribution in PC-3 tumor-bearing mice

[0233] All imaging and biodistribution studies were performed with male NOD.Cg-Rag1 mice. tm1Mom Il2rg tm1Wjl Tumor inoculation was performed using 10 / SzJ(NRG) mice and was carried out in accordance with guidelines established by the Canadian Council on Animal Care and approved by the Animal Ethics Committee at the University of British Columbia. For tumor inoculation, mice were anesthetized by inhalation with 2% isoflurane in oxygen and inoculated with 5 × 10 6 PC-3 cells were implanted subcutaneously. Imaging and biodistribution studies were performed only after the tumors had grown to 5-8 mm in diameter.

[0234] For PET / CT imaging studies, 68Approximately 3-4 MBq of Ga-labeled tracer was injected through the tail vein. After tracer injection, mice were allowed to recover and roam freely in their cages. At 45 min post-injection (pi), mice were sedated again and positioned on the scanner. First, a 10-min CT scan was performed for localization and attenuation correction for PET image reconstruction, followed by 10-min PET images. A heating pad was used throughout the procedure to keep the mice warm. For ex vivo biodistribution studies, mice were placed in a 10-min CT scan and placed in a 10-min PET scanner. 68 Approximately 1.5-3 MBq of Ga-labeled tracer was injected. One hour after injection, mice were euthanized, blood was drawn via the heart, and organs / tissues of interest were collected, rinsed with PBS, blotted dry, weighed, and counted using an automated gamma counter. Uptake in each organ / tissue was normalized to the injected dose and expressed as percentage of injected dose per gram of tissue (ID% / g).

[0235] In mice bearing PC-3 tumor xenografts 68 Ga-LW01025, 68 Ga-LW01029, 68 Ga-LW01107, 68 Ga-LW01108, 68 Ga-LW01110, 68 Ga-LW01142, 68 Ga-LW01158, and 68 Representative maximum intensity projection PET images of Ga-LW01102 are shown in Figure 1. Biodistribution data are shown in Tables 10 and 11.

[0236] [Table 10]

[0237] Table 11 shows the results of the study in mice bearing PC-3 tumor xenografts. 68 Ga-LW01029, 68 Ga-LW01107, 68 Ga-LW01142, 68 Ga-LW01158, and 68 The biodistribution data of Ga-LW01102 are presented.68 Ga-LW01108 and 68 The completed distribution data for Ga-LW01110 is shown.

[0238] [Table 11]

[0239] 68 Ga-LW01025, 68 Ga-LW01029, 68 Ga-LW01107, 68 Ga-LW01108, 68 Ga-LW01110, 68 Ga-LW01102, and 68 In vivo stability of Ga-LW01142

[0240] 68 An in vivo plasma stability study was performed on the Ga-labeled tracer to evaluate its metabolic stability at 15 min after injection. 68 Ga-LW01025, 68 Ga-LW01029, 68 Ga-LW01107, 68 Ga-LW01108, 68 Ga-LW01110, 68 Ga-LW01102, or 68 Ga-LW01142 was injected into three male NRG mice via the tail vein, respectively. 15 days after injection, the mice were sedated and euthanized, and their blood and urine were collected. Plasma was extracted from whole blood with ACN, vortexed, centrifuged, and the supernatant was collected. Plasma and urine were analyzed by radioactive HPLC (C18 analytical column; flow rate: 2.0 mL / min). The HPLC conditions were the same as those for quality control.

[0241] Extracted from mouse urine and plasma samples 68 Ga-LW01025, 68 Ga-LW01029, 68 Ga-LW01107, 68 Ga-LW01108, 68Ga-LW01110, 68 Ga-LW01102, and 68 Representative radioactive HPLC chromatograms of Ga-LW01142 are shown in Figures 2 to 8, respectively.

[0242] Example 7

[0243] Synthesis of LW01045, LW01059, LW01061, LW01090, and LW01117

[0244] The chemical structures of LW01045, LW01059, LW01061, LW01090, and LW01117 are as follows: [ka]

[0245] Synthesis of DOTA-conjugated peptides LW01045, LW01059, LW01061, LW01090, and LW01117.

[0246] LW01045(DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-ψ-Thz-NH2), LW01059(DOTA-Pip-D-2 -NaI-Gln-Trp-Ala-Val-Gly-His-Leu-ψ-Thz-NH2), LW01061(DOTA-Pip-D-Tpi-Gln-Trp-Ala-Val- LW01090 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-NMe-Gly-His-Leu-ψ-Thz-NH2), and LW01117 (DOTA-cysteic acid-Pip-D-2-NaI-Gln-Trp-Ala-Val-Gly-His-Leu-ψ-Thz-NH2), During the ceremony The compound Fmoc-LeuψThz-OH (4), where ψ is a reduced peptide bond, was synthesized using an Fmoc solid-phase synthesis strategy starting from Sieber resin. As described in Example 1, the compound Fmoc-LeuψThz-OH (4), an Fmoc-protected amino acid, Fmoc-4-amino-(1-carboxymethyl)-piperidine, and DOTA (t Bu)3 was sequentially coupled to the resin. After cleavage with TFA / TIS / water / DODT / thioanisole / phenol 81.5:1:5:2.5:5:5) and precipitation with diethyl ether, the crude product was purified by HPLC (C18 semi-preparative column, flow rate: 4.5 mL / min) and lyophilized. The HPLC conditions, retention times, isolated yields, and MS confirmation of the DOTA-conjugated peptides are provided in Table 12.

[0247] [Table 12]

[0248] Synthesis of non-radioactive Ga complex standards of LW01045, LW01059, LW01061, LW01090, and LW01117

[0249] Non-radioactive Ga-complexed standards of LW01045, LW01059, LW01061, LW01090, and LW01117 were prepared according to the procedure described in Example 1. Briefly, LW01045, LW01059, LW01061, LW01090, and LW01117 were mixed and diluted with 0.5 mL of NaOAc buffer (0.1 N, pH 4.2-4.5) and GaCl3 (5 equiv., 0.2 M) for 80 min. o C for 15 min, then purified by HPLC (C18 semi-preparative column) and lyophilized. The HPLC conditions, retention times, isolated yields, and MS confirmation for these non-radioactive Ga complex standards are provided in Table 13.

[0250] [Table 13]

[0251] 68 Synthesis of Ga-labeled compounds

[0252] Radiolabeled LW01045, LW01059, LW01090, and LW01117 were prepared according to the procedure described in Example 1. Briefly, purified LW01045, LW01059, LW01090, and LW01117 in 0.5 mL of water were 68 Ga was added to a 4-mL glass vial pre-filled with 0.7 mL of HEPES buffer (2 M, pH 5.0) and 10 μL of precursor solution (1 mM). The radiolabeling reaction was carried out under microwave heating for 1 min and then purified by HPLC using a semi-preparative column. The elution fractions containing the radiolabeled product were collected, diluted with water (50 mL) and passed through a C18 Sep-Pak cartridge that had been pre-washed with ethanol (10 mL) and water (10 mL). After washing the C18 Sep-Pak cartridge with water (10 mL), 68 The Ga-labeled product was eluted from the cartridge with ethanol (0.4 mL) and diluted with saline for imaging and biodistribution. Quality control was performed using an analytical column. Tracers were obtained with radiochemical purity of >95%. HPLC conditions and retention times are provided in Table 14. Tracers were obtained with decay-corrected radiochemical yields of 42-59%, molar activities of >66 GB / μmol, and radiochemical purity of >92%.

[0253] [Table 14]

[0254] In vitro competitive binding assay

[0255] In vitro competitive binding assays were performed according to the procedures outlined in Example 1. Specifically, the binding affinities of Ga-LW01045, Ga-LW01059, Ga-LW01090, and Ga-LW01117 were measured by cell-based binding assays using GRPR-expressing PC-3 prostate cancer cells. Ga-LW01045, Ga-LW01059, Ga-LW01090, and Ga-LW01117 were dose-dependently [ 125 I-Tyr 4] inhibited the binding of bombesin (Figures 9B, 10B, 11B, and 12B, respectively). The calculated Ki values ​​of Ga-LW01045, Ga-LW01059, Ga-LW01090, and Ga-LW01117 are listed in Table 15.

[0256] [Table 15]

[0257] PET / CT imaging and ex vivo biodistribution in PC-3 tumor-bearing mice

[0258] All imaging and biodistribution studies were performed using the procedures outlined in Example 1. PC-3 tumor xenografts were 68 Ga-LW01045, 68 Ga-LW0159, 68 Ga-LW01090, and 68 Ga-LW0117 was clearly visualized in PET images acquired 1 hour after injection (FIGS. 9A, 10A, 11A, and 12A, respectively, and Table 16).

[0259] [Table 16]

[0260] 68 Ga-LW01045 and 68 In vivo stability of Ga-LW01090

[0261] In vivo tests were carried out similarly according to the procedures described in Example 1. For these tests, 68 Ga-LW01045 and 68 Ga-LW01090 was injected into healthy male NRG mice (n=3) via the lateral tail vein. 15 min after injection, mice were sedated, euthanized, and urine and blood were collected. Plasma was extracted from whole blood by addition of CH3CN (500 μL), vortexing, centrifugation, and separation of the supernatant. Plasma and urine samples were collected from these 68The Ga-labeled radioligand was analyzed via radio-HPLC using conditions for quality control. 68 Ga-LW01045 and 68 We show that Ga-LW01090 is sufficiently stable in vivo in NRG mice, with 83.3±1.45% and 67.1±4.76% remaining intact in plasma after injection. The present invention has been described with reference to one or more embodiments.

[0262] Example 8:

[0263] Synthesis of LW02045 and LW02042

[0264] The chemical structures of LW02045 and LW02042 are as follows: [ka]

[0265] Synthesis of DOTA conjugates LW02045 and LW02042

[0266] LW02045 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-N-MeGly-His-LeuψPro-NH2), where ψ is a reduced peptide bond, was synthesized using a standard Fmoc solid-phase synthesis strategy starting from Sieber resin. Fmoc-LeuψPro-OH, Fmoc-protected amino acids, Fmoc-4-amino-(1-carboxymethyl)-piperidine, and DOTA(tBu)3 were sequentially coupled to the resin. After cleavage with TFA / TIS / water / DODT / thioanisole / phenol 81.5:1:5:2.5:5:5) and precipitation with diethyl ether, the crude product was purified by HPLC (C18 semi-preparative column, flow rate: 4.5 mL / min) and lyophilized to give a white powder. HPLC conditions were 20% ACN and 0.1% TFA in water (retention time = 20.1 min), yield: 37%. ESI-MS: LW02045 C 76 H 114 N20 O 17 Calculated value for S [M+2H] + 790.44;actual value 790.50.

[0267] LW02042 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Phe-Thz-NH2) was synthesized using standard Fmoc solid phase synthesis. Fmoc-protected amino acid, Fmoc-4-amino-(1-carboxymethyl)piperidine, and DOTA(tBu)3 were sequentially coupled to Fmoc-Rink amide-MBHA resin. After cleavage with TFA / TIS / water / DODT / thioanisole / phenol 81.5:1:5:2.5:5:5 and precipitation with diethyl ether, the crude product was purified by HPLC (C18 semi-preparative column, flow rate: 4.5 mL / min) and lyophilized to give a white powder. HPLC conditions were 23% ACN and 0.1% TFA in water (retention time = 11.4 min), yield: 31%. ESI-MS: LW02042 C 77 H 116 N 20 O 18 Calculated value for S [M+2H] + 816.40;actual value 816.44.

[0268] Synthesis of non-radioactive Ga complex standards of LW02045 and LW02042

[0269] LW02045 (2.85 mg) and LW02042 (2.91 mg) were each dissolved in 0.5 mL of NaOAc buffer (0.1 N, pH 4.48) and GaCl3 (5 equiv., 0.2 M) was added. The reaction mixture was incubated at 80° C. for 15 min, then purified by HPLC (C18 semi-preparative column) and lyophilized to give a white powder.

[0270] For Ga-LW02045, the HPLC conditions were 20% ACN and 0.1% TFA in water at a flow rate of 4.5 mL / min (retention time = 23.6 min), yield: 74%. ESI-MS: Ga-LW02045 C 76 H 112 GaN20 O 17 Calculated value for S [M+2H] + 823.90; Found 823.86. For Ga-LW02042, the HPLC conditions were 23% ACN and 0.1% TFA in water at a flow rate of 4.5 mL / min (retention time = 18.9 min), yield: 91%. ESI-MS: Ga-LW02042 C 77 H 104 GaN 20 O 18 Calculated value for S [M+2H] + 849.85;actual value 849.63.

[0271] PET / CT imaging and ex vivo biodistribution in PC-3 tumor-bearing mice

[0272] All imaging and biodistribution studies were performed using male NOD.Cg-Rag1tm1Mom Il2rg tm1Wjl / SzJ (NRG) mice and were conducted in accordance with guidelines established by the Canadian Council on Animal Care and approved by the Animal Ethics Committee at the University of British Columbia. For tumor inoculation, mice were anesthetized by inhalation with 2% isoflurane in oxygen and implanted subcutaneously with 5 × 106 PC-3 cells under the left shoulder. Imaging and biodistribution studies were performed only after tumors had grown to 5–8 mm in diameter.

[0273] For PET / CT imaging studies, approximately 5MBq 68Ga-labeled tracers were injected through the tail vein. After tracer injection, mice were allowed to recover and roam freely in their cages. At 45 min post-injection (pi), mice were sedated again and positioned on the scanner. A 10-min CT scan was first performed for localization and attenuation correction for PET image reconstruction, followed by 10-min PET images. A heating pad was used throughout the procedure to keep the mice warm. For ex vivo biodistribution studies, mice were injected with approximately 3 MBq of 68Ga-labeled tracer. One hour after injection, mice were euthanized, bled via the heart, and organs / tissues of interest were collected, rinsed with PBS, blotted dry, weighed, and counted using an automated gamma counter. Uptake in each organ / tissue was normalized to the injected dose and expressed as a percentage of the injected dose per gram of tissue (%ID / g) (Figure 13 and Table 17).

[0274] [Table 17]

[0275] All publications, patents, and patent applications, including any drawings and appendices therein, are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, and patent application, drawing, or appendices were specifically and individually indicated to be incorporated by reference in its entirety for all purposes. It will be apparent to those skilled in the art that some variations and modifications can be made without departing from the scope of the present invention defined in the following claims. Therefore, the scope of the present invention should not be limited by the preferred embodiments described in the above examples, but should be given the broadest interpretation consistent with the description as a whole.

Claims

1. A structure that may be composited with a radioactive metal: 【Chemistry 1】 A peptide compound having the same, or a salt or solvate thereof.

2. A structure that may be composited with a radioactive metal: 【Chemistry 2】 A peptide compound having the same, or a salt or solvate thereof.

3. The peptide compound, salt thereof, or solvate thereof according to claim 1 or 2, wherein the radioactive metal is 44 Sc, 61 Cu, 64 Cu, 67 Ga, 68 Ga, 72 As, 86 Y, 89 Zr, 90 Nb, 90 Y, 99 m Tc, 110 m In, 111 In, 117 m Sn, 152 Tb, 155 Tb, 177 Lu, 186 Re, or 203 Pb.

4. The peptide compound or a salt or solvate thereof according to claim 3, wherein the radioactive metal is 68 Ga.

5. The peptide compound, salt thereof, or solvate according to claim 1 or 2, wherein the radioactive metal is 47 Sc, 64 Cu, 67 Cu, 77 As, 105 Rh, 109 Pd, 117 m Sn, 142 Pr, 149 Pm, 149 Tb, 153 Sm, 159 Gd, 161 Tb, 165 Er, 166 Ho, 175 Yb, 177 Lu, 188 Re, 198 Au, 199 Au, 211 At, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 225 Ac, or 227 Th.

6. The peptide compound or a salt or solvate thereof according to claim 5, wherein the radioactive metal is 177 Lu or 225 Ac.

7. A pharmaceutical composition comprising a peptide compound according to claim 1 or 2, or a salt or solvate thereof, and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7 for use in imaging gastrin-releasing peptide receptors (GRPRs) in a subject.

9. A pharmaceutical composition according to claim 7 for use in treating cancer in a subject.

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