WO2023178449A1 - Radiolabeled compounds for in vivo imaging of gastrin-releasing peptide receptor (grpr) and treatment of grpr-related disorders - Google Patents

Radiolabeled compounds for in vivo imaging of gastrin-releasing peptide receptor (grpr) and treatment of grpr-related disorders Download PDF

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Publication number
WO2023178449A1
WO2023178449A1 PCT/CA2023/050401 CA2023050401W WO2023178449A1 WO 2023178449 A1 WO2023178449 A1 WO 2023178449A1 CA 2023050401 W CA2023050401 W CA 2023050401W WO 2023178449 A1 WO2023178449 A1 WO 2023178449A1
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WIPO (PCT)
Prior art keywords
xaa
trp
gly
peptidic compound
phe
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PCT/CA2023/050401
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English (en)
French (fr)
Inventor
Chengcheng Zhang
Kuo-Shyan LIN
François BÉNARD
Lei Wang
Zhengxing Zhang
Ivica BRATANOVIC
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University of British Columbia
Provincial Health Services Authority
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University of British Columbia
Provincial Health Services Authority
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Priority to KR1020247035353A priority Critical patent/KR20250007523A/ko
Priority to IL315057A priority patent/IL315057A/en
Priority to CA3246188A priority patent/CA3246188A1/en
Priority to EP23773418.1A priority patent/EP4499663A1/en
Priority to AU2023239751A priority patent/AU2023239751A1/en
Priority to JP2024556499A priority patent/JP2025510161A/ja
Application filed by University of British Columbia, Provincial Health Services Authority filed Critical University of British Columbia
Priority to CN202380029657.8A priority patent/CN119213011A/zh
Publication of WO2023178449A1 publication Critical patent/WO2023178449A1/en
Priority to US18/512,708 priority patent/US12246076B2/en
Anticipated expiration legal-status Critical
Priority to US19/043,780 priority patent/US20250195702A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/595—Gastrins; Cholecystokinins [CCK]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/13—Labelling of peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • the present invention relates to radiolabelled compounds for in vivo imaging or treatment of diseases or conditions characterized by expression of the gastrin-releasing peptide receptor.
  • Gastrin-releasing peptide receptor 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.).
  • GRPR GRPR-associated regional pain syndrome
  • BBN is a 14 amino acid GRPR binding peptide
  • Lu-AMBA Bombesin analogue in hormone refractory prostate cancer patients: a phase I escalation study with single-cycle administrations.
  • JOINT EANM-EORTC Symposium Sah, et al. 2015 J Nucl Med. 56:372-378; Zang, et al.
  • BBN derivatives have been radiolabeled for imaging with single photon emission computed tomography (SPECT), positron emission tomography (PET), and have also been radiolabeled 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).
  • SPECT single photon emission computed tomography
  • PET positron emission tomography
  • a radiolabelled group is appended directly onto the structure or via a linker at the N-terminus, while modifications at the C-terminus dictate agonist/antagonist properties.
  • antagonists are preferred since 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).
  • GRPR antagonists evaluated in the clinic 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.Q7S-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.
  • High pancreas uptake is the major limitation of currently reported GRPR-targeting radioligands.
  • the high pancreas uptake of 68 Ga-labeled AMBA was up to 54.9 SUV (SUV: standard uptake value) (Baum, et al. 2007 Journal of Nuclear Medicine 48, 79P-79P).
  • 68 Ga-labeled RM2 was also reported to show high uptake in pancreas (Kurth, et al. 2020. European journal of nuclear medicine and molecular imaging 47 , 123-135; Minamimoto, etal. 2016 J Nucl Med. 57:557-562). It has also been reported that radiolabeled NeoBOMBI showed high pancreas uptake in both PC-3 tumor-bearing mice and prostate cancer patients (Nock, et al. 2017 J Nucl Med. 58:75-80).
  • Trp 8 -Ala 9 and Gln 7 -Trp 8 were reported to be the main cleavage sites within the AM BA’s sequence, and Trp 8 -Ala 9 , Ala 9 -Val 10 and Gln 7 -Trp 8 were considered to be the cleavage sites 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 field for improved tracers for the non-invasive in-vivo imaging of the GRPR.
  • Such tracers are useful for the diagnosis of disorders related to aberrant/ectopic expression of GRPR, including but not limited to cancer (e.g. prostate cancer).
  • cancer e.g. prostate cancer
  • radiotherapeutic agents for treatment of diseases/disorders related to aberrant/ectopic expression of GRPR, including but not limited to cancer (e.g. prostate cancer).
  • GRPR-targeting radioligands for imaging and/or therapy with lower pancreas uptake, and useful stability in vivo.
  • this disclosure provides a peptidic compound of Formula I (defined below). Such compounds may have lower pancreas uptake than prior art bombesin analogs as well as useful stability in vivo for imaging and/or radiotherapy.
  • FIGURE 1 shows representative maximum-intensity-projection PET images of 68 Ga-LW01025, 68 Ga-LW01029, 68 Ga-LW01107, 68 Ga-LW01108, 68 Ga-LW01110, 68 Ga-LW01142, 68 Ga-LW01158 and 68 Ga-LW01102 in mice bearing PC-3 tumor xenografts. The images were acquired at 1 h post-injection.
  • FIGURE 2 shows representative radio-HPLC chromatograms of 68 Ga -LW01025 extracted from mouse urine and plasma samples.
  • FIGURE 3 shows representative radio-HPLC chromatograms from analysis of intact fraction of 68 Ga-LW01029 in mouse plasma (A) and urine (B) samples collected at 15 min post-injection.
  • FIGURE 4 shows representative radio-HPLC chromatograms of 68 Ga-LW01107 extracted from mouse urine and plasma samples.
  • FIGURE 5 shows representative radio-HPLC chromatograms of 68 Ga-LW01108 extracted from mouse urine and plasma samples.
  • FIGURE 6 shows representative radio-HPLC chromatograms of 68 Ga-LW01110 extracted from mouse urine and plasma samples.
  • FIGURE 7 shows representative radio-HPLC chromatograms of 68 Ga-LW01142 extracted from mouse urine and plasma samples.
  • FIGURE 8 shows representative radio-HPLC chromatograms of 68 Ga-LW01102 extracted from mouse urine and plasma samples.
  • FIGURES 9A-9C show representative data of 68 Ga-LW01045, including a representative maximum-intensity-projection PET image of 68 Ga-LW01045 in a mouse bearing a PC-3 tumor xenograft (Figure 9A); a representative displacement curve of [ 125 l-Tyr 4 ]Bombesin by Ga-LW01045 generated using GRPR-expressing PC-3 cells ( Figure 9B); and radio-HPLC chromatograms of 68 Ga -LW01045 extracted from mouse urine and plasma samples ( Figure 9C).
  • FIGURES 10A-10B show representative data of 68 Ga-LW01059, including a maximum-intensity-projection PET image of 68 Ga-LW01059 in a mouse bearing a PC-3 tumor xenograft ( Figure 10A); and a displacement curve of [ 125 l-Tyr 4 ]Bombesin by Ga-LW01059 generated using GRPR-expressing PC-3 cells ( Figure 10B).
  • FIGURES 11A-11C show representative data of 68 Ga-LW01090, including a maximum-intensity-projection PET image of 68 Ga-LW01090 in a mouse bearing a PC-3 tumor xenograft ( Figure 11 A); a displacement curve of [ 125 l-Tyr 4 ]Bombesin by Ga- LW01090 generated using GRPR-expressing PC-3 cells ( Figure 11 B); and radio-HPLC chromatograms of 68 Ga-LW01090 extracted from mouse urine and plasma samples (Figure 11C).
  • FIGURES 12A-12B show representative data of 68 Ga-LW01117, including a maximum-intensity-projection PET image of 68 Ga-LW01117 in a mouse bearing a PC-3 tumor xenograft ( Figure 12A); and a representative displacement curve of [ 125 l-Tyr 4 ]Bombesin by Ga-LW01117 generated using GRPR-expressing PC-3 cells ( Figure 12B).
  • FIGURE 13 shows a representative maximum-intensity-projection PET image of 68 Ga-LW02045 in a mouse bearing a PC-3 tumor xenograft.
  • the terms “comprising,” “having”, “including” and “containing,” and grammatical variations thereof, are inclusive or open-ended and do not exclude additional, unrecited elements and/or method steps, even if a feature/component defined as a part thereof consists or consists essentially of specified feature(s)/component(s).
  • a compound, composition, use or method described herein as comprising certain elements and/or steps may also, in certain embodiments consist essentially of those elements and/or steps, and in other embodiments consist of those elements and/or steps, whether or not these embodiments are specifically referred to.
  • a use or method described herein as comprising certain elements and/or steps may also, in certain embodiments consist essentially of those elements and/or steps, and in other embodiments consist of those elements and/or steps, whether or not these embodiments are specifically referred to.
  • a reference to an element by the indefinite article “a” does not exclude the possibility that more than one of the elements is present, unless the context clearly requires that there be one and only one of the elements.
  • the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise.
  • the use of the word “a” or “an” when used herein in conjunction with the term “comprising” may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one” and “one or more than one.”
  • a “diagnostic agent” includes an “imaging agent”.
  • a “diagnostic radionuclide” includes radionuclides that are suitable for use in imaging agents.
  • the term “subject” refers to an animal (e.g. a mammal or a non-mammal animal).
  • the subject may be a human or a non-human primate.
  • the subject may be a laboratory mammal (e.g., mouse, rat, rabbit, hamster and the like).
  • the subject may be an agricultural animal (e.g., equine, ovine, bovine, porcine, camelid and the like) or a domestic animal (e.g. , canine, feline and the like).
  • the subject is a human.
  • the compounds disclosed herein may also include base-free forms, solvates, salts or pharmaceutically acceptable salts thereof. Unless otherwise specified or indicated, the compounds claimed and described herein are meant to include all racemic mixtures and all individual enantiomers or combinations thereof, whether or not they are explicitly represented herein.
  • the compounds disclosed herein may be shown as having one or more charged groups, may be shown with ionizable groups in an uncharged (e.g. protonated) state or may be shown without specifying formal charges.
  • the ionization state of certain groups within a compound is dependent, inter alia, on the pKa of that group and the pH at that location.
  • a carboxylic acid group i.e. COOH
  • salts and solvate have their usual meaning in chemistry.
  • the compound when it is a salt or solvate, it is associated with a suitable counter-ion. It is well known in the art how to prepare salts or to exchange counter-ions.
  • salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g. without limitation, Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or in an organic solvent, or in a mixture of the two.
  • a suitable base e.g. without limitation, Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like
  • Counter-ions may be changed, for example, by ion-exchange techniques such as ion-exchange chromatography. All zwitterions, salts, solvates and counter-ions are intended, unless a particular form is specifically indicated.
  • the salt or counter-ion may be pharmaceutically acceptable, for administration to a subject.
  • pharmaceutically acceptable means suitable for in vivo use in a subject, and is not necessarily restricted to therapeutic use, but also includes diagnostic use.
  • non-limiting examples of suitable excipients include any suitable buffers, stabilizing agents, salts, antioxidants, complexing agents, tonicity agents, cryoprotectants, lyoprotectants, suspending agents, emulsifying agents, antimicrobial agents, preservatives, chelating agents, binding agents, surfactants, wetting agents, non-aqueous vehicles such as fixed oils, or polymers for sustained or controlled release.
  • suitable buffers stabilizing agents, salts, antioxidants, complexing agents, tonicity agents, cryoprotectants, lyoprotectants, suspending agents, emulsifying agents, antimicrobial agents, preservatives, chelating agents, binding agents, surfactants, wetting agents, non-aqueous vehicles such as fixed oils, or polymers for sustained or controlled release.
  • C n 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, and the like) or where n is defined as a range of integers (e.g. 1 -20, 1-18, 2-15, 3-20, and the like) refers to the number of carbons in a compound, R-group, L-group, or substituent, or refers to the number of carbons plus heteroatoms in a compound, R-group, L-group, or substituent.
  • a range of integers includes all integers in the range; e.g.
  • heteroatoms may include any, some or all possible heteroatoms.
  • the heteroatoms may be selected from N, O, S, P and Se.
  • the heteroatoms are selected from N, S, or O.
  • Such embodiments are non-limiting.
  • alkyl has at least one carbon-carbon double bond, and may have any number of carbon-carbon single bonds.
  • alkynylenyl has at least one carbon-carbon triple bond, and may have any number of carbon-carbon single bonds.
  • alkylenyl, alkenylenyl and/or alkynylenyl and “alkylenyl, alkenylenyl or alkynylenyl” are intended to be equivalent and each includes hydrocarbon chains that can have any reasonable number or combination of carbon-carbon single bonds, double bonds, and triple bonds. These hydrocarbon chains can 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 nonaromatic, partially aromatic, or aromatic. Unless otherwise specified, the term “cyclic” includes single rings, multiple non-fused rings, fused rings, bridged rings, and combinations thereof.
  • any carbon ... is optionally independently replaced by N, S, or O
  • the defined hydrocarbon e.g. “alkyl”, “alkylenyl”, “alkenylenyl”, or “alkynylenyl”
  • the defined hydrocarbon includes zero, one, more than one, or any reasonable combination of two or more heteroatoms selected from N, S, and O.
  • the above expression therefore expands the defined hydrocarbon to additionally encompass heteroalkyls, heteroalkylenyls, heteroalkenylenyls, and heteroalkynylenyls, etc.
  • the person of skill in the art would understand that various combinations of different heteroatoms may be used.
  • any carbon bonded to two other carbons is optionally independently replaced by N, S, or O
  • any carbon in the defined hydrocarbon bonded to two other carbons e.g. the underlined carbon in -C-C-C-
  • any carbon in the defined hydrocarbon bonded to two other carbons e.g. the underlined carbon in -C-C-C-
  • whether those bonds are single, double, or triple bonds may be a heteroatom, but excludes heteroatoms bonded to other heteroatoms (e.g. excludes -C-N-S-, -S-S-N-, -N-S-C-, and the like).
  • R-groups e.g. R 1 , R 2 , R 3 , etc.
  • L-groups e.g. L 1 , L 2 , L 3 , etc.
  • L-groups generally refer to linkages
  • the size of an R-group or L-group is what would be considered reasonable to the person of skill in the art.
  • the size of an alkyl 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, 89, 90, 91 , 92, 93, 94, 95
  • alkyl, alkenyl or alkynyl and similar expressions, the “alkyl” would be understood to be a saturated alkyl, and the “alkenyl” and the “alkynyl” would be understood to be unsaturated.
  • linear may be used as it is normally understood to a person of skill in the art and generally refers to a chemical entity that comprises a skeleton or main chain that does not split off into more than one contiguous chain.
  • linear alkyls include methyl, ethyl, n-propyl, and n-butyl.
  • branched may be used as it is normally understood to a person of skill in the art and generally refers to a chemical entity that comprises a skeleton or main chain that splits off into more than one contiguous chain.
  • the portions of the skeleton or main chain that split off in more than one direction may be linear, cyclic or any combination thereof.
  • Non-limiting examples of a branched alkyl group include tert-butyl and isopropyl.
  • alkylenyl refers to a divalent analog of an alkyl group.
  • alkylenyl, alkenylenyl and/or alkynylenyl the “alkylenyl” would be understood to be a saturated alkylenyl, and the “alkenylenyl” and the “alkynylenyl” would be understood to be unsaturated.
  • heteroalkylenyl refers to a divalent analog of a heteroalkyl group.
  • heteroalkenylenyl refers to a divalent analog of a heteroalkenyl group.
  • heteroalkynylenyl refers to a divalent analog of a heteroalkynyl group.
  • saturated when referring to a chemical entity may be used as it is normally understood to a person of skill in the art and generally refers to a chemical entity that comprises only single bonds, and may include linear, branched, and/or cyclic groups.
  • Non-limiting examples of a saturated C1-C20 alkyl group may 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,
  • the term “unsaturated” when referring to a chemical entity may be used as it is normally understood to a person of skill in the art and generally refers to a chemical entity that comprises at least one double or triple bond, and may include linear, branched, and/or cyclic groups.
  • Non-limiting examples of a C2-C20 alkenyl group may include vinyl, allyl, isopropenyl, l-propene-2-yl, 1-butene-l-yl, l-butene-2-yl, l-butene-3-yl, 2-butene-l-yl, 2-butene-2-yl, octenyl, decenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononanenyl, cyclodecanenyl, and the like.
  • a C1-C20 alkenylenyl therefore encompasses, without limitation, all divalent analogs of the above-listed alkenyl groups.
  • Non-limiting examples of a C2-C20 alkynyl group may include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like.
  • a C1-C20 alkynylenyl therefore encompasses, without limitation, all divalent analogs of the above-listed alkynyl groups.
  • Non-limiting examples of non-aromatic cyclic groups include cylcopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • Non-limiting examples of non-aromatic heterocyclic groups include aziridinyl, azetidinyl, diazetidinyl, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, imidazolinyl, pyrazolidinyl, imidazolydinyl, phthalimidyl, succinimidyl, oxiranyl, tetrahydropyranyl, oxetanyl, dioxanyl, thietanyl, thiepinyl, morpholinyl, oxathiolanyl, and the like.
  • an “aryl” group includes both single aromatic rings as well as fused rings containing at least one aromatic ring, non-limiting examples of C3-C20 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, pirazinyl, 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, phosphinolin
  • substituted is used as it would normally be understood to a person of skill in the art and generally refers to a compound or chemical entity that has one chemical group replaced with a different chemical group.
  • a substituted alkyl , alkylenyl, alkenylenyl, or alkynylenyl has one or more hydrogen atom(s) independently replaced with an atom that is not hydrogen.
  • chloromethyl is a non-limiting example of a substituted alkyl, more particularly an example of a substituted methyl.
  • Aminoethyl is another non-limiting example of a substituted alkyl, more particularly an example of a substituted ethyl.
  • a substituted compound or group may be substituted with any chemical group reasonable to the person of skill in the art.
  • a hydrogen bonded to a carbon or heteroatom e.g. N
  • halide e.g.
  • each carbon may be independently substituted or unsubstituted with oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphoric acid.
  • the amide substituent is -C(O)-NH 2 .
  • unsubstituted is used as it would normally be understood to a person of skill in the art.
  • Non-limiting examples of unsubstituted alkyls include methyl, ethyl, tert-butyl, pentyl and the like.
  • the expression “optionally substituted” is used interchangeably with the expression “unsubstituted or substituted”.
  • the expression “optionally independently substituted” means that each location may be substituted or may not be substituted, and when substituted each substituent may be the same or different.
  • hydrogen may or may not be shown.
  • hydrogens may be protium (i.e. 1 H), deuterium (i.e. 2 H) or combinations of 1 H and 2 H.
  • Methods for exchanging 1 H with 2 H are well known in the art.
  • solvent-exchangeable hydrogens the exchange of 1 H with 2 H occurs readily in the presence of a suitable deuterium source, without any catalyst.
  • acid, base or metal catalysts coupled with conditions of increased temperature and pressure, can facilitate the exchange of non-exchangeable hydrogen atoms, generally resulting in the exchange of all 1 H to 2 H in a molecule.
  • Xaa refers to an amino acid residue in a peptide chain or an amino acid that is otherwise part of a compound.
  • Amino acids have both an amino group and a carboxylic acid group, either or both of which can be used for covalent attachment.
  • the amino group and/or the carboxylic acid group may be converted to an amide or other structure; e.g. a carboxylic acid group of a first amino acid is converted to an amide (i.e. a peptide bond) when bonded to the amino group of a second amino acid.
  • Xaa may have the formula -N(R a )R b C(O)-, where R a and R b are R-groups.
  • R a will typically be hydrogen or alkyl (e.g. methyl) or R a and R b may form a cyclic structure.
  • the amino acid residues of a peptide may comprise typical peptide (amide) bonds and may further comprise bonds between side chain functional groups and the side chain or main chain functional group of another amino acid.
  • the side chain carboxylate of one amino acid residue in the peptide e.g. Asp, Glu, etc.
  • the side chain carboxylate of one amino acid residue in the peptide e.g. Asp, Glu, etc.
  • Xaa may be any amino acid, including a proteinogenic or nonproteinogenic amino acid.
  • Non-limiting examples of nonproteinogenic amino acids are shown in Table 1 and include: D-amino acids (including without limitation any D-form of the following amino acids), ornithine (Orn), 3-(1-naphtyl)alanine (Nal), 3-(2-naphtyl)alanine (2-Nal), a-aminobutyric acid, norvaline, norleucine (Nle), homonorleucine, beta-(1 ,2,3-triazol-4-yl)-L-alanine,
  • the wavy line “ • ⁇ ” symbol shown through or at the end of a bond in a chemical formula is intended to define the group on one side of the wavy line, without modifying the definition of the structure on the opposite side of the wavy line.
  • any atoms shown outside the wavy lines are intended to clarify orientation of the defined group. As such, only the atoms between the two wavy lines constitute the definition of the R-group or L-group.
  • Xaa 1 is 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, Gin, homoserine (Hse), citrulline (Cit) or His;
  • Xaa 3 is Trp, p-(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 aMe-Trp;
  • Xaa 4 is Ala or Ser
  • Xaa 5 is Vai, Cpg (cyclopentylglycine) or tert-leucine (Tie);
  • 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-terminally 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);
  • ip is a peptide bond or reduced peptide bond between Xaa 8 and Xaa 9 ; excluding compounds in which Xaa 2 , Xaa 3 , Xaa 5 , and Xaa 7 are Gin, Trp, Vai, and His, respectively, in which ip is a reduced peptide bond;
  • R L is -0(0)-, -NH-C(O)-, or -NH-C(S)-;
  • the linker is a linear or branched chain of n1 units of -L 1 R 1 - and/or -(L 1 )2R 1 -, wherein: n1 is 1-20; each R 1 is, independently, a linear, branched, and/or cyclic C n 2 alkylenyl, alkenylenyl and/or alkynylenyl, wherein each n2 is independently 1-20, wherein 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 phosphoric acid;
  • each L 1 is independently -S-, -N(R 2 )C(O)-, -C(O)N(R 2 )-, an albumin binder (R alb ) is optionally bonded to an L 1 of the linker, wherein the albumin binder is:
  • n3 is 8-20;
  • each R rad is a radiolabeling group bonded to or incorporating an L 1 of the linker, wherein each radiolabeling group is independently: a radiometal chelator; an aryl or heteroaryl substituted with a radiohalogen; a prosthetic group containing a trifluoroborate; a prosthetic group containing a silicon-fluorine-acceptor moiety; or a prosthetic group containing a fluorophosphate, fluorosulfate, sulfonyl fluoride, or a combination thereof.
  • the peptidic compound may be a compound with the structure of Formula A or is a salt or solvate of Formula A as follows: R rad n6-[linker]-R L -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -i
  • 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, Gin, homoserine (Hse), citrulline (Cit) or His;
  • Xaa 3 is Trp, p-(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 aMe-Trp;
  • Xaa 4 is Ala or Ser; Xaa 5 is Vai, 2,3-dehydro-Val, Cpg (cyclopentylglycine), cyclopropylglycine, cyclobutylglycine, or tert-leucine (Tie);
  • 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-terminally 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);
  • ip represents a peptide bond or reduced peptide bond joining Xaa 8 to Xaa 9 ; excluding compounds in which Xaa 2 , Xaa 3 , Xaa 5 , and Xaa 7 are Gin, Trp, Vai, and His, respectively, in which ip is a reduced peptide bond;
  • R L is -0(0)-, -NH-C(O)-, or -NH-C(S)-;
  • the linker is a linear or branched chain of n1 units of -L 1 R 1 - and/or -(L
  • each L 1 bonds to carbon, wherein each L 1 is independently -S-, -N(R 2 )C(O)-, -C(O)N(R 2 )-, andR 2 is H, methyl or ethyl; andan albumin binder (R alb ) is optionally bonded to an L 1 of the linker, wherein the albumin binder is: -(CH2)n3-CH3 wherein n3 is 8-20; -(CH2)n4-C(O)OH wherein n4 is 8-20; wherein n5 is 1-4 and R 3a is H or methyl, and R 3b is I, Br, F, Cl, H, OH, OCH3, NH2, NO2 or C1-C6 alkyl; or n6 is 1-5; and each R rad is a radiolabeling group bonded to or incorporating an L 1 of the linker, wherein each radiolabeling group is independently: a radiometal chelator; an aryl or heteroaryl
  • the invention may include a peptidic compound 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-Nal, 3-(2-naphthyl)alanine (2-Nal), or D-2-Nal;
  • Xaa 3 is Trp, P-(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 aMe-Trp; and Xaa 5 is Vai, Cpg (cyclopentylglycine), or ter
  • Xaa 1 is an N-terminal amino acid residue selected from D-Phe, or D-2-Nal.
  • Xaa 2 is Gin, or His.
  • Xaa 5 is Vai, or tert-leucine (Tie).
  • Xaa 6 is Gly, or NMe-Gly.
  • Xaa 9 -NH2 is a C-terminally amidated amino acid residue selected from Pro or thiazoline-4-carboxylic acid (Thz).
  • Xaa 1 is an N-terminal amino acid residue selected from D-Phe, or D-2-Nal; Xaa 2 is Gin, or His; Xaa 4 is Ala; Xaa 5 is Vai, or tert-leucine (Tie); Xaa 6 is Gly, or NMe-Gly; Xaa 8 is Leu; and Xaa 9 -NH2 is a C-terminally amidated amino acid residue selected from Pro or thiazoline-4-carboxylic acid (Thz).
  • Xaa 3 is p-(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 aMe-Trp.
  • ip is a peptide bond.
  • Xaa 9 is Thz.
  • Xaa 2 is His.
  • wherein Xaa 3 is Trp.
  • Xaa 5 is Tie.
  • Xaa 7 is NMe-His.
  • ip is a peptide bond; Xaa 9 is Thz; Xaa 2 is His; Xaa 3 is Trp; Xaa 5 is Tie; and Xaa 7 is NMe-His.
  • Xaa 3 is aMe-Trp.
  • Xaa 6 is Gly.ln another embodiment, Xaa 8 is Leu.
  • At least one of Xaa 1 , Xaa 2 , Xaa 3 , Xaa 4 , Xaa 5 , Xaa 6 , Xaa 7 , Xaa 8 , or Xaa 9 is methylated.
  • the peptidic compounds of the present invention may have the structure of Formula B or is a salt or solvate of Formula B, wherein Formula B is as follows:
  • 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, Gin, homoserine (Hse), citrulline (Cit) or His;
  • Xaa 3 is Trp, p-(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 aMe-Trp;
  • Xaa 4 is Ala or Ser
  • Xaa 5 is Vai, 2,3-dehydro-Val, Cpg (cyclopentylglycine), cyclopropylglycine, cyclobuylglycine, or tert-leucine (Tie);
  • 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-terminally 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); i represents a peptide bond or reduced peptide bond joining Xaa 8 to Xaa 9 ;
  • R L is -0(0)-, -NH-C(O)-, or -NH-C(S)-;
  • the linker is a linear or branched chain of n1 units of -L 1 R 1 - and/or -(L 1 )2R 1 -, wherein: n1 is 1-20; each R 1 is, independently, a linear, branched, and/or cyclic C n 2 alkylenyl, alkenylenyl and/or alkynylenyl, wherein each n2 is independently 1-20, wherein 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 phosphoric acid;
  • L 1 bonds to carbon, wherein each L 1 is independently -S-, -N(R 2 )C(O)-, -C(O)N(R 2 )-,
  • R 2 is H, methyl or ethyl; and an albumin binder (R alb ) is optionally bonded to an L 1 of the linker, wherein the albumin binder is:
  • n3 is 8-20;
  • n4 is 8-20; wherein n5 is 1-4 and R 3a is H or methyl, and R 3b is I, Br, F, Cl, H, OH, OCH3,
  • each R rad is a radiolabeling group bonded to or incorporating an L 1 of the linker, wherein each radiolabeling group is independently: a radiometal chelator; an aryl or heteroaryl substituted with a radiohalogen; a prosthetic group containing a trifluoroborate; a prosthetic group containing a silicon-fluorine-acceptor moiety; or a prosthetic group containing a fluorophosphate, fluorosulfate, sulfonyl fluoride, or a combination thereof.
  • the compounds of Formulas I, A, or B do not comprise the albumin binder R alb in the linker.
  • Xaa 1 , Xaa 2 , Xaa 3 , Xaa 4 , Xaa 5 , Xaa 6 , Xaa 7 , Xaa 8 , or Xaa 9 is methylated.
  • i is a reduced peptide bond joining Xaa 8 to Xaa 9 .
  • Xaa 1 is D-Phe; and/or Xaa 6 is Gly; and/or Xaa 8 is Leu; and/or Xaa 9 is Pro, Thz or 4-oxa-L-Pro.
  • Xaa 6 is Gly or N-methyl-Gly.
  • Xaa 9 is Thz.
  • Xaa 9 is Pro.
  • Xaa 1 is D-phe
  • Xaa 2 is Gin
  • Xaa 3 is Trp
  • Xaa 4 is Ala
  • Xaa 5 is Vai
  • Xaa 6 Xaa 6 is Gly or N-methyl-Gly
  • Xaa 7 is His
  • Xaa 8 is Leu
  • Xaa 9 is Thz
  • i is a reduced peptide bond joining Xaa 8 to Xaa 9 .
  • Xaa 6 is N-methyl-Gly.
  • the peptidic compound is any compound from Formula I, A, or B, wherein the compounds described in PCT application publication W02009/109332, which is incorporated by reference in its entirety herein, are excluded.
  • the peptidic compound is any compound from Formula B, wherein the compounds described in PCT application publication W02009/109332, which is incorporated by reference in its entirety herein, are excluded.
  • the peptidic compound is any compound from Formula I, A, or B, wherein the compounds described in PCT application publication WO2021/068051 , which is incorporated by reference in its entirety herein, are excluded.
  • the peptidic compound is any compound from Formula B, wherein the compounds described in PCT application publication W02021/068051 , which is incorporated by reference in its entirety herein, are excluded.
  • the peptidic compound is any compound described in PCT application publication WO2021/068051 , which is incorporated by reference in its entirety herein.
  • the peptidic compound is any compound from Formula B, wherein the compounds described in Wang, L et al., Molecules, 2022 27, 3777, which is incorporated by reference in its entirety herein, are excluded.
  • the peptidic compound is any compound described in Wang, L et al., Molecules, 2022 27, 3777, which is incorporated by reference in its entirety herein.
  • peptidic compounds of Formula I, A, or B exclude R rad n6-[linker]-R L -, or R rad n 6, or [linker] or R L -.
  • the radiometal, the radionuclide-bound metal, or the radionuclide-bound metal-containing prosthetic group is: 68 Ga, 61 Cu, 64 Cu, 67 Ga, 99m Tc, 110m ln, 111 In, 44 Sc, 86 Y, 89 Zr, 90 Nb, 152 Tb, 155 Tb, [ 18 F]AIF, 131 l, 123 l , 124 l , and 203 Pb, 72 As.
  • the radiometal, the radionuclide-bound metal, or the 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 ln, 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.
  • the compounds or peptidic compounds may be included in a pharmaceutical composition.
  • the pharmaceutical composition may include one or more compounds from Formula I, A, or B and a pharmaceutically acceptable carrier.
  • the peptidic compound(s) may be bound to or include a radiometal.
  • the radiometal 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.
  • the invention may include using the peptidic compounds described herein for imaging methods.
  • the methods may include imaging Gastrin-releasing peptide receptor (GRPR) in a subject, the method comprising: administering to the subject a peptidic compound of any one of Formulas I, A or B; and imaging tissue of the subject.
  • the methods may include the methods of treating cancer in a subject comprising, administering to the subject in need thereof a peptidic compound of any one of Formulas I, A or B and a pharmaceutically acceptable excipient.
  • the methods may include treating a GRPR-expressing condition or disease.
  • the GRPR-expressing condition or disease may be a psychiatric disorder, neurological disorder, 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.
  • the cancer is prostate cancer.
  • -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -i -Xaa 9 -NH2 is the GRPR-targeting moiety of the compound; i.e. it is capable of specifically binding GRPR and potentially producing antagonist effects.
  • Xaa 1 is D-Phe. In other embodiments, Xaa 1 is Cpa. In other embodiments, Xaa 1 is D-Cpa. In other embodiments, Xaa 1 is Nal. In other embodiments, Xaa 1 is D-Nal. In other embodiments, Xaa 1 is 2-Nal. In other embodiments, Xaa 1 is D-2-Nal. D-Phe at position Xaa 1 has been reported to retain binding affinity for GRPR (e.g. see: Lau, et al., 2019, ACS Omega 4:1470-1478).
  • D-Cpa, Tpi, D-Tpi and D-Nal at position Xaa 1 have been reported to retain strong binding affinity for GRPR (e.g. see: 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 would also retain strong binding affinity for GRPR.
  • Xaa 2 is Asn. In other embodiments, Xaa 2 is Gin. In other embodiments, Xaa 2 is Hse. In other embodiments, Xaa 2 is Cit. In other embodiments, Xaa 2 is His. Gin at position Xaa 2 is found in wildtype BBN. His at position Xaa 2 is found in wildtype GRP. Hse and Cit at position Xaa 2 have been reported to retain binding affinity for GRPR (see Gunther, et al., 2021 , J Nucl Med. 62 (supplement 1) 1474).
  • Xaa 3 is Trp. In other embodiments, Xaa 3 is Bta. In other embodiments, Xaa 3 is aMe-Trp. In other embodiments, Xaa 3 is Trp(Me). In other embodiments, Xaa 3 is Trp(7-Me). In other embodiments, Xaa 3 is Trp(6-Me). In other embodiments, Xaa 3 is Trp(5-Me). In other embodiments, Xaa 3 is Trp(4-Me). In other embodiments, Xaa 3 is Trp(2-Me). In other embodiments, Xaa 3 is T rp(7-F).
  • Xaa 3 is T rp(6-F). In other embodiments, Xaa 3 is Trp(5-F). In other embodiments, Xaa 3 is Trp(4-F). In other embodiments, Xaa 3 is Trp(5-OH). Trp at position Xaa 3 is found in wildtype BBN and GRP. Bta and aMe-Trp at position Xaa 3 have been reported to retain binding affinity for GRPR (see Gunther, et al., 2021 , Journal of Nuclear Medicine 62 (supplement 1) 1474; Gunther, et al., J Nucl Med. 2022, jnumed.121.263323; DOI: https://doi.org/10.2967/jnumed.121.263323).
  • Xaa 4 is Ala. In other embodiments, Xaa 4 is Ser.
  • Xaa 5 is Vai. In other embodiments, Xaa 5 is Cpg. In other embodiments, Xaa 5 is Tie. Vai in position Xaa 5 is found in wildtype BBN and GRP.
  • Xaa 6 is Gly. In other embodiments, Xaa 6 is N-methyl-Gly. In other embodiments, Xaa 6 is D-Ala. N-methyl-Gly and D-Ala at position Xaa 6 have been reported to retain strong binding affinity for GRPR (e.g. see: 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).
  • Xaa 7 is His. In other embodiments, Xaa 7 is NMe-His. His at position Xaa 7 is found in wildtype BBN and GRP. NMe-His at position Xaa7 has been reported to retain binding affinity for GRPR (e.g. see: Table 4 in Horwell et al., 1996 Int. J. Peptide Protein Res. 48:522-531).
  • Xaa 8 is Leu. In other embodiments, Xaa 8 is D-Pro. In other embodiments, Xaa 8 is Phe. Leu at position Xaa 8 is found in wildtype BBN and GRP. D-Pro at position Xaa 8 has been reported to retain binding affinity for GRPR (e.g. see: Leban, et al., 1994, J. Med. Chem. 37:439-445). Phe at position Xaa 8 is supported by Phe at this position in ranatensin and litorin, which have very strong binding affinity to the GRPR (Heimbrook et al., 1991 J. Med. Chem. 34:2102-2107; Lin et al., 1995 European Journal of Phamacology 294:55-69).
  • Xaa 9 is Pro (i.e. Xaa 9 -NH2 is C-terminally amidated Pro).
  • Xaa 9 is Phe (i.e. Xaa 9 -NH2 is C-terminally amidated Phe).
  • Xaa 9 is 4-oxa-L-Pro (i.e. Xaa 9 'NH 2 is C-terminally amidated 4-oxa-L-Pro).
  • Xaa 9 is Me2Thz (i.e. Xaa 9 -NH2 is C-terminally amidated Me2Thz).
  • Xaa 9 is Thz (i.e.
  • Xaa 9 -NH2 is C-terminally amidated Thz).
  • Pro at position Xaa 9 has been reported to retain binding affinity for GRPR (e.g. see: Lau, et al., 2019, ACS Omega 4:1470-1478; WO/2021/068051).
  • Phe at position Xaa 9 has been reported to retain binding affinity for GRPR (e.g. see: Leban, et al., 1994, J. Med. Chem. 37:439-445).
  • Thz at position Xaa 9 has been reported to retain binding affinity for GRPR (e.g. see: Cai, et al., 1994 Proc Natl Acad Sci USA 91 :12664-12668).
  • ip represents a peptide bond joining Xaa 8 and Xaa 9 . In other embodiments, “ip” represents a reduced peptide bond joining Xaa 8 and Xaa 9 , meaning that the main
  • -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -ip-Xaa 9 -NH2 is -D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 .
  • -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -ip-Xaa 9 -NH2 is -D-2-Nal-Gln-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 .
  • -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -ip-Xaa 9 -NH2 is -D-Phe-Gln-Trp-Ala-Val-Gly-NMe-His-Leu-Thz-NH 2 .
  • -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -ip-Xaa 9 -NH2 is -D-Phe-Gln-Trp-Ala-Tle-Gly-His-Leu-Thz-NH 2 .
  • -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -ip-Xaa 9 -NH2 is -Phe-Gln-Trp-Ala-Tle-Gly-NMe-His-Leu-Thz-NH 2 .
  • -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -ip-Xaa 9 -NH2 is -D-Phe-His-Trp-Ala-Val-Gly-His-LeuipThz-NH 2 .
  • -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -ip-Xaa 9 -NH2 is -D-Phe-His-Trp-Ala-Tle-Gly-NMe-His-Leu-Thz-NH 2 .
  • -Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -ip-Xaa 9 -NH2 is -D-Phe-Gln-Trp-Ala-Tle-Gly-His-LeuipThz-NH 2 .
  • R L is a linkage moiety joining the linker to the N-terminus of Xaa 1 .
  • R L is -C(O)-.
  • R L is -NH-C(O)-.
  • R L is-NH-C(S)-;
  • the linker enables attachment of 1-5 radiolabelling groups, and optionally an albumin binder, to the compound.
  • a non-limiting example of a suitable linker is a peptide linker. More generally, the linker is a linear or branched chain of n1 units of -L 1 R 1 - and/or -(L 1 ) 2 R 1 - (i.e. each unit is independently -L 1 R 1 - or-(L 1 )2R 1 -), wherein 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.
  • n6 is 1 and n1 is 1.
  • n6 is 1
  • n1 is 1
  • L 1 is -C(O)NH-
  • n6 is 1
  • n1 is 1
  • L 1 is -C(O)NH-
  • R L is -C(O)-.
  • n6 is 1
  • n1 is 1
  • L 1 is -C(O)NH-
  • R L is -C(O)-
  • R 1 is a linear C1-5 alkylenyl or -(CH 2 )2-[0(CH 2 )2]I-6-(CH 2 )O-2.
  • R rad n 6-[linker]- is configured as shown in Formula II: wherein L 1 and R 1 are as defined in the definition of the linker in Formula I, and R rad/alb is either R rad or R alb , and wherein 0-1 R rad/alb is Raib
  • Each R 1 is, independently, a linear, branched, and/or cyclic C n 2 alkylenyl, alkenylenyl and/or alkynylenyl, wherein each n2 is independently 1 -20, wherein any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted.
  • each n2 is independently 1-15 or 1-10.
  • 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.
  • each R 1 is independently a C n 2 alkylenyl wherein any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted.
  • each R 1 is independently a linear C1-5 alkylenyl or -(CH2)2-[0(CH2)2]I-6-(CH2)O-2-; in some of these embodiments, n1 is 1-7.
  • each R 1 is independently -C(R aa )H-, wherein each R aa is independently the sidechain of a proteinogenic amino acid or the sidechain of an alpha amino acid from Table 1.
  • each R 1 is independently a proteinogenic amino acid or an amino acid from Table 1 omitting the backbone amino and carboxylic acid groups of the amino acid.
  • Each L 1 is a linkage group.
  • at least one L 1 is -S-.
  • at least one L 1 is -N(R 2 )C(O)-; in some of these embodiments, at least one R 2 is hydrogen.
  • at least one L 1 is -C(O)N(R 2 )-; in some of these embodiments, at least one R 2 is hydrogen.
  • at least one L 1 is -NH-C(O)-NH-.
  • the linker has the configuration shown in Formula II, and each R 1 is independently a linear C1-5 alkylenyl or -(CH2)2-[0(CH2)2]i-6-(CH2)o-2-.
  • n6 is 1
  • the linker is L 1 R 1 and together with R L forms -C(O)-Xaa 11 - wherein Xaa 11 is a proteinogenic amino acid residue or an amino acid residue selected from Table 1.
  • Xaa 11 is pABzA-DIG.
  • Xaa 11 is Pip.
  • Xaa 11 is dPEG2.
  • Xaa 11 is Acp.
  • the linker together with R L forms a peptide linker, wherein peptide (amide) bonds are independently optionally methylated, optionally replacing one or more amide bonds with 1 ,2,3-triazole linkages (product of a reaction between an azide and an alkyne).
  • the peptide linker is a linear peptide linker, optionally replacing one or more amide bonds with 1 ,2,3-triazole linkages.
  • the peptide linker is a branched peptide linker, where the amino acid residues may be connected through a combination of main chain amide (peptide) bonds and ‘side chain’-to-‘main chain’ or ‘side chain’-to-‘side chain’ bonds.
  • a branched peptide may be connected by one or more of: backbone (main chain) peptide (amide) bonds, ‘main chain’-to-side chain amide bonds (between an amino group and a carboxylic acid group), optionally replacing one or more amide bonds with 1 ,2,3-triazole linkages.
  • the peptide linker is (Xaa 1o )i-2o, wherein each Xaa 10 is independently a proteinogenic amino acid residue or a non-proteinogenic amino acid residue (e.g. selected from Table 1) linked together as a linear or branched peptide linker.
  • (Xaa 1o )i-2o is a linear peptide linker.
  • (Xaa 1o )i-2o is a branched peptide linker.
  • R rad is bonded to the peptide linker through an amide bond or another L 1 linkage group; in some embodiments, Rrad is bonded to the peptide linker through an amide bond.
  • each Xaa 10 is independently -N(R a )R b C(O)- wherein: R a may be H or methyl; R b may be a 1- to 30-atom alkylenyl, heterolakylenyl, alkenylenyl, heteroalkenylenyl, alkynylenyl, or heteroal kynylenyl, including linear, branched, and/or cyclic (whether aromatic or nonaromatic as well as mono-cyclic, multicyclic or fused cyclic) structures; or N, R a and R b together may form a 5- to 7-atom heteroalkylenyl or heteroalkenylenyl.
  • (Xaa 1o )i-2o consists of a single amino acid or residue.
  • (Xaa 1o )i-2o is a dipeptide, wherein each Xaa 10 may be the same or different.
  • (Xaa 1o )i-2o is a tripeptide, wherein each Xaa 10 may be the same, different or a combination thereof.
  • (Xaa 1o )i-2o consists of 4 amino acid residues connected by peptide bonds, wherein each Xaa 10 may be the same, different or a combination thereof.
  • each Xaa 10 is independently selected from proteinogenic amino acids and the non-proteinogenic amino acids listed in Table 1 , wherein 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.
  • 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.
  • the linker does not comprise R alb .
  • the linker comprises R alb bonded to an L 1 of the linker.
  • R alb is -(CH2)n3-CH3 wherein n3 is 8-20. In alternative embodiments, n3 is 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • R alb is -(CH2)n4-C(O)OH wherein n4 is 8-20. In alternative embodiments, n4 is 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20. [00113] In some embodiments, R alb is wherein n5 is 1-4 and R 3a is H or methyl, and R 3b is I, Br, F, Cl, H, OH, OCH3, NH2, NO2 or Ci-Ce alkyl. In alternative embodiments, n5 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 para position.
  • R 3b is H. In certain embodiments, R 3b is OH, optionally in para position. In certain embodiments, R 3b is OCH3, optionally in para position. In certain embodiments, R 3b is NH2, optionally in para position In certain embodiments, R 3b is NO2, optionally in para position. In certain embodiments, R 3b is Ci-Ce alkyl, optionally in para position. In certain embodiments, R 3a is H and R 3b is OCH3 or NO2. In some embodiments, R 3a is methyl and R 3b is isobutyl, optionally para-isobutyl.
  • At least one R rad is or comprises a radiometal chelator.
  • the radiometal chelator may be any chelator suitable for binding a radiometal, a radionuclide-bound metal, or a radionuclide-bound metal-containing prosthetic group, and which 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, e.g. as summarized in Price and Orvig, Chem. Soc.
  • each radiometal chelator is independently selected from the group consisting of: DOTA and DOTA derivatives; DOTAGA; NOTA; NODAGA; NODASA; CB-DO2A; 3p-C-DEPA; TCMC; DO3A; DTPA and DTPA analogues optionally selected from CHX-A”-DTPA and 1 B4M-DTPA; TETA; NOPO; Me-3,2-HOPO; CB-TE1A1 P; CB-TE2P; MM-TE2A; DM-TE2A; sarcophagine and sarcophagine derivatives optionally selected from SarAr, SarAr-NCS, diamSar, AmBaSar, and BaBaSar; TRAP; AAZTA; DATA and DATA derivatives; H2-macropa or a derivative thereof; H2dedpa, H4octapa, H4py4pa
  • radiometal chelators and example radionuclides that may be chelated by these chelators are shown in Table 2.
  • at least one R rad is a radiometal chelator selected from those listed above or in Table 2. It is noted, however, that one skilled in the art could replace any of the chelators listed herein with another chelator.
  • each radiometal chelator is independently selected from Table 2, wherein 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.
  • 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.
  • at least one R rad is CB-DO2A, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2).
  • at least one R rad is TCMC, or a derivative thereof, linked via an amide (e.g. formed from one of the -CONH2 groups shown in Table 2).
  • the chelator at least one R rad is 3p-C-DEPA, or a derivative thereof, linked via an amide (e.g.
  • 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).
  • at least one R rad is TETA, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2).
  • 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).
  • At least one R rad is Diamsar, or a 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 rad is NOTA, 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 NETA, 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 HxTSE, or a derivative thereof, linked via an amide (e.g. formed from one of the amino groups shown in Table 2).
  • At least one R rad is P2N2Ph2, or a derivative thereof, linked via an amide (e.g. formed from one of the amino groups shown in Table 2).
  • at least one R rad is DTPA, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2).
  • at least one R rad is CHX-A00-DTPA, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2).
  • at least one R rad is H2dedpa, or a derivative thereof, linked via an amide (e.g.
  • At least one R rad is H2azapa, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2).
  • 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).
  • at least one R rad is Hephospa, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2).
  • 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).
  • at least one R rad is Hsdecapa, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2).
  • at least one R 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).
  • at least one R rad is SHBED, or a derivative thereof, linked via an amide (e.g.
  • At least one R rad is BPCA, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2).
  • at least one R rad is PCTA, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2).
  • at least one R rad is H2-MACROPA, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2).
  • at least one R rad is Crown, or a derivative thereof, linked via an amide (e.g.
  • At least one R rad is HYNIC, or a derivative thereof, linked via an amide (e.g. formed from the carboxyl group shown in Table 2). In some embodiments, at least one R rad is N4, or a derivative thereof, linked via an amide (e.g. formed from the carboxyl group shown in Table 2). In some embodiments, at least one R rad is HBED-CC, or a derivative thereof, linked via an amide (e.g. formed from one of the carboxyl groups shown in Table 2).
  • the radiometal chelator (or one of the radiometal chelators) is a derivative of a radiometal chelator shown in Table 2.
  • a derivative may include, e.g. (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 an ethylene carbon located between two nitrogen atoms, wherein the R-group is a functional group fused to a spacer).
  • a carboxyl functional group shown in Table 2 is replaced with azidopropyl ethylacetamide (e.g.
  • these derivative chelators can be linked either via an amide (formed from a remaining carboxyl group) or via -C(O)-NH-(CH2)2-3-(triazole) or -C(O)-NH-(CH2)2-3-(thiomaleimide).
  • p-SCN-Bn-DOTA S-2-(4-isothiocyanatobenzyl)-1 ,4,7,10-tetraazacyclododecane tetraacetic acid
  • p-SCN-Bn-NOTA 2-S-(4-isothiocyanatobenzyl)-1 ,4,7-triazacyclononane-1 ,4,7-triacetic acid
  • these derivatives can form a urea linkage (formed from isocyanate) or a thiourea linkage (formed from isothiocyanate).
  • a radiometal chelator is conjugated with a radiometal, a radionuclide-bound metal, or a radionuclide-bound metal-containing prosthetic group, and the radiometal, the radionuclide-bound metal, or the radionuclide-bound metal-containing prosthetic group is chelated to the radionuclide-chelator complex.
  • the radiometal, the radionuclide-bound metal, or the radionuclide-bound metal-containing prosthetic group is: 68 Ga, 61 Cu, 64 Cu, 67 Cu, 67 Ga, 111 ln, 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, i42p r , 114m ln, 94m Tc, 99m Tc, 149 Tb, 152 Tb, 155 Tb, 161 Tb, or [ 18 F]AIF.
  • the radiometal, the radionuclide-bound metal, or the radionuclide-bound metal-containing prosthetic group is: 68 Ga, 61 Cu, 64 Cu, 67 Cu, 67 Ga, 111 ln, 44 Sc, 86 Y, 177 Lu, 90 Y, 225 Ac, 213 Bi, or 212 Bi.
  • the chelator is a chelator from Table 2 and the chelated radionuclide is a radionuclide indicated in Table 2 as a binder of the chelator.
  • the chelator is: DOTA or a derivative thereof, conjugated with 177 Lu, 111 1 n, 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 Cu; H2-MACROPA conjugated with 225 Ac; Me-3,2-HOPO conjugated with 227 Th; H4py4pa conjugated with 225 Ac, 227 Th or 177 Lu; F pypa conjugated with 177 Lu; NODAGA conjugated with 68 Ga; DTPA conjugated with 111 ln; or DFO conjugated with 89 Zr.
  • the chelator is TETA (1 ,4,8,11-tetraazacyclotetradecane-1 ,4,8,11-tetraacetic acid), SarAr
  • an R rad is a chelator for radiolabelling with 99m Tc, 94m Tc, 186 Re, or 188 Re, such as mercaptoacetyl, hydrazinonicotinamide, dimercaptosuccinic acid, 1 ,2-ethylenediylbis-L-cysteine diethyl ester, methylenediphosphonate, hexamethylpropyleneamineoxime and hexakis(methoxy isobutyl isonitrile), and the like.
  • a chelator for radiolabelling with 99m Tc, 94m Tc, 186 Re, or 188 Re such as mercaptoacetyl, hydrazinonicotinamide, dimercaptosuccinic acid, 1 ,2-ethylenediylbis-L-cysteine diethyl ester, methylenediphosphonate, hexamethylpropyleneamineoxime and hexakis(methoxy isobuty
  • an R rad is a chelator, wherein the chelator is mercaptoacetyl, hydrazinonicotinamide, dimercaptosuccinic acid, 1 ,2-ethylenediylbis-L-cysteine diethyl ester, methylenediphosphonate, hexamethylpropyleneamineoxime or hexakis(methoxy isobutyl isonitrile).
  • the chelator is bound by a radionuclide. In some such embodiments, the radionuclide is 99m-
  • an R rad is a chelator that can bind 18 F-aluminum fluoride ([ 18 F]AIF), such as 1 ,4,7-triazacyclononane-1 ,4-diacetate (NODA) and the like.
  • 18 F]AIF 18 F-aluminum fluoride
  • NODA 1 ,4,7-triazacyclononane-1 ,4-diacetate
  • the chelator is NODA.
  • the chelator is bound by [ 18 F]AIF.
  • an R rad is a chelator that can bind 72 As or 77 As, such as a trithiol chelate and the like.
  • the chelator is a trithiol chelate.
  • the chelator is conjugated to 72 As.
  • the chelator is conjugated to 77 As.
  • At least one R rad is a prosthetic group containing a trifluoroborate (BF3), capable of 18 F/ 19 F exchange radiolabeling.
  • the R rad is BF3-R 5 -R 4 -, wherein R 4 is -(CH2)I-S, optionally methylene, and wherein BF3-R 5 - forms: wherein R 5a and R 5b are each independently a C1-C5 linear or branched alkyl group, or a structure listed in Table 3 (below) or Table 4 (below).
  • each R group in each pyridine substituted with -OR, -SR, -NR-, -NHR or -NR2 is independently a C1-C5 linear or branched alkyl.
  • at least one of the BF3-R 5 - group(s) is/are selected from those listed in Table 3.
  • at least one of the BF3-R 5 -group(s) is/are selected from those listed in Table 4.
  • the trifluoroborate-containing prosthetic group(s) may comprise 18 F.
  • one fluorine in BF3 forms is 18 F.
  • all three fluorines in BF3 are 18 F.
  • all three fluorines in BF3 are 19 F.
  • -NR 2 is independently a linear or branched C1-C5 alkyl.
  • R is methyl.
  • R is ethyl.
  • R is propyl.
  • R is isopropyl.
  • R is n-butyl.
  • the trifluoroborate-containing prosthetic group(s) may comprise 18 F.
  • one fluorine is a BF3-R 5 - is 18 F.
  • all three fluorines in a BF3-R 5 - are 18 F.
  • all three fluorines in a BF3-R 5 - are 19 F.
  • a BF3-R 5 - may independently form
  • R is methyl.
  • R is ethyl.
  • R is propyl.
  • R is isopropyl.
  • R is n-butyl.
  • all three fluorines in a BF3-R 5 - are 18 F.
  • one fluorine in a BF3-R 5 - is 18 F.
  • all three fluorines in a BF3-R 5 - are 19 F.
  • At least one BF3-R 5 - or optionally each BF3-R 5 - is independently wherein R 5a and R 5b are each independently a C1-C5 linear or branched alkyl group.
  • R 5a is methyl.
  • R 5a is ethyl.
  • R 5a is propyl.
  • R 5a is isopropyl.
  • R 5a is butyl.
  • R 5a is n-butyl.
  • R 5a is pentyl.
  • R 5b is methyl.
  • R 5b is ethyl.
  • 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 may comprise 18 F. In some embodiments, one fluorine in BF3-R 5 - is 18 F. In some embodiments, all three fluorines in BF3-R 5 - are 18 F. In some embodiments, all three fluorines in BF3-R 5 - are 19 F.
  • the compound is conjugated with a radionuclide for positron emission tomography (PET) or single photon emission computed tomography (SPECT) imaging of GRPR expressing tumors, wherein the compound is conjugated with a radionuclide that is a positron emitter or a gamma emitter.
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • the positron or gamma emitting radionuclide is 68 Ga, 67 Ga, 61 Cu, 64 Cu, 67 Ga, 99m Tc, 110m l n, 111 1n, 44 Sc, 86 Y, 89 Zr, 90 Nb, 152 Tb, 155 Tb, 18 F, 131 l, 123 l, 124 l, 203 Pb and 72 As.
  • the compound is conjugated with a radionuclide that is used for therapy.
  • a radionuclide that is used for therapy.
  • radioisotopes such as 165 Er, 212 Bi, 211 At, 166 Ho, 149 Pm, 159 Gd, 105 Rh, 109 Pd, 198 Au, 199
  • n6 is 1
  • 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-dioxanonanoic acid (dPEG2) linker, or a 4-(2-aminoethyl)-1-carboxymethyl-piperazine (Acp) linker.
  • the linker and R L together form: [00136]
  • the compound is LW01025, optionally conjugated by a radiometal.
  • the compound is LW01029, optionally conjugated by a radiometal. In some embodiments, the compound is LW01107, optionally conjugated by a radiometal. In some embodiments, the compound is LW01108, optionally conjugated by a radiometal. In some embodiments, the compound is LW01110, optionally conjugated by a radiometal. In some embodiments, the compound is LW01102, optionally conjugated by a radiometal. In some embodiments, the compound is LW01142, optionally conjugated by a radiometal. In some embodiments, the compound is LW01158, optionally conjugated by a radiometal. In some embodiments, the compound is LW01186, optionally conjugated by a radiometal.
  • the compound is LW02002, optionally conjugated by a radiometal.
  • the compound is LW02021 , optionally conjugated by a radiometal.
  • the compound is LW02023, optionally conjugated by a radiometal.
  • the compound is LW02025, optionally conjugated by a radiometal.
  • the compound is LW01045, optionally conjugated by a radiometal.
  • the compound is LW01059, optionally conjugated by a radiometal.
  • the compound is LW01061 , optionally conjugated by a radiometal.
  • the compound is LW01090, optionally conjugated by a radiometal.
  • the compound is LW01117, optionally conjugated by a radiometal.
  • the compound is:
  • LW01025 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 );
  • LW01029 (DOTA-Pip-D-2-Nal-Gln-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 );
  • LW01107 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-NMe-His-Leu-Thz-NH 2 );
  • LW01108 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Tle-Gly-His-Leu-Thz-NH 2 );
  • LW01110 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Tle-Gly-NMe-His-Leu-Thz-NH 2 );
  • LW01142 (DOTA-Pip-D-Phe-His-Trp-Ala-Tle-Gly-NMe-His-Leu-Thz-NH 2 ); LW01102 (DOTA-Pip-D-Phe-His-Trp-Ala-Val-Gly-His-Leui Thz-NH 2 );
  • LW01158 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Tle-Gly-His-LeuipThz-NH 2 );
  • LW01080 (D-Phe-Gln-Trp-Ala-Tle-Gly-His-Leu-Thz-NH 2 );
  • LW01088 (D-Phe-Gln-Trp-Ala-Val-Gly-NMe-His-Leu-Thz-NH 2 );
  • LW01136 (D-Phe-Gln-Trp(Me)-Ala-Val-Gly-His-Leu-Thz-NH 2 );
  • LW01186 (DOTA-Pip-D-Phe-Gln-aMe-Trp-Ala-Tle-Gly-His-Leui Thz-NH 2 );
  • LW02002 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Tle-N-Me-Gly-His-Leui Thz-NH 2 );
  • LW02021 (DOTA-Pip-D-Phe-Gln-7-F-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 );
  • LW01142 (DOTA-Pip-D-Phe-His-Trp-Ala-Tle-Gly-NMe-His-Leu-Thz-NH 2 );
  • LW02023 (DOTA-Pip-D-Phe-Gln-5-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 );
  • LW02025 (DOTA-Pip-D-Phe-Gln-2-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 );
  • LW02045 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-N-MeGly-His-LeuipPro-NH 2 );
  • LW02042 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Phe-Thz-NH 2 );
  • LW02011 D-Phe-Gln-Trp-Ala-2,3-dehydro-Val-Gly-His-Leu-Thz-NH 2 );
  • LW01166 (D-Phe-Gln-5-F-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 );
  • LW01171 (D-Phe-Gln-6-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 );
  • LW01173 (D-Phe-Gln-5-OH-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 );
  • LW01175 (D-Phe-Gln-6-F-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 );
  • LW01177 (D-Phe-Gln-7-F-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 );
  • LW01180 (D-Phe-Gln-4-F-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 );
  • LW01182 (D-Phe-Gln-5-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 );
  • LW01191 (D-Phe-Gln-D-Tpi-Ala-Val-Gly-His-Leu-Thz-NH 2 ); LW02007 (D-Phe-Gln-7-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 );
  • LW02013 D-Phe-Gln-7-Aza-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 ); or
  • LW02015 (D-Phe-Gln-Bta-Ala-Val-Gly-His-Leu-Thz-NH 2 ), wherein i for these compounds is a reduced peptide bond.
  • the compound is:
  • LW01080* (DOTA-Pip-D-Phe-Gln-Trp-Ala-Tle-Gly-His-Leu-Thz-NH 2 );
  • LW01088* (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-NMe-His-Leu-Thz-NH 2 );
  • LW02011* (DOTA-Pip-D-Phe-Gln-Trp-Ala-2,3-dehydro-Val-Gly-His-Leu-Thz-NH 2 );
  • LW01171* (DOTA-Pip-D-Phe-Gln-6-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 );
  • LW01173* (DOTA-Pip-D-Phe-Gln-5-OH-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 );
  • LW01175* (DOTA-Pip-D-Phe-Gln-6-F-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 );
  • LW01182* (DOTA-Pip-D-Phe-Gln-5-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 );
  • LW01191* (DOTA-Pip-D-Phe-Gln-D-Tpi-Ala-Val-Gly-His-Leu-Thz-NH 2 );
  • LW02007* (DOTA-Pip-D-Phe-Gln-7-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 );
  • LW02013* (DOTA-Pip-D-Phe-Gln-7-Aza-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 ); or
  • LW02015* (DOTA-Pip-D-Phe-Gln-Bta-Ala-Val-Gly-His-Leu-Thz-NH 2 ), wherein i for these compounds is a reduced peptide bond.
  • the compound is:
  • LW01045 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-ip-Thz-NH 2 ),
  • LW01059 (DOTA-Pip-D-2-Nal-Gln-Trp-Ala-Val-Gly-His-Leu-ip-Thz-NH 2 ),
  • LW01061 (DOTA-Pip-D-Tpi-Gln-Trp-Ala-Val-Gly-His-Leu-ip-Thz-NH 2 ),
  • LW01090 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-NMe-Gly-His-Leu-ip-Thz-NH 2 ), or
  • LW01117 (DOTA-Cysteic acid-Pip-D-2-Nal-Gln-Trp-Ala-Val-Gly-His-Leu-ip-Thz-NH 2 ), wherein i for these compounds is a reduced peptide bond.
  • the LWO compounds listed above and described herein may be included in a pharmaceutical composition.
  • the pharmaceutical composition may include one or more compounds from LWO compounds listed above and described herein or Formula I, A, or B and a pharmaceutically acceptable carrier.
  • the compound(s) may be bound to or include a radiometal.
  • the radiometal 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.
  • the LWO compounds listed above and described herein may used for imaging methods.
  • the methods may include imaging Gastrin-releasing peptide receptor (GRPR) in a subject, the method comprising: administering to the subject a peptidic compound, including the LWO compounds listed above and described herein, and/or any compound of Formulas I, A or B; and imaging tissue of the subject.
  • the methods may include the methods of treating cancer in a subject comprising, administering to the subject in need thereof a peptidic compound including the LW0 compounds listed above and described herein, and/or any compound of Formulas I, A or B.
  • the methods may include treating a GRPR-expressing condition or disease.
  • the GRPR-expressing condition or disease may be a psychiatric disorder, neurological disorder, 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.
  • the cancer is prostate cancer.
  • the compounds described herein are optionally conjugated by a radiometal, and may be used for the methods described herein.
  • the radiometal is 177 Lu, 111 ln, 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 Cu.
  • the radiometal is 68 Ga.
  • the radiometal is 64 Cu.
  • the radiometal is 67 Cu.
  • the radiometal is 67 Ga. In some embodiments, the radiometal is 111 ln. In some embodiments, the radiometal is 177 Lu. In some embodiments, the radiometal is 90 Y In some embodiments, the radiometal is 225 Ac.
  • the radiolabeling group i.e. R rad in Formula I
  • R rad in Formula I comprises or is conjugated to a diagnostic radionuclide
  • the method comprises: administering to the subject a composition comprising a compound described herein and a pharmaceutically acceptable excipient; and imaging tissue of the subject, e.g. using PET or SPECT.
  • tissue is a diseased tissue (e.g. a GRPR-expressing cancer)
  • GRPR-targeted treatment may then be selected for treating the subject.
  • the radiolabeling group i.e. R rad in Formula I
  • R rad in Formula I comprises or is conjugated to a therapeutic radionuclide
  • certain embodiments of the compound (or a pharmaceutical composition thereof) for the treatment of GRPR-expressing conditions or diseases (e.g. cancer and the like) in a subject.
  • a compound disclosed herein in preparation of a medicament for treating a GRPR-expressing condition or disease in a subject.
  • the method comprises: administering to the subject a composition comprising the compound and a pharmaceutically acceptable excipient.
  • the disease may be a GRPR-expressing cancer.
  • the LWO compounds listed above and described herein may include or be conjugated to a radiometal.
  • the methods may include imaging Gastrin-releasing peptide receptor (GRPR) in a subject, the method comprising: administering to the subject a peptidic compound, including the LWO compounds listed above with a radiometal and described herein, and/or any compound of Formulas I, A or B with a radiometal; and imaging tissue of the subject.
  • GRPR Gastrin-releasing peptide receptor
  • the methods may include the methods of treating cancer in a subject comprising, administering to the subject in need thereof a peptidic compound including the LWO compounds listed above with a radiometal and described herein, and/or any compound of Formulas I, A or B with a radiometal.
  • the GRPR-expressing condition or disease may be psychiatric disorder, neurological disorder, 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.
  • the cancer is prostate cancer.
  • the compounds presented herein incorporate peptides, which may be synthesized by any of a variety of methods established in the art. This includes but is not limited to liquid-phase as well as solid-phase peptide synthesis using methods employing 9-fluorenylmethoxycarbonyl (Fmoc) and/or t-butyloxycarbonyl (Boc) chemistries, and/or other synthetic approaches.
  • Fmoc 9-fluorenylmethoxycarbonyl
  • Boc t-butyloxycarbonyl
  • peptides may be synthesized by sequential incorporation of the amino acid residues of interest one at a time.
  • peptide synthesis is typically initiated by attaching the C-terminal amino acid of the peptide of interest to a suitable resin.
  • suitable protecting groups Prior to this, reactive side chain and alpha amino groups of the amino acids are protected from reaction by suitable protecting groups, allowing only the alpha carboxyl group to react with a functional group such as an amine group, a hydroxyl group, or an alkyl halide group on the solid support.
  • the protecting group on the side chain and/or the alpha amino group of the amino acid is selectively removed, allowing the coupling of the next amino acid of interest. This process is repeated until the desired peptide is fully synthesized, at which point the peptide 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.
  • Fmoc protecting groups may be removed from the amino acid on the solid support, e.g. under mild basic conditions, such as piperidine (20-50% v/v) in DMF.
  • the amino acid to be added must also have been activated for coupling (e.g. at the alpha carboxylate).
  • activating reagents include without limitation 2-(1 H-benzotriazol-1-yl)-1 , 1 ,3,3-tetramethyluronium hexafluorophosphate (HBTLI),
  • H-benzotriazole-1-yl 2-(7-Aza-1 H-benzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (HATLI), benzotriazole-1-yl-oxy-tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazole-1-yl-oxy-tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP). Racemization is minimized by using triazoles, such as 1 -hydroxy-benzotriazole (HOBt) and 1-hydroxy-7-aza-benzotriazole (HOAt). Coupling may be performed in the presence of a suitable base, such as N,N-diisopropylethylamine (DIPEA/DIEA) and the like.
  • DIPEA/DIEA N,N-diisopropylethylamine
  • peptides may be elongated in a branched fashion by attaching to side chain functional groups (e.g. carboxylic acid groups or amino groups), 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 an amide between an amino acid side chain containing a carboxyl group (e.g. Asp, D-Asp, Glu, D-Glu, and the like) and an amino acid side chain containing an amino group (e.g.
  • Non-limiting examples of selectively removable protecting groups include 2-phenylisopropyl esters (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
  • O-2-PhiPr and Mtt protecting groups can be selectively deprotected under mild acidic conditions, such as 2.5% trifluoroacetic acid (TFA) in DCM.
  • TFA trifluoroacetic acid
  • Alloc protecting groups can be selectively deprotected using tetrakis(triphenylphosphine)palladium(0) and phenyl silane in DCM.
  • Dde and ivDde protecting groups can be selectively deprotected using 2-5% of hydrazine in DMF.
  • Deprotected side chains of Asp/Glu (L- or D-forms) and Lys/Orn/Dab/Dap (L- or D-forms) can then be coupled, e.g. by using the coupling reaction conditions described above.
  • the above provides means for including multiple BF3 groups.
  • Peptide backbone amides may be N-methylated (i.e. alpha amino methylated) or N-alkylated. This may be achieved 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, a free primary amine group is protected using a solution of 4-nitrobenzenesulfonyl chloride (Ns-CI) and 2,4,6-trimethylpyridine (collidine) in NMP.
  • Ns-CI 4-nitrobenzenesulfonyl chloride
  • collidine 2,4,6-trimethylpyridine
  • N-methylation (or N-alkylation) may then be achieved in the presence of triphenylphosphine, diisopropyl azodicarboxylate (DIAD) and methanol. Subsequently, N-deprotection may be performed using mercaptoethanol and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBll) in NMP.
  • DBll 1 ,8-diazabicyclo[5.4.0]undec-7-ene
  • HATLI, HOAt and DIEA may be used for coupling protected amino acids to N-methylated (or N-alkylated) alpha amino groups.
  • thioether (-S-) linkages can be achieved either on solid phase or in solution phase.
  • the formation of thioether (-S-) linkage can be achieved by coupling between a thiol-containing compound (such as the thiol group on cysteine side chain) and an alkyl halide (such as 3-(Fmoc-amino)propyl bromide and the like) in an appropriate solvent (such as N,N-dimethylformamide and the like) in the presence of base (such as N,N-diisopropylethylamine and the like).
  • a thiol-containing compound such as the thiol group on cysteine side chain
  • an alkyl halide such as 3-(Fmoc-amino)propyl bromide and the like
  • an appropriate solvent such as N,N-dimethylformamide and the like
  • base such as N,N-diisopropylethylamine and the like.
  • the reactants used are preferably in equivalent molar ratio (1 to 1), and the desired products can be purified by flash column chromatography or high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the reactions are carried out on solid phase, meaning one reactant has been attached to a solid phase, then the other reactant is normally used in excess amount (> 3 equivalents of the reactant attached to the solid phase).
  • the excess unreacted reactant and reagents can be removed by sequentially washing the solid phase (resin) using a combination of solvents, such as N,N-dimethylformamide, methanol and dichloromethane, for example.
  • the formation of the linkage (e.g. for L 1 ) between a thiol group and a maleimide group can be performed using the conditions described above for the formation of the thioether (-S-) linkage simply by replacing the alkyl halide with a maleimide-containing compounds. Similarly, this reaction can be conducted in solid phase or solution phase. If the reactions are carried out in solution phase, the reactants used are preferably in equivalent molar ratio (1 to 1), and the desired products can be purified by flash column chromatography or high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the reactions are carried out on solid phase, meaning one reactant has been attached to a solid phase, then the other reactant is normally used in excess amount (> 3 equivalents of the reactant attached to the solid phase).
  • the excess unreacted reactant and reagents can be removed by sequentially washing the solid phase (resin) using a combination of solvents, such as N,N-dimethylformamide, methanol and dichloromethane, for example.
  • Urea or thiourea linkages can be made from reaction of an amine group with an isocyanate or an isothiocyanate, respectively, which are common functional groups on radiometal chelators.
  • the isothiocyanate functional group may be added to the radiometal chelator by reacting an amino group on the chelator with thiophosgene [i.e. C(S)Cl2].
  • the isocyanate functional group may be added to the radiometal chelator by reacting an amino group on the chelator with phosgene [i.e. C(O)Cl2].
  • Non-peptide moieties e.g. radiolabeling groups and/or albumin binders
  • a bifunctional chelator such as 1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10-tetraacetic acid (DOTA) tris(tert-butyl ester) may be activated in the presence of N -hydroxysuccinimide (NHS) and N,N'-dicyclohexylcarbodiimide (DCC) for coupling to a peptide.
  • N S N -hydroxysuccinimide
  • DCC N,N'-dicyclohexylcarbodiimide
  • a non-peptide moiety may be incorporated into the compound via a copper-catalyzed click reaction under either liquid or solid phase conditions. Copper-catalyzed click reactions are well established in the art.
  • 2-azidoacetic acid is first activated by NHS and DCC and coupled to a peptide. Then, an alkyne-containing non-peptide moiety may be clicked to the azide-containing peptide in the presence of Cu 2+ and sodium ascorbate in water and organic solvent, such as acetonitrile (ACN) and DMF and the like. Non-peptide moieties may also be added in solution phase, which is routinely performed.
  • radiometal chelators are well-known and many chelators are commercially available (e.g. from Sigma-Aldrich TM /Milipore SigmaTM and others). Protocols for conjugation of radiometals to the chelators is also well known (e.g. see Examples, below).
  • the BFs-containing motif can be coupled to the linker via click chemistry by forming a 1 ,2,3-triazole ring between a BFs-containg azido (or alkynyl) group and an alkynyl (or azido) group on the linker, or by forming an amide linkage between a BFs-containg carboxylate and an amino group on the linker.
  • a boronic acid ester-containing azide, alkyne or carboxylate is first prepared following by the conversion of the boronic acid ester to BF3 in a mixture of HCI, DMF and KHF2.
  • the boronic acid ester-containing azide, alkyne or carboxylate can be prepared by coupling boronic acid ester-containing alkyl halide (such as iodomethylboronic acid pinacol ester) with an amine-containing azide, alkyne or carboxylate (such as N,N-dimethylpropargylamine).
  • boronic acid ester-containing alkyl halide such as iodomethylboronic acid pinacol ester
  • an amine-containing azide, alkyne or carboxylate such as N,N-dimethylpropargylamine.
  • the boronic acid ester can be prepared via Suzuki coupling using aryl halide (iodine or bromide) and bis(pinacolato)diboron.
  • HPLC high performance liquid chromatography
  • the desired peptide may be cleaved from the solid support using suitable reagents, such as TFA, tri-isopropylsilane (TIS) and water.
  • suitable reagents such as TFA, tri-isopropylsilane (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. deprotection).
  • the crude peptide may be precipitated and collected from the solution by adding cold ether followed by centrifugation.
  • Purification and characterization of the peptides may be performed by standard separation techniques, such as high performance liquid chromatography (HPLC) based on the size, charge and polarity of the peptides.
  • HPLC high performance liquid chromatography
  • the identity of the purified peptides may be confirmed by mass spectrometry or other similar approaches.
  • the inventions described herein are further represented by the following embodiments.
  • Embodiment 1 A peptidic compound, wherein the compound has the structure of Formula I or is a salt or solvate of Formula I,
  • 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, Gin, homoserine (Hse), citrulline (Cit) or His;
  • Xaa 3 is Trp, p-(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 aMe-Trp;
  • Xaa 4 is Ala or Ser
  • Xaa 5 is Vai, Cpg (cyclopentylglycine) or tert-leucine (Tie);
  • 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-terminally 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);
  • ip represents a peptide bond or reduced peptide bond joining Xaa 8 to Xaa 9 ; excluding compounds in which Xaa 2 , Xaa 3 , Xaa 5 , and Xaa 7 are Gin, Trp, Vai, and His, respectively, in which ip is a reduced peptide bond;
  • R L is -0(0)-, -NH-C(O)-, or -NH-C(S)-;
  • the linker is a linear or branched chain of n1 units of -L 1 R 1 - and/or -(L 1 )2R 1 -, wherein: n1 is 1-20; each R 1 is, independently, a linear, branched, and/or cyclic C n 2 alkylenyl, alkenylenyl and/or alkynylenyl, wherein each n2 is independently 1-20, wherein 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 phosphoric acid;
  • L 1 bonds to carbon, wherein each L 1 is independently -S-, -N(R 2 )C(O)-, -C(O)N(R 2 )-,
  • R 2 is H, methyl or ethyl; and an albumin binder (R alb ) is optionally bonded to an L 1 of the linker, wherein the albumin binder is:
  • n3 is 8-20;
  • each R rad is a radiolabeling group bonded to or incorporating an L 1 of the linker, wherein each radiolabeling group is independently: a radiometal chelator; an aryl or heteroaryl substituted with a radiohalogen; a prosthetic group containing a trifluoroborate; a prosthetic group containing a silicon-fluorine-acceptor moiety; or a prosthetic group containing a fluorophosphate, fluorosulfate, sulfonyl fluoride, or a combination thereof.
  • Embodiment 2 The peptidic compound of Embodiment 1 , wherein i is a peptide bond.
  • Embodiment 3 The peptidic compound of Embodiment 1 or 2, wherein Xaa 3 is aMe-Trp.
  • Embodiment 4 The peptidic compound of any one of Embodiments 1 to 3, wherein
  • Xaa 5 is Tie.
  • Embodiment 5 The peptidic compound of any one of Embodiments 1 to 4, wherein
  • Xaa 7 is NMe-His.
  • Embodiment 6 The peptidic compound of any one of Embodiments 1 to 5, wherein
  • Xaa 1 is D-Phe or D-2-Nal.
  • Embodiment 7 The peptidic compound of any one of Embodiments 1 to 6, wherein
  • Xaa 2 is Gin or His.
  • Embodiment 8 The peptidic compound of any one of Embodiments 1 to 7, wherein
  • Xaa 3 is Trp.
  • Embodiment 9 The peptidic compound of any one of Embodiments 1 to 8, wherein
  • Embodiment 10 is Gly.
  • Embodiment 10 The peptidic compound of any one of Embodiments 1 to 9, wherein Xaa 8 is Leu.
  • Embodiment 11 The peptidic compound of any one of Embodiments 1 to 10, wherein Xaa 9 is Thz.
  • Embodiment 12 The peptidic compound of any one of Embodiments 1 to 11 , wherein at least one R rad is a radiometal chelator, optionally selected from the group consisting of: DOTA and derivatives; DOTAGA; NOTA; NODAGA; NODASA; CB-DO2A; 3p-C-DEPA; TCMC; DO3A; DTPA and DTPA analogues optionally selected from CHX-A”-DTPA and 1 B4M-DTPA; TETA; NOPO; Me-3,2-HOPO; CB-TE1A1 P; CB-TE2P; MM-TE2A; DM-TE2A; sarcophagine and sarcophagine derivatives optionally selected from SarAr, SarAr-NCS, diamSar, AmBaSar, and BaBaSar; TRAP; AAZTA; DATA and DATA derivatives; H2-macropa or a derivative thereof; H2dedpa
  • Embodiment 13 The peptidic compound of Embodiment 12, wherein the radiometal chelator is bound by a radiometal, a radionuclide-bound metal, or a radionuclide-bound metal-containing prosthetic group, optionally selected from the group consisting of: 68 Ga, 61 Cu, 64 Cu, 67 Cu, 67 Ga, 111 ln, 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
  • Embodiment 14 The peptidic compound of any one of Embodiments 1 to 13, wherein at least one R rad is a trifluoroborate containing prosthetic group BF3-R 5 -R 4 -, wherein R 4 is -(CH2)I-S- and optionally methylene, and wherein BF3-R 5 - forms: which the R in each pyridine substituted -OR,
  • -SR, -NR-, -NHR or -NR2 is independently a branched or linear C1-C5 alkyl, optionally wherein the fluorines in BF3-R 5 -R 4 - comprise 18 F.
  • Embodiment 15 The peptidic compound of any one of Embodiment 1 to 11 , wherein n6 is 2 and R rad n e comprises a first R rad and a second R rad , wherein 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 wherein the second R rad is a trifluoroborate containing prosthetic group as defined in Embodiment 14 or an aryl or heteroaryl substituted with a radiofluoride.
  • the first R rad is a radiometal chelator as defined in Embodiment 12
  • the second R rad is a trifluoroborate containing prosthetic group as defined in Embodiment 14 or an aryl or heteroaryl substituted with a radiofluoride.
  • Embodiment 16 The peptidic compound of any one of Embodiments 1 to 15, wherein the linker and R L together form a linear or branched peptide linker (Xaa 1 °)i-2o, wherein each Xaa 10 is independently a proteinogenic or non-proteinogenic amino acid residue, wherein each peptide backbone amino group is independently optionally methylated, and wherein each non-proteinogenic amino acid residue is independently selected from Table 1.
  • Embodiment 17 The peptidic compound of any one of Embodiments 1 to 11 , wherein n6 is 1 , and wherein 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-dioxanonanoic acid (dPEG2) linker, or a 4-(2-aminoethyl)-1-carboxymethyl-piperazine (Acp) linker, optionally wherein the linker and R L together form:
  • HPLC columns used were a semipreparative column (Luna C18, 5 pm particle size, 100 A pore size, 250 x 10 mm) and an analytical column (Luna C18, 5 pm particle size, 100 A pore size, 250 x 4.6 mm) from Phenomenex (Torrance, CA).
  • the collected HPLC eluates containing the desired peptides were lyophilized using a Labconco (Kansas City, MO) FreeZone 4.5 Plus freeze drier.
  • Mass analyses were 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) were obtained from Waters (Milford, MA).
  • 68 Ga was eluted from an iThemba Laboratories (Somerset West, South Africa) generator and purified using a DGA resin column from Eichrom Technologies LLC (Lisle, IL).
  • Radioactivity of 68 Ga-labeled peptides was measured using a Capintec (Ramsey, NJ) CRC-25R/W dose calibrator.
  • PET/CT imaging was performed using a Siemens Inveon (Knoxville, TN) micro PET/CT scanner.
  • the radioactivity of mouse tissues collected from biodistribution studies was counted using a PerkinElmer (Waltham, MA) Wizard2 2480 automatic gamma counter.
  • the collected aqueous fraction was adjusted to pH 3 by using concentrated hydrochloric acid before extracted with ethyl acetate (100 mL x 2), dried over magnesium sulfate, filtered, and evaporated to obtain white solid.
  • the obtained white solid was dissolved in 30 mL dichloromethane with tert-butyl 2,2,2-trichloroacetimidate (8.74 g, 40 mmol) and the mixture was stirred for 48 hours at room temperature. The mixture was filtered and the filtrate was concentrated in vacuo and purified by flash column chromatography eluted with 1 :5 ethyl acetate/hexane to obtain compound 1 (4.36 g, 75% yield) as a colorless oil.
  • Thz-OtBu HCI salt (2) Compound 1 (4.31 g) was dissolved in a mixture of ethyl acetate (56.3 mL) and 4M HCI in 1 ,4-dioxane (18.8 mL), and stirred for 4 hours at room temperature. The precipitate was collected by filtration to obtain 2 as a white solid (1.78 g, 53% yield).
  • Solution 2 Compound 2 was dissolved in saturated NaHCOs aqueous solution (35 mL) and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined, dried over anhydrous magnesium sulfate, evaporated in vacuo to obtain colorless oil. The oil was mixed with acetic acid (400 pL, 7.0 mmol) in dichloromethane (30 mL).
  • LW01025 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 ) and LW01029
  • 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 for LW01025/Fmoc-D-2-Nal-OH for LW01029
  • Fmoc-4-amino-(1 -carboxymethyl) piperidine and DOTA(‘BU)3 were sequentially coupled to the Fmoc-Rink amide-MBHA resin.
  • LW01107, LW01108, LW01110, and LW01142 are shown below:
  • LW01107 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-NMe-His-Leu-Thz-NH 2 ), LW01108
  • LW01102 and LW01158 are shown below:
  • LW01102 (DOTA-Pip-D-Phe-His-Trp-Ala-Val-Gly-His-LeuipThz-NH 2 ) and LW01158
  • LW01186, LW02002, LW02021 , LW02023, and LW02025 are as follows:
  • LW01186 (DOTA-Pip-D-Phe-Gln-aMe-Trp-Ala-Tle-Gly-His-Leui Thz-NH 2 )
  • LW02002 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Tle-N-Me-Gly-His-Leui Thz-NH 2 ), wherein iy is a reduced peptide bond, were synthesized using the Fmoc solid phase synthesis strategy starting from Sieber resin. As described above in Example 1 , the compound Fmoc-Leui Thz-OH (4), Fmoc-protected amino acids, Fmoc-4-amino-(1-carboxymethyl)-piperidine and DOTA(‘Bu)3 were sequentially coupled to the resin.
  • LW02021 (DOTA-Pip-D-Phe-Gln-7-F-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 ), LW02023
  • LW01080 D-Phe-Gln-Trp-Ala-Tle-Gly-His-Leu-Thz-NH 2
  • LW01085 D-Phe-Gln-Trp-Ala-Tle-Gly-His-Leu-Thz-NH 2
  • LW02011 , LW02016, LW02019, LW01166, LW01171 , LW01173, LW01175, LW01177, LW01180, LW01182, LW01183, LW01191 , LW02007, LW02009, LW02013, and LW02015 are as follows:
  • LW01171 (D-Phe-Gln-6-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 ),
  • LW01191 (D-Phe-Gln-D-Tpi-Ala-Val-Gly-His-Leu-Thz-NH 2 ), LW02007(D-Phe-Gln-7-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 ), LW02009(D-Phe-Gln-2-Me-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 ), LW02013(D-Phe-Gln-7-Aza-Trp-Ala-Val-Gly-His-Leu-Thz-NH 2 ), and
  • LW02015(D-Phe-Gln-Bta-Ala-Val-Gly-His-Leu-Thz-NH 2 ) were synthesized using standard Fmoc solid phase synthesis. Fmoc-protected amino acids were sequentially coupled to the Fmoc-Rink amide-MBHA resin. After being cleaved with TFA/TIS/water/DODT/thioanisole/phenol 81.5:1 :5:2.5:5:5 and precipitated with diethyl ether, the crude products were purified with HPLC (C18 semi-prep column; flow rate: 4.5 mL/min) and lyophilized to give white powders. The HPLC conditions are shown below in Table 6.
  • LW01110 (2.03mg), LW01102 (2.17 mg), LW01142 (1.81 mg), LW01158 (2.54 mg) were dissolved respectively in 0.5 mL NaOAc buffer (0.1 N, pH 4.53) and GaCI 3 (5 eq., 0.2 M) was added.
  • the respective reaction mixtures were incubated at 80 °C for 15 min and then purified with HPLC (C18 semi-prep column) and lyophilized to give white powders.
  • the HPLC conditions are shown below in Table 7.
  • the 68 Ga-labeled product was eluted off the cartridge with ethanol (0.4 mL), and diluted with saline for imaging and biodistribution. Quality control was performed using the analytical column. The tracers were obtained with more than 95% radiochemical purity.
  • PC-3 cells were seeded at 2 x 10 5 cells/well in 24-well poly-D-lysine plates 24-48 hours prior to the experiment.
  • the growth medium was replaced by 400 pL of reaction medium (RPMI 1640 containing 2 mg/mL BSA, 4.8 mg/mL HEPES, 1 U/mL penicillin G and 1 pg/mL streptomycin).
  • Cells were incubated for 30-60 min at 37 °C.
  • Peptides as provided in Table 9 below provided in 50 pL of decreasing concentrations (10 pM to 1 pM) and 50 pL of 0.011 nM [ 125
  • mice were anesthetized by inhalation with 2% isoflurane in oxygen and implanted subcutaneously with 5 x 10 6 PC-3 cells below the left shoulder. Imaging and biodistribution studies were performed only after tumors grew to 5-8 mm in diameter.
  • mice were injected through the tail vein. Mice were allowed to recover and roam freely in the cages after injecting the tracer. At 45 min post-injection (p. i .) , mice were sedated again and positioned on the scanner. First, a 10 min CT scan was conducted for localization and attenuation correction for reconstruction of PET images, before a 10 min PET image was acquired. Heating pads were used during the entire procedure to keep the mice warm. For ex vivo biodistribution studies, mice were injected with -1.5-3 MBq of the 68 Ga-labeled tracer.
  • mice were euthanized, blood was drawn from heart, and organs/tissues of interest were collected, rinsed with PBS, blotted dry, weighed, and counted using an automated gamma counter. The uptake in each organ/tissue was normalized to the injected dose and expressed as the percentage of the injected dose per gram of tissue (% I D/g).
  • a representative maximum-intensity-projection PET image of 68 Ga-LW01025, 68 Ga-LW01029, 68 Ga-LW01107, 68 Ga-LW01108, 68 Ga-LW01110, 68 Ga-LW01142, 68 Ga-LW01158, and 68 Ga-LW01102 in mice bearing PC-3 tumor xenografts is shown in Figure 1.
  • Biodistribution data is shown in T ables 10 and 11 .
  • Table 10 Biodistribution data (at 1 h post-injection, %ID/g) of 68 Ga-LW01025, 68 Ga-LW01108, and 68 Ga-LW01110 in mice bearing PC-3 tumor xenografts.
  • Table 11 shows Biodistribution data of 68 Ga-LW01029, 68 Ga-LW01107, 68 Ga-LW01142, 68 Ga-LW01158, and 68 Ga-LW01102 and further completed distribution data of 68 Ga-LW01108 and 68 Ga-LW01110 in mice bearing PC-3 tumor xenografts.
  • Table 11 Biodistribution data (at 1 h post injection, %ID/g) in mice bearing PC-3 tumor xenografts.
  • LW01045 LW01059, LW01061 , LW01090, and LW01117 are as follows:
  • LW01045 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-ip-Thz-NH 2 ), LW01059
  • Table 12 HPLC Purification conditions and MS characterizations of LW01045, LW01059, LW01061, LW01090, and LW01117
  • Non-radioactive Ga-complexed standards of LW01045, LW01059, LW01061 , LW01090, and LW01117 were prepared according to the procedure set forth in Example 1 . Briefly, LW01045, LW01059, LW01061 , LW01090, and LW01117 were mixed and incubated with 0.5 mL NaOAc buffer (0.1 N, pH 4.2 - 4.5) and GaCI 3 (5 eq., 0.2 M) at 80 °C for 15 min and then purified with HPLC (C18 semi-prep column) and lyophilized. The HPLC conditions, retention times, isolated yields and MS confirmations of these non-radioactive Ga-complexed standards are provided in Table 13.
  • Table 13 HPLC purification conditions and MS characterizations of Ga-complexed LW01045, LW01059, LW01061, LW01090, and LW01117
  • Radiolabeled LW01045, LW01059, LW01090, and LW01117 were prepared according to the procedure set forth in Example 1 . Briefly, purified 68 Ga in 0.5 mL water was added into a 4-mL glass vial preloaded with 0.7 mL of HEPES buffer (2 M, pH 5.0) and 10 pL precursor solution (1 mM). The radiolabeling reaction was carried out under microwave heating for 1 min before being purified by HPLC using the semi-preparative column.
  • the eluate fraction containing the radiolabeled product was collected, diluted with water (50 mL), and passed through a C18 Sep-Pak cartridge that was pre-washed with ethanol (10 mL) and water (10 mL). After washing the C18 Sep-Pak cartridge with water (10 mL), the 68 Ga-labeled product was eluted off the cartridge with ethanol (0.4 mL), and diluted with saline for imaging and biodistribution. Quality control was performed using the analytical column. The tracers were obtained with more than 95% radiochemical purity.
  • the HPLC conditions and retention times are provided in Table 14.
  • Table 15 Binding affinities (Ki, nM) of GRPR-targeting peptides.
  • Table 16 Biodistribution data (at 1 h post-injection, %ID/g) of 68 Ga-LW01045, 6 8 Ga-LW0159, 68 Ga-LW01090, and 68 Ga-LW0117 in mice bearing PC-3 tumor xenografts.
  • Figures 90 and 11C show that 68 Ga-LW01045 and 68 Ga-LW01090 were sufficiently stable in vivo in NRG mice with 83.3 ⁇ 1.45% and 67.1 ⁇ 4.76% remaining intact in plasma post-injection.
  • the present invention has been described with regard to one or more embodiments.
  • LW02045 and LW02042 are as follows:
  • LW02045 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-N-MeGly-His-Leui Pro-NH 2 ), wherein i is a reduced peptide bond, was synthesized using standard Fmoc solid phase synthesis strategy starting from Sieber resin. Fmoc-LeuipPro-OH, Fmoc-protected amino acids, Fmoc-4-amino-(1-carboxymethyl)-piperidine and DOTA(tBu)3 were sequentially coupled to the resin.
  • LW02042 (DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Phe-Thz-NH 2 ) was synthesized using standard Fmoc solid phase synthesis. Fmoc-protected amino acids, Fmoc-4-amino-(1-carboxymethyl) piperidine and DOTA(tBu)3 were sequentially coupled to the Fmoc-Rink amide-MBHA resin.
  • ESI-MS calculated [M+2H]2+ for Ga-LW02045 C7eHn2GaN2oOi7S 823.90; found 823.86.
  • ESI-MS calculated [M+2H]2+ for Ga-LW02042 C 7 7Hi 0 4GaN 2 oOi8S 849.85; found 849.63.
  • mice NOD.Cg-Rag1tm1 Mom H2rgtm1Wjl/SzJ mice and conducted according to the guidelines established by the Canadian Council on Animal Care and approved by Animal Ethics Committee of the University of British Columbia.
  • mice were anesthetized by inhalation with 2% isoflurane in oxygen and implanted subcutaneously with 5 x 106 PC-3 cells below the left shoulder. Imaging and biodistribution studies were performed only after tumors grew to 5-8 mm in diameter.
  • mice were injected through the tail vein. Mice were allowed to recover and roam freely in the cages after injecting the tracer. At 45 min post-injection (p.i.), mice were sedated again and positioned on the scanner. First, a 10 min CT scan was conducted for localization and attenuation correction for reconstruction of PET images, before a 10 min PET image was acquired. Heating pads were used during the entire procedure to keep the mice warm. For ex vivo biodistribution studies, mice were injected with ⁇ 3 MBq of the 68Ga-labeled tracer.
  • mice were euthanized, blood was drawn from heart, and organs/tissues of interest were collected, rinsed with PBS, blotted dry, weighed, and counted using an automated gamma counter. The uptake in each organ/tissue was normalized to the injected dose and expressed as the percentage of the injected dose per gram of tissue (%ID/g) ( Figure 13 and Table 17).

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CA3246188A CA3246188A1 (en) 2022-03-25 2023-03-24 Radiolabeled compounds for in vivo imaging of the gastrin-releasing peptide (GRPR) receptor and treatment of GRPR-related disorders
EP23773418.1A EP4499663A1 (en) 2022-03-25 2023-03-24 Radiolabeled compounds for in vivo imaging of gastrin-releasing peptide receptor (grpr) and treatment of grpr-related disorders
AU2023239751A AU2023239751A1 (en) 2022-03-25 2023-03-24 Radiolabeled compounds for in vivo imaging of gastrin-releasing peptide receptor (grpr) and treatment of grpr-related disorders
JP2024556499A JP2025510161A (ja) 2022-03-25 2023-03-24 ガストリン放出ペプチド受容体（ｇｒｐｒ）のインビボイメージング及びｇｒｐｒ関連障害の治療のための放射性標識化合物
KR1020247035353A KR20250007523A (ko) 2022-03-25 2023-03-24 가스트린 방출 펩티드 수용체(grpr)를 생체 내에서 영상화하고 grpr 관련 장애를 치료하기 위한 방사성 표지된 화합물
CN202380029657.8A CN119213011A (zh) 2022-03-25 2023-03-24 用于胃泌素释放肽受体（grpr）体内成像和治疗grpr相关病症的放射性标记化合物
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