Compositions targeting bradykinin receptor b1 for medical imaging and treatment of cancer and other disorders

Abstract

Bradykinin B1 receptor (B1R) targeting compounds, and radiolabelled B1R targeting compounds and their use in in vivo medical imaging applications for imaging tissues or tumors expressing B1R, or in radiotherapy for treatment of a disease or condition in which B1R is expressed or overexpressed.

Description

COMPOSITIONS TARGETING BRADYKININ RECEPTOR Bl FORMEDICAL IMAGING AND TREATMENT OF CANCER AND OTHERDISORDERSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application ciaims benefit to U.S. Provisional Patent Application No. 63 / 619,475, filed January 10, 2024. The entire content of the above application is incorporated by reference as if recited in full herein.FIELD OF THE INVENTION

[0002] The present invention relates to the fields of medical imaging and radiotherapy and, in particular, to compounds that may be radiolabelled for imaging or treating tissues or tumors expressing the bradykinin B l receptor.INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0003] This application contains references to amino acids and / or nucleic acid sequences that have been filed concurrently herewith as sequence listing XML file “A9OC-029WO-seq.xml”, file size of 29,602 bytes, created on December 30, 2024. The aforementioned sequence listing is hereby incorporated by reference in its entirety pursuant to 37 C.F.R. § 1.52(e)(5).BACKGROUND OF THE INVENTION

[0004] Bradykinin Bl and B2 receptors (B1R and B2R) are G protein-coupled receptors (GPCRs) and have long been known to have an important role in pain and inflammation pathways (Campos et al, TRENDS in Pharmacological Sciences 2006, 27:646-651; Calixto et al, British Journal of Pharmacology 2004, 143:803-818). The peptides, bradykinin (BK; Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg (SEQ ID NO: 1)) and kallidin (Lys-BK; Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg (SEQ ID NO: 2)), are produced by enzymatic cleavage of kininogens and act as the endogenous agonists for the constitutively expressed and widely distributed B2R (Leeb-Lundberg et al.Pharmacological Reviews 2005, 57:27-77). The removal of the C-terminal Arg from BK and kallidin by carboxypeptidase N generates [des-Arg9]BK and [desArg1°]kallidin, respectively, which are the natural agonists for the inducible B1R (Leeb-Lundberg et al, ibid.).

[0005] B1R is known to be involved in various types of pain and inflammatory syndromes (Calixto et al, British Journal of Pharmacology, 2004, 143:803-818), cardiovascular inflammatory pathologies, such as endotoxic shock, atheromatous disease and myocardial ischemia (McLean et al, Cardiovascular Research, 2000, 48: 194-210) and a variety of cancers (Molina et al. Breast Cancer Research and Treatment 2009, 118:499-510: Taub et al. Cancer Research 2003, 63:2037-2041;Chee et al. Biological Chemistry 2008, 389:1225-1233; Yang et al, Journal of Cellular Biochemistry 2010, 109:82-92: Raidoo et al, Immunopharmacology’ 1999, 43:255-263; and Wu et al, International Journal of Cancer 2002, 98:29-35).

[0006] Receptors such as B1R can be useful targets for various in vivo imaging techniques (see, Mankoff et al., Journal of Nuclear Medicine, 2008, 49:149S-163S), such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) which employ radionuclides. B1R receptor targeting moieties also hold promise for radiotherapeutic methods to selectively bind and kill cancer cells using radionuclides. For both diagnostic and therapeutic methods, the targeting moieties ideally have a relatively high uptake in the targeted tissue and / or cells, as compared to uptake in otherwise normal or healthy cells and tissues.

[0007] While certain B 1 R- targeting radiopharmaceuticals for cancer imaging and therapy have been explored (see Lau et al., Pharmaceuticals (Basel) 2020; 13(8): 199; and U.S. Patent No. 10,039,846 to Lin et al, issued August 7, 2018), including the compound [68Ga]Ga-Z02176 (6SGa-DOTA-Pip-Lys!-Lys2-Arg3-Pro4-Hyp5-Gly6-Cpg7-Ser8-D-Tic9-Cpg10(SEQ ID NO: 3)), (Zhang et al., Mol Pharmaceutics 2016;13(8):2823), there remains a need for B 1 R-targeting radiopharmaceuticals with enhanced specificity.SUMMARY OF THE INVENTION

[0008] The present invention relates generally to compositions targeting bradykinin Bl receptor for in vivo medical imaging of cancer and other disorders, as well as for radiotherapeutic treatments. In accordance with one aspect, the invention relates to a bradykinin Bl receptor (B1R) targeting compound comprising a peptidic compound that selectively binds to B1R, and that may be optionally radiolabelled with a radiolabel suitable for in vivo imaging or radiotherapy.

[0009] Certain embodiments of the invention relate to B1R targeting compounds of the general Formula I (below) that are antagonists of the Bradykinin Bl receptor (B1R) and, when labelled with the appropriate diagnostic or radiotherapeutic isotope, are useful for the in-vivo imaging or therapy of subjects with diseases or disorders characterized by aberrant / ectopic expression of B1R. These diseases include but are not limited to various forms of cancer including esophageal, cervical, gastric, prostate, breast, lung, and renal cancers.

[0010] In one embodiment, the B 1 R targeting compound comprises general Formula (I) below, or a pharmaceutically acceptable salt of solvate thereof:Xaa1- Xaa2-Xaa3- Pro4-Hyp5-Gly6-Cpg7-Ser8-D-Tic9-Cpg10(I) (SEQ ID NO: 4) wherein:Xaa1, Xaa2and Xaa3are independently a proteinogenic or non-proteinogenic amino acid, with the proviso that at least one of Xaa1, Xaa2and Xaa3is a non- proteinogenic amino acid.

[0011] According to one embodiment, the B1R targeting compound comprising general Formula (I) comprises the sequence Lys1-Lys(Me2)2-Arg3-Pro4-Hyp:'-Gly6- Cpg'-Ser8-D-Tic9-Cpg!<>(SEQ ID NO: 5), which can optionally be labelled with the chelator DOTA (l,4,7,10-tetraazacyclododecane-l,4,7,10-tetraacetic acid) via the linker 4-amino-l-carboxymethylpiperidine (Pip) to provide the radionuclide-chelator containing compound DOTA-Pip-Lysi-Lys(Me2)2-Arg3-Pro4-Hyp5-Gly6-Cpg7-Sers-D- Tic9-Cpg10(HTK-AO7O18) (SEQ ID NO: 5). In yet another embodiment, the B1R targeting compound comprising general Formula (I) comprises the sequence Lys(Me2)1-Lys(Me2)2-Arg-’-Pro4-Hyp5-Gly6-Cpg7-Ser8-D-Tic9-Cpgie(SEQ ID NO: 6),which can optionally be labelled with the chelator DOTA via the linker Pip to provide the radionuclide-chelator containing compound DOTA-Pip-Lys(Me2)1-Lys(Me2)2-Arg3- Pro4-Hyi?5-Gly6-Cpg7-Sers-D-Tic9-Cpg’° (HTK-A07016) (SEQ ID NO: 6). In yet another embodiment, the B1R targeting compound comprising general Formula (I) comprises the sequence Lys(Me;)i-Lys2-Arg!-Pro4-Hyp5-Giy'’-Cpg’-Serx-D-Tic<i-Cpgli)(SEQ ID NO: 7), which can optionally be labelled with the chelator DOTA via the linker Pip to provide the radionuclide-chelator containing compound DOTA-Pip- Lys(Me2)I-Lys2-Arg3-Pro4-Hyp5-Gly6-Cpg7-Sers-D-Tic9-Cpg10(HTK-AO7O17) (SEQ ID NO: 7). In certain embodiments, these and other compounds according to the invention can be radiolabeled with6SGa, to provide radiolabelled compounds useful for in-vivo PET imaging of tissues expressing B1R. Accordingly, these and other compounds and compositions according to embodiments of the in vention are useful for the diagnosis and detection of diseases or disorders characterized by aberrant / ectopic expression of the B 1R, including but not limited to various forms of cancer. According to certain further embodiments of the invention, the radionuclide68Ga may be replaced by other trivalent radiometals such asWY ori77Lu, which can form stable complexes with DOTA. Such compounds (representing a theranostic pair with [68Ga]Ga-HTK- A07018) may serve as radiotherapeutic agents for treatment of disorder or diseases (including but not limited to cancer) characterized by aberrant / ectopic expression of B1R. In an alternative aspect of the invention, the chelator DOTA may be substituted / replaced by other suitable chelators including but not limited to other radiometal chelators such as DOTAGA, NOTA, or NODAGA, or trifluoroborate for radiolabeling with fluorine-18 (!8F).

[0012] In accordance with another aspect, the invention relates to a use of a radio- labelled bradykinin Bl receptor (B1R) targeting compound for in vivo imaging of a tissue or cancer expressing or overexpressing B1R, the radio-labelled B1R targeting compound comprising a peptidic compound that selectively binds to B1R and a radiolabel suitable for in vivo imaging.

[0013] In accordance with another aspect, the invention relates to a method for imaging a tissue or cancer expressing or overexpressing bradykinin B l receptor (B1R) in a patient, comprising administering to the patient a radio-labelled B1R targetingcompound comprising a peptidic compound that selectively binds to BIR and a radiolabel suitable for in vivo imaging.

[0014] In certain embodiments, in the uses for, and methods of, in vivo imaging, the B1R targeting compound, which may be radiolabelled, is a peptidic compound having general Formula (II):B- L-Xaa1- Xaa2-Xaa3- Pro4-Hyp5-Gly6-Cpg7-Sers-D-Tic9-Cpg10(II) (SEQ ID NO: 8) wherein:B is selected from the group consisting of (i) radiolabelled moieties, (ii) radiometal chelating agents, (iii) moieties configured for19F / !SF exchange, and (iv) boronate precursors tha t are capab le of conversion to an18F-labeled tri fluoroborate;L is a linker; andXaa1, Xaa2and Xaa3are independently (i) a bond, or (ii) a protemogenic or non- proteinogenic amino acid, with the proviso that either ( 1 ) at least one of Xaa1, Xaa2and Xaa3is a bond or a non-proteinogenic amino acid, or (2) L is a bond or a linking moiety that is other than 4-amino-(l-carboxymethyl)piperidine (Pip) or 9-amino-4,7- dioxanonanoic acid.

[0015] In one embodiment, the radiolabelled BIR targeting compound for in vivo imaging is DOTA-Pip-Lys1-Lys(Me2)2-Arg3-Pro4-Hyp5-Gly6-Cpg7-Ser8-D-Tic9-Cpgi0(HTK-AO7O18) (SEQ ID NO: 5), and the DOTA chelator is complexed with an imaging radionuclide such as6sGa.

[0016] In accordance with another aspect, the invention relates to a use of a radio- labelled bradykinin Bl receptor (BIR) targeting compound in radiotherapy for treatment of a disease or condition in which BIR is expressed or overexpressed, wherein the radio-labelled BIR targeting compound comprises a peptidic compound that selectively binds to BIR and a radiolabel suitable for radiotherapy.

[0017] In accordance with another aspect, the invention relates to a method of radiotherapy to treat a disease or condition in which bradykinin Bl receptor (B1R) is expressed or overexpressed in a patient, comprising administering to the patient a radio-labelled B1R targeting compound comprising a peptidic compound that selectively binds to B1R and a radiolabel suitable for radiotherapy.

[0018] In certain embodiments, in the uses for, and methods of, radiotherapy, the B1R targeting compound, which may be radiolabelled, is a peptidic compound having general Formula (II):B- L-Xaa1- Xaa2-Xaa3- Pro4-Hyp5-Gly's-Cpg7-Ser8-D-Tic'5-Cpg10(II) (SEQ ID NO: 8) wherein:B is selected from the group consisting of (i) radiolabelled moieties, and (ii) radiometal chelating agents;L is a linker; and Xaa1, Xaa2and Xaa3are independently (i) a bond, or (ii) a protemogenic or non- proteinogenic amino acid, with the proviso that either (1) at least one of Xaa1, Xaa2and Xaa3is a bond or a non- proteinogenic amino acid, or (2) L is a bond or a linking moiety that is other than 4-amino-(l-carboxymethyl)piperidine (Pip) or 9-amino-4,7- dioxanonanoic acid.

[0019] In one embodiment, the radiolabelled B1R targeting compound for radiotherapy is DOTA-Pip-Lys!-Lys(Me2)2-Arg3- Pro4-Hyp5-Gly6-Cpg7-Sers-D-Tic9- Cpgw(HTK-A07018) (SEQ ID NO: 5), and the DOTA chelator is complexed with a radiotherapeutic nuclide, such as177Lu or225Ac.

[0020] Further aspects of the invention will become apparent from consideration of the ensuing description of preferred embodiments of the invention. A person skilled in the art will realise that other embodiments of the invention are possible and that the details of the invention can be modified in a number of respects, all without departingfrom the inventive concept. Thus, the following drawings, descriptions and examples are to be regarded as illustrative in nature and not restrictive.BRIEF DESCRIPTION OF THE DRA WINGS

[0021] These and other features of the invention will become more apparent in the following detailed description in which reference is made to the appended drawings.

[0022] Figure 1 depicts chemical structures of (A) HTK-A07013, (B) HTK-A07015, (C) HTK- A07016, (D) HTK-A07017 and (E) HTK-A07018.

[0023] Figure 2 depicts chemical structures of (A) HTK-A07019, (B) HTK-A07020, (C) HTK-A07030 and (D) HTK-A07031.

[0024] Figure 3 depicts chemical structures of (A) AR01001, (B) AR01002, (C) AR01003 and (D) AR01004.

[0025] Figure 4 shows images of PET maximal intensity projections of68Ga-labeled peptides at 1 h post-injection in HEK293T::hBlR tumor-bearing male mice. The scale bar is in units of %ID / g from 0 to 15. t = tumor; k = kidney; bl = bladder.

[0026] Figure 5 is a table of biodistribution data (%ID / g) of |feGa|Ga-ZO2 l 76, [6SGa]Ga-HTK-A07013, [6SGa]Ga-HTK-A07015, [68Ga]Ga-HTK-A07016, and[68Ga]Ga-HTK-A07017 in HEK293T::hBl R tumor-bearing male mice at 1 h postinjection.

[0027] Figure 6 is a table of biodistribution data (%ID / g) of [6SGa]Ga-HTK-A07018, [bSGa]Ga-HTK-A07019, [6sGa]Ga-HTK-A07020, [S8Ga]Ga-HTK-A07030, and HTK- A07031 in HEK293T: :hBlR tumor-bearing male mice at 1 h post-injection.DETAILED DESCRIPTION OF THE INVENTION

[0028] In a broad aspect, the invention relates to bradykinin Bl receptor (B1R) targeting compounds that are optionally radiolabelled, and their use in in vivo medical imaging applications for imaging tissues or tumors expressing B1R, or in radiotherapy for treatment of a disease or condition in which B1 R is expressed, particularly for imaging tissues or tumors, and / or treatment of a disease or condition where B1R is aberrantly expressed, ectopically expressed, or overexpressed. Accordingly, in certain embodiments, the invention relates to radio-labelled B1R targeting compounds comprising a compound that selectively binds to B1R and a radiolabel suitable for in vivo imaging or radiotherapy, and to precursors of such B1R targeting compounds that may subsequently be radio-labelled.

[0029] In one aspect, the invention relates to B1R targeting compounds, and radiolabelled compositions containing the compounds, for use as imaging probes, which selectively bind to B1R and are suitable for in vivo imaging, for example positron emission tomography (PET) or single photon emission computed tomography (SPECT) based imaging, of patients having a disease or disorder in which B1R is expressed such as, for example, cancer, an inflammatory condition, an infection or cardiovascular disease.

[0030] In another broad aspect, the invention relates to B1R targeting compounds, and radiolabelled compositions containing the compounds, which selectively bind to B1R and are suitable for treatment of patients having a disease or disorder in which B1R is expressed such as, for example, cancer, an inflammatory condition, an infection or cardiovascular disease.

[0031] Certain embodiments relate to unlabelled precursors of the above compounds and compositions, which can subsequently be radio-labelled and used as probes or therapeutic compositions. The radiolabel may be introduced, for example, by incorporating a radiolabel by readily available synthetic procedures, such as “click” chemistry, or via a chelating moiety comprised by the precursor which is capable of chelating a suitable radiolabel, or other methods.

[0032] In certain embodiments, the invention relates to the use of the B1R targeting compounds, and radiolabelled compositions containing the compounds, for the detection and early diagnosis of breast cancer, prostate cancer, lung cancer, esophageal cancer, cervical cancer, gastric cancer, renal cancer, or other malignancies. In some embodiments, the invention relates to the use of the peptidic imaging probes as adjunct imaging agents for the diagnosis of breast cancer.

[0033] In certain embodiments, the invention relates to the use of B1R targeting compounds, and radiolabelled compositions containing the compounds, for monitoring response to therapy for a disease or condition in which B1R is expressed such as, for example, cancer, inflammatory disease, infection or cardiovascular disease.

[0034] In certain embodiments, the invention relates to the use of B1R targeting compounds, and radiolabelled compositions containing the compounds, in diagnostic procedures (non-invasive detection of B1R expression by diagnostic imaging) for predicting response of patients to treatment with B1R antagonists and selecting patients for treatment accordingly.

[0035] In certain embodiments, the invention relates to the use of B1R targeting sequences and compounds, and radiolabelled compositions containing the compounds, for radiotherapeutic treatment of breast cancer, prostate cancer, lung cancer, esophageal cancer, cervical cancer, gastric cancer, renal cancer, or other malignancies.

[0036] Based on the data provided in the Examples, the B 1R targeting compounds are expected to show high contrast, rapid renal clearance, minimal non-target organ uptake, and high tumour to normal tissue ratios, which properties make these compounds well- suited for use as diagnostic imaging agents and for radiotherapy applications.Definitions

[0037] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0038] It is contemplated that any embodiment discussed herein can be implemented with respect to any method, use or composition of the invention, and vice versa. Furthermore, compositions and kits of the invention can be used to achieve methods and uses of the invention.

[0039] As used herein, the term “about” refers to an approximately -s- / -10% variation from a given value. It is to be understood that such a variation is always included in any given value provided herein, whether or not it is specifically referred to.

[0040] The terms “subject” and “patient” as used herein refer to an animal in need of treatment.

[0041] The term “animal,” as used herein, refers to both human and non-human animals, including, but not limited to, mammals, birds and fish, and encompasses domestic, farm, zoo, laboratory and wild animals, such as, for example, cows, pigs, horses, goats, sheep and other hoofed animals; dogs; cats; chickens; ducks; non-human primates; guinea pigs; rabbits; ferrets; rats; hamsters and mice.

[0042] 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.”

[0043] The term “Xaa” as used herein may be an amino acid, an amino acid mimetic or an amino acid derivative, or may simply indicate the presence of a bond between adjacent moieties. It is to be understood, that the term amino acid encompasses not only a-amino acids, but also other amino acids such as [F, y- or 8-amino acids, and so forth. In embodiments, where Xaa is a chiral a-amino acid, Xaa may be present in its L- or D- foitn. In embodiments, where Xaa is a chiral P-, y- or 8-amino acid, Xaa may be present in its S- or R-form. Thus, in its broadest sense, the term “amino acid”, as used herein, may refer to any organic compound that contains an amino group (-NH?) and a carboxyl group (-COOH). Thus, whenever the residue Xaa is referred to as an amino acid throughout this disclosure, it is to be understood that the term amino acid may also encompass amino acid mimetics or derivatives.

[0044] The term “proteinogenic amino acid” as used herein refers to the 22 amino acids that can be incorporated biosynthetically into proteins during translation, and which includes the 20 amino acids that are in the standard genetic code, specifically alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine, as well as the 2 additional amino acids (selenocysteine and pyrrolysine) that can be incorporated by special translation mechanisms. The term “non-proteinogenic amino acid” as used herein refers to all other amino acids that are distinct from tlie proteinogenic amino acids, and includes non-canonical amino acids as well as non-natural or synthetic amino acids.

[0045] Further, it is to be understood that the term amino acid is not limited to the known set of proteinogenic amino acids, namely alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine (along with pyrrolysine and selenocysteine), but also encompasses non-canonical and non-natural amino acids. A “non-canonical amino acid”, as used herein, may be any amino acid that is not part of the set of proteinogenic amino acids, but that can be obtained from a natural source. However, it has to be noted that some non-canonical amino acids may also be found in naturally occurring peptides and / or proteins.

[0046] A “non-natural amino acid” or “synthetic amino acid”, as used herein, may be any molecule that falls under the general definition of an amino acid, i.e., that comprises an amino group and a carboxyl group, but that is not found in nature. Thus, non-natural amino acids are preferably obtained by chemical synthesis. It is to be understood that the differentiation between a non-canonical amino acid and a non- natural amino acid may be uncertain in some instances. For example, an amino acid that is defined as a non-natural amino acid may be, at a later time point, identified in nature and thus reclassified as a non-canonical amino acid.

[0047] In certain embodiments, the residue Xaa may be an amino acid mimetic. The term “amino acid mimetic”, as used herein, refers to a compound that has a structure that is different from a particular amino acid, but that functions in a manner similar tosaid particular amino acid and may thus be used to replace said particular amino acid. An amino acid mimetic is said to function in a similar manner as a particular amino acid, if it fulfils, at least to some extent, similar structural and / or functional features as the amino acid it mimics.

[0048] In certain embodiments, the residue Xaa may be an amino acid derivative. The term “amino acid derivative” refers to an amino acid as defined herein, wherein one or more functional groups comprised in the amino acid is (are) modified or substituted. An amino acid derivative may preferably be a derivative of a proteinogenic or non- proteinogenic amino acid. In an amino acid derivative, any functional group may be substituted or modified.

[0049] As used herein, the term “peptidic compound” refers to a compound having at least two or more amino acids (including naturally occurring, non-natural ly occurring, or modified ammo acids) that are joined through amide bond formation involving the carboxyl group of one amino acid and the amino group of the adjacent amino acid, with the chemical bond between the carbon and nitrogen atoms of each amide group forming the “peptide bond,” Accordingly, “peptidic compounds” as described herein may be entirely composed of amino acids (proteinogenic, non-proteinogenic, naturally occurring, non-naturally occurring, canonical, non-canonical, or otherwise modified amino acids) linked together through peptide bonds, or may have just a few or even only a single peptide bond between adjacent amino acids (proteinogenic, non- proteinogenic, naturally occurring, non-naturally occurring, canonical, non-canonical, or otherwise modified). The “peptidic compounds” as described herein may also, in certain embodiments, comprise moieties other than amino acid moieties that make up the chemical structure of the compounds, such as other non-amino acid moieties (e.g. DOTA or a linker L) that may be joined via an amide bond.

[0050] As used herein, the terms “comprising,” “having,” “including” and “containing,” and grammatical variations thereof, are inclusive or open-ended and do not exclude additional, unrecited elements and / or method steps. The term “consisting essentially of’ when used herein in connection with a composition, use or method, denotes that additional elements and / or method steps may be present, but that theseadditions do not materially affect the manner in which the recited composition, method or use functions. The term “consisting of’ when used herein in connection with a composition, use or method, excludes the presence of additional elements and / or method steps. A 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.

[0051] Naturally occurring amino acids are identified throughout by the conventional three- or one-letter abbreviations indicated in Table 1 below, which are as generally accepted in the peptide art and recommended by the IUPAC-IUB commission in biochemical nomenclature.Table 1. Amino acid codes

[0052] The peptide sequences set out herein are widen according to the generally accepted convention whereby the N-terminal amino acid is on the left and the C- terminal amino acid is on the right. By convention, L-amino acids are represented by upper case letters and D-ainino acids by lower case letters or preceded by the designation “D.”BRADYKININ Bl RECEPTOR (B1R) TARGETING COMPOUNDS

[0053] The bradykinin Bl receptor (B1R) targeting compounds that may be radiolabelled as described herein may be peptidic compounds that specifically bind to B1R. The radio-labelled peptidic B1R targeting compounds comprise a B1R targeting moiety that is capable of binding to B1R attached via a linker to a radiolabelled moiety. The radiolabel may be incorporated into the radiolabelled moiety via a covalent bond or via chelation.

[0054] Various peptide-based compounds that are capable of binding to B1R are known in the art and may serve as B1R targeting moieties in accordance with certain embodiments of the invention. These compounds include known peptide agonists and antagonists of B1R.

[0055] In certain embodiments, B1R targeting moieties for radio-labelling may be derived from a potent agonist or antagonist peptidic compound, ideally with high binding affinity and selectivity for B1R. For example, B 1R targeting moieties used to prepare radio-labelled peptidic compounds may be modified versions of one of the natural B1R agonists: [des-Arg9]-BK and [des-Arg!0]-kallidin. Examples of B1R targeting moieties (antagonists and agonists) are provided in Tables 2 and 3.Table 2: Peptidic B1R Antagonists1Abbreviations for non-naturally occurring amino acids are as follows:Cha: P-eyclohexylalanine;Cpg: a -cyclopentylglycineHyp: hydroxyproiine Igl: 2-indanylgiycine(otMe)Phe: a-methylphenylalanine f!Nal: p-napthylalanineOic: octahydroindole-2-cafboxylic acidOrn: ornithine Thi: 2-thienylalanineTic: 1 ,2,3 ,4-tetrahydroisoquinoline-3-carboxylic acidTable 3: Peptidic B1R Agonists

[0056] Other examples include, but are not limited to, the peptidic B1R antagonists described in International Patent Application Publication No. WO98 / 07746 and in U.S. Patent Application Publication No. US2008 / 0064642, as well as the peptidic B1R targeting compounds described in U.S. Patent No. 10,039,846 and the article to Zhang el al. Molecular Pharmaceutics 2016, 13:2823-2832.

[0057] In certain embodiments of the invention, the B1R targeting compound comprises a modified version of a parental peptide corresponding to any one of those in Tables 2 and 3. Modified amino acid sequences include, for example, sequences that differ from a parental amino acid sequence in that they comprise one or more amino acid substitutions, additions and / or deletions. Substitutions include substitution of a proteinogenic amino acid with a different proteinogenic amino acid, as well as substitution of a proteinogenic amino acid with a non- proteinogenic amino acid. Substitutions may also include substitution of a non- proteinogenic amino acid with a different non- proteinogenic amino acid, as well as substitution with a proteinogenic amino acid. The substituted amino acid may provide the same functionality as the amino acid it replaces or it may provide a different or additional functionality.

[0058] Examples of non-proteinogenic, non-canonical and non-naturally occurring amino acids include, but are not limited to, D-amino acids (i.e. an ammo acid of an opposite chirality to the naturally occurring form), N-a-methyl amino acids, C-a- methyl amino acids, p-methyl amino acids and D- or L-fl-amino acids. More specific examples include, but are not limited to, 2-aminobutyric acid (Abu), 4-aminobutyric acid (y-Abu), 6-aminohexanoic acid (g-Ahx or Ahx), a-aminoisobutync acid (Alb), p- alanine (P-Ala), P-aspartic acid (P-Asp), P-cyclohexylalanine (Cha), a- cyclohexylglycine (Chg), citrulline (Cit), diaminobutyric acid (Dab), diaminopimelic acid (Dap), y-glutamic acid (y-Glu), pyroglutamic acid (pGlu), homocysteine (Hey), homoserine (Hse), hydroxyproline (Hyp), N-s-dinitrophenyl-lysine (Lys(Dnp)), N-s- methyl-lysine (Lys(Me)), N,N-E-dimethyl-lysine (LysfMe?), N,N,N-e-trimethyl-lysine (Lys(Me3)), N-s-isopropyl-lysine (Lys(iPr)), S-2-amino-5-(aminooxy)pentanoic acid (L-homocanaline, also called hCan), A®-monomethyl-L-arginine (Arg(Me)), asymmetric dimethylarginine (Arg(Me2)), symmetric dimethylarginine(Arg(Me,Me)), 3-mercaptopropionic acid (Mpa), L-l-napthylalanine (L-l-Nal), L-2- napthylalanine (L-2-Nal), norleucine (Nle), norvaline (Nva), norleucine (Nle), ornithine (Om), 3-(2-pyridyl)-L-alanine (L-2-Pal), 3-(3-pyridyl)-L-alanine (L-2-Pal), 3-(4- pyridyl)-L-alamne (L-4-Pal), penacillamine (Pen), 4-chlorophenyl-L-alanine (L-4-C1- Phe), 4-fluorophenyl-L-alanine (L-4-F-Phe), 4-iodophenyl-L-alanine (L-4-I-Phe), 4- nitrophenyi-L-alanine (L-4-NO2-Phe). phenylglycine (Phg), sarcosine (Sar), Dimethyl -tryptophan (D-2-Me-Trp), phosphor-serine (pSer), phosphor-threonine (pThr), phosphor-tyrosine (pTyr), 1 l-amino-3.6.9,-trioxa-undecanoic acid (mini-PEG), cysteic acid, cyclohexylalanine, t-butylglycine, t-butylalanine, 3 -aminopropionic acid, 2,3- diaminopropionic acid (2,3-diaP), D-2-naphthylalanine (D-2-NaI), 1, 2,3,4- tetrahydroisoquiiioline-3-carboxylic acid (Tic), octahydroindole-2-carboxylic acid (Oic), a-cyclopentylglycine (Cpg), 2-indanylglycine (Igl), D- or L-2-thienylalanine (Thi), D- or L-3-thienylalanine, D- or L-1-, 2-, 3- or 4-pyrenylalanine, D-(2-pyridinyi)- alanine, D-(3-pyridinyl)-alanine, D- or L-(2-pyrazmyl)-alanine, D- or L-(4-isopropyl)- phenylglycine , D-( trifluoromethyll-phenylglycine , D-(tri fluoromethyl)-phenylalanine, D-p-fluorophenylalanine, D- or L-p-biphenylalanine, D- or L-p- methoxybiphenylalanine, methionine sulphoxide (MSO) and homoarginine (Har). Other examples include substituted fl-alanine (p-Ala) comprising one or more substituents selected from arylsulphonyl (such as benzenesulphonyl or 2-naphthalene sulphonyl) and alkoxycarbonyl (such as t-butoxycarbonyl); phosphono- or sulphated (e.g. -SOsH) non-carboxylate amino acids; D- or L-2-indole(alkyl)alanines, and D- or L-alkylalanines, wherein alkyl is substituted or unsubstituted methyl, ethyl, propyl, hexyl, butyl, pentyl, hexyl, octyl, isopropyl, iso-butyl, or iso-pentyl.

[0059] Additions and deletion that may be comprised by a modified amino acid sequence include addition or deletion of one or more amino acids at the N-terminus, the C-terminus or both termini of the parental peptide, as well as addition or deletion of one or more internal amino acids.

[0060] In certain embodiments of the invention, the BIR targeting moiety comprises a modified version of the parental peptide corresponding to B-9958 in Table 2, Lys- Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-D-Tic-Cpg (SEQ ID NO: 18). In some embodiments, the BIR targeting moiety comprises a modified version of the parental peptide B-9958that comprises addition or deletion of one or more amino acids at the N-terminus. In some embodiments, the B1R targeting moiety comprises a modified version of the parental peptide B-9958 that comprises one or more deletions of an amino acid at one or more of positions 1, 2 and 3, such as at position 1. In some embodiments, the B1R targeting moiety comprises a modified version of the parental peptide B-9958 that comprises substitution of the amino acid at one or more of positions I, 2 and 3 with a proteinogenic or non-proteinogenic amino acid. In certain embodiments, the B1R targeting moiety comprises a modified version of the parental peptide B-9958 that comprises substitution of the amino acid at each of positions 1 and 2 with a proteinogenic or non-proteinogenic amino acid. In certain embodiments, the B1R targeting moiety comprises a modified version of the parental peptide B-9958 that comprises substitution of the amino acid at position 1 with a proteinogenic or non- proteinogenic amino acid. In certain embodiments, the B1R targeting moiety comprises a modified version of the parental peptide B-9958 that comprises substitution of the amino acid at position 2 with a proteinogenic or non-proteinogenic amino acid. In certain embodiments, the B1R targeting moiety comprises a modified version of the parental peptide B-9958 that comprises substitution of the amino acid at position 3 with a proteinogenic or non-proteinogenic amino acid.

[0061] Certain embodiments of the invention relate to BIR-specific PET / SPECT imaging or radio-therapeutic probes for diagnosis or treatment of diseases (including but not limited to cancer, inflammation, infection and cardiovascular disease) having an amino-acid sequence that is 70 %, 80%, 90%, 95% or 99% identical to the amino-acid sequences of the compounds disclosed in Tables 2 and 3, such as the compound B- 9958. For example, embodiments of the invention may relate to replacement of the naturally occurring amino acids Lys and Arg at one or more of positions 1 to 3 with other non-proteinogenic amino acids, such as ornithine (Om), N-e-methyl-lysine (Lys(Me)), N,N-E-dimethyl-lysine (Lys(Me2)), N,N,N-£-trimethyl-lysine (Lys(Mes)), N-s-isopropyl-lysine (Lys(iPr)), A°’-monomethyl-L-arginine (Arg(Me)), asymmetric dimethylarginine (Arg(Me2», symmetric dimethyiarginine (Arg(Me,Me)), and S-2- amino-5-(aminooxy)pentanoic acid (hCan), and may also involve deletion of thenaturally occurring amino acids Lys and Arg at one or of the positions 1 to 3 of the sequence.

[0062] In certain embodiments, the B1R targeting moiety comprises a B1R targeting compound comprising general Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Xaa1- Xaa2-Xaa3- Pro4-Hyp5-Gly6-Cpg7-Ser8-D-Tic9-Cpg10(I) (SEQ ID NO: 4) wherein:Xaa1, Xaa2and Xaa3are independently a proteinogenic or non-proteinogenic amino acid, with the proviso that at least one of Xaa1, Xaa2and Xaa3is a non- proteinogenic amino acid.

[0063] In certain embodiments, at least one of Xaa1, Xaa2and Xaa3in general Formula (I) is a proteinogenic or non-proteinogenic amino acid having a side chain R corresponding to Formula (III) below:-CHj-CTL-X’-X2(III) whereX1is a bond or (-CH2-)n group, where n can be 1 to 3, andX2is selected from the group consisting of -NR!2, -NH-C(=NR1)-NR12, and -O- NRb, with each R' independently being any selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl and isobutyl.

[0064] According to certain embodiments, the B1R targeting compound of general Formula (I) distinguishes from B-9958, at least in that one or more of the amino acids at positions 1 through 3 have been replaced with a non-proteinogenic amino acid. Accordingly, in one embodiment, the B1R targeting compound of general Formula (I) has the proviso that at least one of Xaa1and Xaa2is other than Lys. According to another embodiment, the B1R targeting compound of general Formula (I) has the proviso that Xaa2is other than Arg. In certain embodiments, in the B1R targeting compound of general Formula (I): X1is -CH2-, -CH2-CH2- or -CH2-CH2-CH2-. In certain further embodiments, X2in general Formula (I) is any selected from the groupconsisting of -NI K -NHCFK -NCCFLK -N(CH3)3, -NHCH(CHs)2, -NH-C(=NH)-NH2, -NH-C(=NCH3)-NH2, -NH-C(=NCH3)-NHCH3, -NH-C(=NH)-N(CH3)2 and -O-NH2. In yet another embodiment, Xaa1, Xaa2and Xaa3in general Formula (I) are any selected from the group consisting of Lys, Lys(Me), N,N-E-dimethyl-lysine (Lys(Me2))» Lys(Me)?, ornithine (Om), S-2-amino-5-(aminooxy)pentanoic acid (hCan), Arg, Arg(Me), Arg(Me2), Arg(Me,Me) and N-e-isopropyl-lysine (Lys(iPr)). In another embodiment, two or more of Xaa1, Xaa2and Xaa3are non-proteinogenic amino acids. In yet another embodiment, at least one of Xaa1, Xaa2and Xaa3in general Formula (I) are any selected from the group consisting of Lys(Me2), Om, hCan, and Lys(iPr). According to one embodiment, Xaa1in general Formula (I) is any selected from the group consisting of Lys, Lys(Me), Lys(Me2) and Lys(Me3). In one embodiment, Xaa2in general Formula (I) is any selected from the group consisting of Lys, Om, Lys(Me2), and hCan. In one embodiment, Xaa1in general Formula (I) is any selected from the group consisting of Arg, Arg(Me), Arg(Me2), Arg(Me,Me), and Lys(iPr). In yet another embodiment, at least one of Xaa1and Xaa2are Lys(Me2) in general Formula(I). In another embodiment, both of Xaa1and Xaa2in general Formula (I) are Lys(Me2). In one embodiment, Xaa1and Xaa2are Lys in general Formula (I). In another embodiment, Xaa1is Lys and Xaa3is Arg in general Formula (I). In yet another embodiment, Xaa2is Lys and Xaa3is Arg in general Formula (I).

[0065] According to one embodiment, the B1R targeting compound of general Formula (I) comprises any of the following sequences:(1) Lys-Orn-Arg-Pro-Hyp-Gly-Cpg-Ser-D-Tic-Cpg (SEQ ID NO: 26)(2) Lys(Me2)- Lys(Me2)-Arg-Pro-Hy'p-Gly-Cpg-Ser-D-Tic-Cpg (SEQ ID NO: 6)(3) Lys(Me2)-Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-D-Tic-Cpg (SEQ ID NO: 7)(4) Lys- Lys(Me2)-Arg-Pro-Hyp-Gly-Cpg-Ser-D-Tic-Cpg (SEQ ID NO: 5)(5) Lys-hCan-Arg-Pro-Hyp-Gly-Cpg-Ser-D-Tic-Cpg (SEQ ID NO: 27)(6) Lys- Lys-Lys(iPr)-Pro-Hyp-Gly-Cpg-Ser-D-Tic-Cpg (SEQ ID NO: 28)

[0066] According to certain embodiments, the B1R targeting compounds are radio- labelled at a position which is not required for receptor binding and which is separatedfrom the BIR targeting compound via a linker of appropriate length to minimize interference of the radiolabelled moiety with receptor binding.

[0067] In general, suitable linkers are between about 2 and about 50 atoms in length, for example, between about 2 and about 45 atoms in length, between about 2 and about 40 atoms in length, between about 2 and about 35 atoms in length, between about 2 and about 30 atoms in length, between about 2 and about 25 atoms in length, or between about 2 and about 20 atoms in length, or any amount therebetween. In certain embodiments, the linker is at least 2 atoms in length, for example, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 atoms in length.

[0068] Suitable linkers are typically capable of forming covalent bonds to both theBLR targeting moiety and the radiolabelled moiety. Accordingly, in certain embodiments, the linker comprises functional groups capable of forming covalent bonds, such as primary or secondary amines, hydroxyl groups, carboxylic acid groups or thiol-reactive groups (for example, maleimido groups and chloroacetyl, bromoacetyl and iodoacetyl groups). In certain embodiments of the invention, the peptidic B1R targeting compounds are modified at their N-terminus to include a suitable linker. In other embodiments, the linker may be a bond that attaches a radiolabelled moiety (or precursor thereto) to the B1R targeting moiety.

[0069] In certain embodiments, the linker comprises carboxylic acid and amine reactive groups. Examples of such linkers include, but are not limited to, 4-amino-(l- carboxymethyl)piperidine (Pip), 2-aminobutyric acid (Abu), 4-aminobutyric acid (y- Abu or GABA), a-aminoisobutyric acid (Aib), 5-aminovaleric acid (5-Ava), 6- aminohexanoic acid (c-Ahx or Ahx), 7-aminoheptanoic acid, 8-aminooctanoic acid (8- Aoc), 9-aminononanoic acid, 10-aminodecanoic acid, 11-aminoundecanoic acid (LI- Ann), [2-(2-amino-ethoxy)-ethoxy]-acetic acid (also known as 9-amino-4,7- dioxanonanoic acid (mini-PEG)), {2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy} -acetic acid (mini-PEG3), 3-[2-(2-aminoethoxy)ethoxy]propanoic acid (PEG2), PEG4, and the like. Other examples include peptide linkers such as glycine linkers (for example, GG, GGG, GGGG, GGGGG); AAA; SAT; PYP; ASA; SGG; GGSGGS; ASASA; PSGSP;PSPSP; ASASA; PSPSP; KKKK; RRRR; GlyrSer; (Gly4Ser)2; (Gly4Ser)3; (Gly4Ser)4;(Gly4Ser)5 and (Gly4Ser)s.

[0070] According to certain embodiments, the linker may be chosen to enhance uptake of the B1R targeting compound in targeted cells and / or tissues, such as cancer cells, while reducing uptake and / or increasing clearance in non-targeted areas, such as reducing renal accumulation. In one embodiment, the linker L comprises at least one selected from the group consisting of 4-amino-(l -carboxymethyl )piperidine (Pip), 4- aminobutyric acid (GABA), and 9-amino-4,7-dioxanonanoic acid. In one embodiment, the linker L is omitted (is simply a bond between the B1R binding moiety and radiolabelled moiety, or moiety that is capable of being radiolabelled), and the B1R binding moiety is directly bound to a radiolabelled moiety, or a moiety that is capable of being radiolabelled.

[0071] Various linkers are commercially available, for example, from Pierce Chemical Company (Rockford Ill), Peptides International (Louisville, KY) and Sigma- Aldrich (St Louis, MO).

[0072] According to certain embodiments, the radiolabelled moiety that is incorporated into the B1R targeting compounds may be a radiometal chelating agent that is chelated to a radiolabel, or it may be a chemical group covalently bound to a radiolabel. In one embodiment, the B1R targeting compound comprises an unlabelled moiety that is bound to the B1R targeting compound, where the unlabelled moiety is one that can be subsequently labelled with a desired radionuclide, such as an unlabelled radiometal chelating agent that is capable of chelating radiometals, a moiety configured for19F / i8F exchange, or a boronate precursor that is capable of conversion to anlsF- labelled trifluoroborate. The exact group selected for incorporation into the peptidic B1R targeting compound will depend on the radiolabel to be used and can be readily determined by one skilled in the art. Examples of radiometal chelating agents include, but are not limited to, diethylenetriamine pentaacetic acid (DTP A), 1,4,7,10- tetraazacyclotetradecane-l,4,7,10-tetraacetic acid (DOTA), 1,4,7,10- tetraazacyclododececane,! -(glutaric acid)-4,7,10-triacetic acid (DOTA GA), ethylenediaminetetraacetic acid (EDTA), 1 ,4,7-triazacyclononane-triacetic acid(NOTA), 1 ,4,7-tnazacyclononane-l-glutaric acid-4, 7-diacetic acid (NODAGA), 1,8- N,N'-bis-(carboxymethyi)-l,4,8,l 1-tetraazacyclotetradecane (TE2A), 3,6,9,15- tetraazabicyclo[9.3. l]pentadeca-l(15),l I, 13-triene-3,6,9-triacetic acid (PCTA), 1- substituted l,4,7,-iricarboxymethyl-l,4,7, 10-teraaz.acyclododecane triacetic acid (DO3A), DEDPA (6,6’-[l,2-ethanediylbis(iminomethylene)]bis(2-pyridinecarboxylic acid) and l,4,8,l l-tetraazacyclotetradecane-I,4,8,ll-tetraacetic acid (TETA), NODASA, CB-DO2A, 3p-C-DEPA, TCMC, DO3A, DTPA and DTPA analogues optionally selected from CHX-A”-DTPA and 1B4M-DTPA; TETA; NOPO; Me-3,2- HOPO, CB-TE1A1P, 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, Fbdedpa, EUoctapa, H4py4pa, FhPypa, Fhazapa, Hsdecapa, and other picolinic acid derivatives, EECHXoctapa, H4neunpa-p-Bn-NO2, CP256, PCTA, {4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[ 1 ,4,7]triazonan- 1 -yl} -acetic acid (NETA), C-NETA, C-NE3TA, HBED, BCPA, CP256, YM103, desferrioxamine (DFO) and DFO derivatives, Hophospa, a trithiol chelate, mercaptoacetyl, hydrazinoni cotinamide, dimercaptosuccinic acid, 1,2-ethylenediylbis-L-cysteine diethyl ester, methylenediphosphonate, N, N0-bis(2-liydroxy-5-sulfobenzyl)-ethylenediamine- N, N — diacetic acid (SITBED), hexamethylpropyleneamineoxime, hexakis(methoxy isobutyl isonitrile), and 2,2’,2",2”'-(l,10-dioxa-4,7,13,16-tetraazacyclooctadecane- 4,7,13,16-tetrayl)tetraacetic acid (CROWN) and derivatives thereof. In one embodiment, the radiometal chelating group comprises DOTA.

[0073] Examples of chemical groups that are covalently bound to radiolabels include, but are not limited to, trifluoroborate, N-succinimidyl-4-[I8F]fluorobenzoate (SFB) and D-propargyiglycine (D-Pra) labelled withi xF?via an18F-labelled azide-containing synthon such as I-azido-3-[!!sF]lluoropropane. In one embodiment, the chemical group that is covalently bound to a radiolabel is trifluoroborate, where one or more of the fluorine groups can be substituted vrith!8F. In one embodiment, the chemical group comprises a moiety configured forl9F / I8F exchange, or a boronate precursor that is capable of conversion to an18F-labeIled IriHuoroborate, for example as described in US PG-Pub No. 2022 / 0062446 to Perrin et al. published on March 3, 2022.

[0074] Certain embodiments of the invention, therefore, also provide for unlabeiled precursors of the radio-labelled BIR targeting compounds, for example, compounds comprising a chelating agent without a radiolabel, and compounds comprising a reactive moiety (such as D-Pra) that may be reacted with a suitable radio-labelled synthon in order to incorporate the radiolabel. In certain embodiments, the reactive moiety comprises an alkyne group that can be reacted with a radio-labelled synthon comprising an azide group via click chemistry. For example, the reactive moiety may be D-Pra and the radio-labelled synthon may be l-azido-3-[lsF]fluoropropane.

[0075] According to one embodiment, the BIR targeting compounds comprise compounds of general Formula (II), or a pharmaceutically acceptable salt of solvate thereof:B- L-Xaa1- Xaa2-Xaa3- Pro4-HyT)5-Gly6-Cpg7-Ser8-D-Tic9-Cpgi0(II) (SEQ ID NO: 8) wherein:B is selected from the group consisting of (i) radiolabelled moieties, (ii) radiometal chelating agents, (iii) moieties configured for19F / 18F exchange, and (iv) boronate precursors that are capable of conversion to an18F-labeled trifluoroborate;L is a linker; andXaa1, Xaa2and Xaa3are independently (i) a bond, or (ii) a proteinogenic or non- proteinogenic amino acid, with the proviso that either ( 1 ) at least one of Xaa1, Xaa2and Xaa3is a bond or a non-protemogenic amino acid, or (2) L is a bond or a linking moiety that is other than 4-amino-(l-carboxymethyl)piperidine (Pip) or 9-amino-4,7- dioxanonanoic acid.

[0076] According to certain embodiments, the BIR targeting compounds of general Formula (II) comprise the BIR targeting compound of general Formula (I). According to certain embodiments, each of Xaa1, Xaa2and Xaa3in general Formula (II) comprise (i) a bond, or (ii) a proteinogenic or non-proteinogenic amino acid having a side chain R corresponding to Formula (III) below:-CH2-CH2-Xi-X3(III)whereX1is a bond or (-CH2-)n group, where n can be 1 to 3, andX2is selected from the group consisting of -NR1?, -NH-C(=NR1)-N Rb, and -O- NRh, with each R1independently being any selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl and isobutyl.

[0077] In one embodiment, the compound of general Formula (II) has the proviso that at least one of Xaa1and Xaa2is other than Lys. In another embodiment, the compound of general Formula (II) has the proviso that Xaa3is other than Arg. In one embodiment, X1in general Formula (II) is -CH?-, -CH2-CH2- or -CH2-CH2-CH2-. In another embodiment, X2in general Formula (II) is any selected from the group consisting of - NH2, -NHCHs, -N(CH3)2, -N(CH3)3, -NHCH(CH3)2, -NH-C(=NH)-NH2, -NH- C(=NCH3)-NH2, -NH-C(=NCH3)-NHCH3, -NH-C(=NH)-N(CH3)2 and -O-NH2. In another embodiment, Xaa1, Xaa2and Xaa3in general Formula (II) are any selected from the group consisting of a bond, Lys, Lys(Me), N,N-s-dimethyl-lysine (Lys(Me2)), Lys(Me3), ornithine (Orn), S-2-amino-5-(aminooxy)pentanoic acid (hCan), Arg, Arg(Me), Arg(Me2), Arg(Me,Me), and N-s-isopropyl-lysine (Lys(iPr)). In one embodiment, two or more of Xaa1, Xaa2and Xaa3are non-proteinogenic amino acids. In another embodiment, Xaa1, Xaa2and Xaa3in general Formula (II) are any selected from the group consisting of a bond, Lys(Me), LyslMe?), Lys(Mes), Orn, hCan, Arg(Me), Arg(Me2), Arg(Me,Me), and Lys(iPr). In another embodiment, Xaa1in general Formula (II) is any selected from the group consisting of a bond, Lys, Lys(Me), Lys(Me?) and Lys(Mes). In another embodiment Xaa2in general Formula (II) is any selected from the group consisting of Lys, Orn, Lys(Me), Lys(Me2), Lys(Me3), and hCan. In yet another embodiment, at least one of Xaa1and Xaa2in general Formula (II) is LysiMe?). In yet another embodiment, both of Xaa1and Xaa2in general Formula (II) are Lys(Me?). In yet another embodiment, Xaa3in general Formula (II) is any- selected from the group consisting of Arg, Arg(Me), ArgfMe?), Arg(Me,Me), and Lys(iPr). In a further embodiment, Xaa1and Xaa2in general Formula (IT) are Lys. In a further embodiment, Xaa1is Lys and Xaa3is Arg in general Formula (II). In another embodiment, Xaa2is Lys and Xaa3is Arg in general Formula (II).

[0078] In certain embodiments, in the B1R targeting compounds of general Formula (II), the linker L is selected from the group consisting of a bond and a proteinogenic or non-proteinogenic amino acid. In certain embodiments, in the B1R targeting compounds of general Formula (II), the linker L is any selected from the group consisting of 4-amino-(l-carboxymethyI)piperidine (Pip), Abu, gamma-aminobutyric acid (GABA), Aib, 5-Ava, Ahx, 7-aminoheptanoic acid, 8-Aoc, 9-aminononanoic acid, 10-aminodecanoic acid, 11-Aun, a glycine linker (such as GG, GGG or GGGG), 9- ammo-4,7-dioxanonanoic acid, mini-PEG, mim-PEG3, PEG2 and PEG4. In certain embodiments, the linker L is a bond. In other embodiments, the linker L is Pip. In yet other embodiments, the linker L is GABA. In another embodiment, the linker L is 9- amino-4,7-dioxanonanoic acid.

[0079] According to certain embodiments, the B1R targeting compounds of general Formula (II) comprise any of the following B1R targeting sequences:

[0080] (1) Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in HTK-A07013) (SEQ ID NO: 29)

[0081] (2) Lys-Orn-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in HTK-A070I5) (SEQ ID NO: 26)

[0082] (3) Lys(Me2)-Lys(Me2)-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in HTK- A070I6) (SEQ ID NO: 6)

[0083] (4) Lys(Me2)-Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in HTK-A07017) (SEQ ID NO: 7)

[0084] (5) Lys-Lys(Me2)-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in HTK-AO7O18) (SEQ ID NO: 5)

[0085] (6) Lys-hCan-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in HTK-A07019) (SEQ ID NO: 27)

[0086] (7) Lys-Lys-Lys(iPr)-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in HTK-A07020) (SEQ ID NO: 28)

[0087] (8) Lys- Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in HTK-A07030) (SEQ ID NO: 18)

[0088] (9) Lys- Lys(Me)-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in AR01001) (SEQ ID NO: 30)

[0089] (10) Lys(Me)- Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in AR01002) (SEQ ID NO: 31)

[0090] (11) Lys- Lys(Me3)-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in AR01003) (SEQ ID NO: 32)

[0091] (12) Lys(Me3)- Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in AR01004) (SEQ ID NO: 33).

[0092] In certain embodiments, in the B1R targeting compounds of general Formula (II), the radiometal chelating agent is DTPA, DOTA, DOTAGA, NOTA, NODAGA, TE2A, PCTA, DO3A, DEDPA or TETA. In one embodiment, the radiometal chelating agent is any selected from the group consisting of DOTA, DOTAGA, NOTA and NODAGA, such as DOTA. In one embodiment the B1R targeting compounds comprise radiolabelled trifluoroborate, or an unlabelled precursor.

[0093] In certain embodiments, in the optionally radiolabelled BIR targeting compound of general Formula (II), Xaa1, Xaa2and Xaa3may be any of the amino acids and combinations thereof as described for general Formula (I) above. That is, in certain embodiments, general Formula (II) can be expressed as B-L-Formula (I). Furthermore, according to certain embodiments, the BIR targeting compound of general Formula (II) has a BIR targeting moiety that distinguishes from B-9958, at least in that one or more of the amino acids at positions 1 through 3 have been replaced with a non- proteinogenic amino acid, or are deleted (have been replaced by a single bond). Accordingly, in one embodiment, the BIR targeting compound of general Formula (II) has the proviso that either (I) at least one of Xaa1and Xaa2is other than Lys, or (2) Xaa2is other than Arg. According to yet another embodiment, the linker L is selected to be a bond or a linking moiety other than 4-amino-(l-carboxymethyl)piperidine (Pip) or 9-amino-4,7-dioxanonanoic acid. In one embodiment, the BIR targeting compound according to general Formula (II) has the proviso that either (1) at least one of Xaa1and Xaa2is a bond or is other than Lys, (2) Xaa2is other than Arg, or (3) L is a bond or is alinking moiety other than 4-amino-(l-carboxymethyl)piperidine (Pip) or 9-arnino-4,7- dioxanonanoic acid.

[0094] According to one embodiment, the B1R targeting compound of generalFormula (II) comprises any of the following compounds, in either unlabelled form or as radiolabelled with a radiometal:

[0095] Suitable radiolabels for incorporation into the peplidic B1R targeting compounds include any selected from tire group consisting of6SGa,1SF,!231,! 3 iI9(Y, 177Lu,6,CU,64CU,67Cu,67Ga,11'in,44Sc,S6Y,89Zr,90Nb,! !7ffiSn,! 65Er,227Th,225Ac, 213Bi,2t2Bi,72As,77As,211At,2O3Pb,2!2Pb,47Sc,i66Ho,l88Re,186Re,149Pm,15SGd,!05Rh, W9Pd,198Au,l99Au,175Yb,142Pr,! 14fflIn,94ffiTc, "fflTc,149Tb,152Tb,!55Tb, and161Tb.The exact radiolabel selected for incorporation into the B1R targeting compound will be dependent on the nature of the chelating agent or chemical group present in the compound for radiolabel attachment and the intended use of the final compound. For example,1SF,i23I, "mTc,H1ln,6SGa,64Cu,86Y and44Sc are suitable for PET and / or SPECT imaging, and1 ! iIn,MCu,67Cu,90Y,2i3Bi,177Lu,225Ac,!86Re andixxRe are suitable for radiotherapy applications. In one embodiment, the B1R targeting compound is radiolabeled with a diagnostic radionuclide corresponding to any selected from the group consisting ofi23I, "“Tc,15Tn,68Ga,I8F,44Sc,2O3Pb,64Cu,61Cu, and86Y. In one embodiment, the B1R targeting compound is radiolabeled with a therapeutic radionuclide corresponding to any selected from the group consisting of177LU,! ! !ln,90Y,225AC,2I2Pb,2!3Bi,64Cu,6Cu,i86Re andJ88Re. Selection of an appropriate label taking these factors into account can be readily made by one skilled in the art. One skilled in the art will also appreciate the certain radioisotopes may require modification to facilitate their incorporation into the peptides and / or for stabilization. For example,18F may be used in the form of18F-A1 to allow for chelation by a chelating group on the peptide. Likewise,I86Re and188Re may be used in the form of Re(CO)3.

[0096] The radio-labelled B1R targeting compounds according to the invention may be prepared by standard peptide and synthetic chemistry procedures from commercially available starting materials. Exemplary, non-limiting procedures are provided in the Examples.

[0097] In certain embodiments, the invention relates to conjugates of the abovedescribed B1R targeting compounds, m which the compound is conjugated to one or more additional chemical or biochemical moieties that provide additional functionality to the peptide, for example, increased stability, improved bioavailability or improved pharmacokinetics and / or that assist in delivery of the compound to the appropriate tissue(s) or organ(s). Conjugates include B1R targeting compounds fused to one or more biological moieties as well as B1R targeting compounds in which the aminoterminus and-'or carboxy-terminus and / or one or more amino acid side chain has been derivatized with a suitable chemical substituent group for conjugation to one or more chemical or biological moieties. Examples of such chemical or biological moietiesinclude, but are not limited to, various carriers, lipophilic moieties, antibodies and other biological ligands, liposomes, polymeric matrices, non-polymeric matrices, particles such as gold particles, microdevices and nanodevices, and nano-scale semiconductor materials.

[0098] In certain embodiments, the B1R targeting compounds of general Formulas (I) and (II) may possess a sufficiently acidic group, a sufficiently basic group, or both functional groups, and accordingly react with a number of organic and inorganic bases, or organic and inorganic acids, to form pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” as used herein, refers to a salt of a sequence or compound of Formula (I), or (II), which is substantially non-toxic to living organisms.Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compound of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.

[0099] Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulphonic acid, methanesulphonic acid, oxalic acid, p-bromophenylsulphonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulphate, pyrosulphate, bisulphate, sulphite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne- 1,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulphonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulphonate, propanesulphonate, naphthalene- 1 -sulfonate, napththalene-2- sulfonate, mandelate and the like. Pharmaceutically acceptable acid addition salts of particular interest are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid andmethanesulphonic acid.

[0100] Saits of amine groups may also comprise quarternary ammonium salts in which the amino nitrogen carries a suitable organic group such as an alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, or aralkyl moiety.

[0101] Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Bases useful in preparing pharmaceutically acceptable salts thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.

[0102] One skilled in the art will understand that the particular counterion forming a part of a pharmaceutically acceptable salt is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.

[0103] In some embodiments, the present invention further encompasses pharmaceutically acceptable solvates of a B1R targeting sequence or compound of Formula (I) or (II). The sequences and / or compounds of Formula (I) or (II) can combine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate.PHARMACEUTICAL COMPOSITIONS

[0104] The B1R targeting compounds are typically formulated for administration to a patient, either before or after incorporation of a radiolabel. Certain embodiments of the invention thus relate to pharmaceutical compositions comprising one or more of the radio-labelled B1R targeting compounds, or unlabelled BIR targeting compounds, and a pharmaceutically acceptable carrier, diluent, or excipient. The pharmaceutical compositions are prepared by known procedures using well-known and readilyavailable ingredients.

[0105] The pharmaceutical compositions comprising the B1R targeting compounds are typically formulated for parenteral administration. The term parenteral as used herein includes subcutaneous, intradermal, intra-articular, intravenous, intraperitoneal, intramuscular, intravascular, intrastemal, intrathecal injection or infusion techniques.

[0106] In certain embodiments, the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or a suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Adjuvants such as local anaesthetics, preservatives and buffering agents can also be included in the injectable solution or suspension.

[0107] Other pharmaceutical compositions and methods of preparing pharmaceutical compositions are known in the art and are described, for example, in “Remington: The Science and Practice of Pharmacy” (formerly “Remingtons Pharmaceutical Sciences”},' Gennaro, A., Lippincott, Williams & Wilkins, Philadelphia, PA (2000).USESIn certain embodiments, the invention relates to the use of the radio-labelled B1R targeting compounds in in vivo medical imaging applications or in radiotherapy in patients having a disease or disorder associated with expression, aberrant expression, ectopic expression, or overexpression of B1R. In pathologies, B1R is expressed in malignancies, chronic inflammation and selected cardiac disorders. Accordingly, radiolabeled B1R targeting compounds can be used both for diagnosis and therapy.According to certain embodiments, for diagnostic applications, a single-photon (such as99mTc) or positron-emitting (such as68Ga,i8F,44Sc,64Cu,61Cu,86Y) radioisotope is attached to the BTR targeting compound, allowing non-invasive imaging of the abnormal expression of these receptors. In other embodiments, such as for therapeutic applications, including cancer treatment, a radioisotope that delivers a high radiation dose (such as! 7'Lu,90Y,225Ac,64Cu) can be attached to the B1R targeting compound, and deliver targeted radiotherapy to the cells.Diagnostic Applications

[0108] Certain embodiments relate to diagnostic applications of the radio- labelledBLR targeting compounds for imaging a cancer or tissue in which B1R is expressed, aberrantly expressed, ectopically expressed, or over expressed, for example, in oncology, inflammation or cardiovascular disease.Oncology

[0109] Overexpression of B1R has been demonstrated in many malignancies, including early breast and prostate cancers (prostatic intraepithelial neoplasia and malignancy), lung cancers, brain cancers, esophageal cancers, cervical cancers, gastric cancers, and renal cancers. B1R activation has been shown to potentiate malignant behaviors by inducing cell proliferation, migration, and angiogenesis. The pro- inflammatory effect of B1R activation can modulate the tumor microenvironment, priming for distant metastasis. Certain embodiments of the invention thus contemplate that the radio-labelled B1R targeting compounds could be used as imaging probes for cancers of the breast, prostate, lung, brain, esophagus, cervix, stomach, and kidneys, including for use in early diagnosis of solid malignancies that express B1R, as imaging agents to confirm the diagnostic of malignancy, or to guide focal ablative treatment if the disease is localized. According to certain embodiments, the B1R targeting compounds could also be used to monitor response to therapy, by providing an independent assessment of the residual cellular content of a tumor known to overexpress B1R. According to further embodiments, the B1R targeting compoundscan be used for endoradiotherapy targeting cells expressing BIR, by radiolabelling the compound with a radioisotope, usually a P- or a-particle emitter, to deliver a high local dose of radiation to lesions, to inflict DNA damage and inducing cellular death. Unlike external beam radiation therapy, in certain embodiments this systemic treatment can be effective even in the treatment of metastases.

[0110] In the breast, ductal carcinomas in situ also overexpress the BIR receptor. Overexpression of B1R has been observed in 76% of primary breast cancers. In the prostate, benign prostate lesions do not overexpress BIR. Accordingly, certain embodiments of the invention contemplate that the radio-labelled B IR targeting compounds will find use as probes for the diagnosis of early stage breast cancer, prostate cancer and other malignancies. Based on the data provided in the Examples, radio-labelled B IR targeting compounds are expected to show high contrast, rapid renal clearance, minimal non-target organ uptake, and high tumour to normal tissue ratios, which properties make these compounds well-suited for use as imaging agents for cancer diagnosis, including diagnosis of early stage cancer. In particular, certain BIR targeting compounds according to embodiments of the invention exhibit relatively low renal retention, and relatively high ratio of tumorikidney uptake, facilitating safe and effective use of the compounds in diagnostic and radiotherapeutic treatments.

[0111] Certain embodiments of the invention contemplate the use of the radio- labelled BIR targeting compounds as adjunct imaging agents for the diagnosis of cancer, such as breast cancer. In some embodiments, the radio-labelled BIR targeting compounds can be labelled with positron emitters and could be used with positron emission mammography (or breast gamma imaging) to detect abnormal breast lesions at an early stage, and / or be used to characterize equivocal lesions on mammography or breast MRI, which would be followed up with repeat examinations rather than biopsy.

[0112] Certain embodiments of the invention contemplate that the radio-labelled BIR targeting compounds may be used as probes to localize primary or recurrent cancers, such as prostate cancers in patients with elevated tumour markers (such as elevated PSA). Such imaging agents could find use, for example, to confirm the diagnostic ofmalignancy, guide focal ablative treatment if the disease is localized, or guide salvage treatment in the case of cancer recurrence.

[0113] In some embodiments of the invention, it is contemplated that the radio- labelled B1R targeting compounds may be used as PET / SPECT imaging probes to assist with precise localization of primary’ or recurrent cancer, such as prostate cancer, in order to guide and assist with focal ablative therapies.

[0114] In some embodiments, the invention contemplates that the radio-labelled BIR targeting compounds could be used to monitor response to therapy, by providing an independent assessment of the residual cellular content of a tumour known to overexpress BIR. Overexpression of BIR may be an indicator of angiogenesis in tumours, as blocking of BIR activation is known to have antiangiogenic activity. In certain embodiments, therefore, the radio-labelled BIR targeting compounds could find use to predict or monitor response to anti-angiogenic medications, such as Avastin.

[0115] There is some evidence that B 1R antagonists might cause growth inhibition in some cancers. In certain embodiments, BIR expression and receptor blockage could be detected by imaging with the radio- labelled BIR targeting compounds, which could then act as a predictive biomarker for treatment success.

[0116] In some embodiments, the use of the radio-labelled BIR targeting compounds in multimodality imaging of cancers is contemplated, for example, combined functional imaging and anatomical imaging, such as PET / CT or SPECT / CT. Multimodality’ imaging may be useful in situations in which a cancer is present, but the uptake of imaging agent is low.Inflammation

[0117] Inflammation and infection can cause local tissue damage, which leads to the overexpression of BIR, which involved in the inflammatory and nociceptive response. Certain embodiments of the invention contemplate that the radio-labelled B 1R targeting compounds could be used to provide images outlining sites of active inflammation or infection, and a quantitative assessment disease involvement, in inflammatory disordersof the joints. In some embodiments, the radio-labelled B1R targeting compounds could be used to monitor inflammatory disease activity and response to therapy.Cardiovascular disease

[0118] B1R has been reported to be overexpressed when the endovascular intima is damaged. Certain embodiments contemplate the use of the radio-labelled B 1 R targeting compounds to detect endovascular damage, such as can occur with autoimmune vasculitis or atherosclerosis. Some embodiments of the invention contemplate that the radio-labelled B1R compounds could be used, for example, to guide intervention in patients with abdominal aortic aneurysm - the evidence of intimal damage could be a precursor for aneurysm rupture, as a predictor of unstable plaques m coronary artery disease, in order to predict the likelihood of myocardial infarction in patients with borderline coronary stenoses and / or as a guide to whether carotid endarterectomy is needed in patients with stenotic carotid arteries.Therapeutic Applications

[0119] Certain embodiments relate to therapeutic applications of the radio-labelledBTR targeting compounds in cancer. Cancers that are B1R positive could be amenable to treatment by radionuclide therapy. In such applications, the radio- labelled B1R targeting compound would incorporate a radioisotope that delivers a high local dose of radiation. Therapeutic radioisotopes include but are not restricted to177Lu,90Y,225Ac and64Cu. A dose of the compound calculated to deliver an effective radiation dose to the tumour, while avoiding or minimizing normal organ damage, is administered to the patient. The accumulated radioactivity in the tumour can lead to cell death and tumour regression. In certain cases, this type of systemic therapy can be effective even in the metastatic setting. PHARMACEUTICAL PACKS OR KITS

[0120] Certain embodiments of the invention relate to pharmaceutical packs or kits containing one or more B1R targeting compounds, for example, therapeutic or diagnostic packs or kits. The compounds may be provided radio-labelled or asprecursors suitable for radio-labelling, in which case the kit may optionally include additional reagents for radio-labelling the compounds.

[0121] In certain embodiments, one or more of the components of the kit can be lyophilized and the kit can additionally contain a suitable solvent for reconstitution of the lyophilized components. Individual components of the kit would typically be packaged in separate containers and, associated with such containers, can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufac ture, for use or sale for human or animal administration.

[0122] In certain embodiments, the compound(s) are provided in the kit in the form of pharmaceutical compositions suitable for administration to a subject. In this case, if desired, the container may itself be an inhalant, sy ringe, pipette, eye dropper, or other such like apparatus, from which die composition maybe administered to the subject.

[0123] B1R targeting compounds according to general Formulas (I) and (II) herein can be synthesized according to conventional Na-Fmoc solid phase peptide synthesis strategies (see Zhang et al.. Mol Pharmaceutics 2016;13(8):2823; and Lin et al., J. Nucl. Med. 2015, 56, 622-627), as well as according to other methods known to those of ordinary' skill in the art.

[0124] To gain a better understanding of the invention described herein, the following examples are set forth. It will be understood that these examples are intended to describe illustrative embodiments of the invention and are not intended to limit the scope of the invention in any" way.EXAMPLES

[0125] Studies were performed to evaluate improved B1R targeting compounds exhibiting relatively high uptake in tumor tissues and / or cells, with relatively low renal accumulation. Specifically, it was found that the B1R antagonist compound [68Ga]Ga- Z02176 (68Ga-DOTA-Pip-Lys1-Lys2-Arg'-Pro4-Hyp:,-Gly6-Cpg7-Ser8-D-Tic9-Cpg!0), while capable of binding to B IR-expressing tumor xenografts wi th excellent sensitivityand selectivity (Zhang et al., Mol Pharmaceutics 20I6;13(8):2823), also exhibited a relatively high retention in the kidneys, which is a concern for potential nephrotoxicity in therapeutic applications. Without being limited by any particular theory herein, it was hypothesized that high renal retention may be attributable to the cationic properties of the linker L (Pip in Z02176) and amino acids at the N-terminus of the peptide (Lys- Lys-Arg in Z02176). Accordingly, compounds were developed and evaluated with modifications to the linker L and Lys1, Lys2, Arg-’ of Z02176, to replace with different linkers and / or non-proteinogenic amino acids, to determine effects on both renal and tumor accumulation.EXPERIMENTALPeptide synthesis of Fmoc-Pro-Hyp( / Bu)-Gly-Cpg-Ser(rBu)-D-Tic-Cpg-Resin

[0126] A starting peptide was synthesized via a N“-Fmoc (fluorenylmethoxycarbonyl protecting group) solid phase peptide synthesis strategy. 2-Chlorotrityl chloride resin (0.6 mmol, 0.6 mmol / g loading) was suspended in dry dichloromethane for 30 min.Fmoc-Cpg-OH was coupled to the resin using Fmoc-protected amino acid (1.2 eq.) and N,N-diisopropylethyl amine (DIEA) (3.75 eq.) overnight followed by capping with CH2Ch / 'MeOH / DIEA (8 / 2 / 1) solution for 1 h. After washing the resin with dimethylformamide (DMF), the Fmoc -protecting group was removed with 20% v / v piperidine. Fmoc-D-Tic-OH, Fmoc-Ser(rBu)-OH, Fmoc-Cpg-OH, Fmoc-Gly-OH, Fmoc-Hyp( / Bu)-OH, and Fmoc-Pro-OH -were sequentially coupled to the peptidyl resin following similar procedures using Fmoc-protected amino acid (4 eq.), hexafluorophosphate azabenzotriazole tetramethyl uromum (HATU) (4 eq.) and DIEA (7 eq.) in DMF. The resin was dried and divided into 12 portions for elongation (each portion was 0.05 mmol).Synthesis of HTK-A07013

[0127] Continuing from Fmoc-Pro-Hyp( / Bu)-GIy-Cpg-Ser(ZBu)-D-Tic-Cpg-Resin, Fmoc-Arg(pbf)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Pip-OH, and DOTA-tris( / Bu)ester were coupled sequentially following described procedures. The peptide was deprotected and simultaneously cleaved from the resin by treating with a cocktail solution of 95 / 5 trifluoroacetic acid (TFA) / triisopropylsilane (TIPS) for 2 h at room temperature. After filtration, the TFA was removed in vacuo and the peptide was precipitated by the addition of cold diethyl ether. The crude peptide purified by high- performance liquid chromatography (HPLC) using a preparative column eluted with 20% acetonitrile in water with 0.1% TFA at a How rate of 30 mL / min. The retention time was 15.7 min. The isolated yield was 27.4%. Electrospray Ionization Mass Spectrometry (ESI-MS): calculated [M+2H]2+for C74H117N19O20 797.0; found [M+2H]2+797.1 .Synthesis of HTK-A07015

[0128] Continuing from Fmoc-Pro-Hyp( / Bu)-Gly-Cpg-Ser( / Bu)-D-Tic-Cpg-Resin, Frnoc-Arg(pbf)-OH, Fmoc-Orn(Boc)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Pip-OH, and DOTA-tris( / Bu)ester were coupled sequentially following described procedures. The peptide was deprotected and simultaneously cleaved from the resin by treating with a cocktail solution of 95 / 5 TFA / TIPS for 2 h at room temperature. After filtration, the TFA was removed in vacuo and the peptide was precipitated by the addition of cold diethyl ether. The crude peptide purified by HPLC using a preparative column eluted with 19% acetonitrile in water with 0.1% TFA at a flow rate of 30 mL / min. The retention time was 12.1 min. The isolated yield was 36.4%. ESI-MS: calculated [M+2H]2+for C79H127N21O21 854.0; found [M+2H]2^ 854.3.Synthesis of HTK-A07016

[0129] Continuing from Fmoc-Pro-Hyp(ZBu)-Gly-Cpg-Ser( / Bu)-D-Tic-Cpg-Resin, Fmoc-Arg(pbf)-OH, Fmoc-Lys(Me2)-OH, Fmoc-Pip-OH, and DOTA-tris( / Bu)esterwere coupled sequentially following described procedures. The peptide was deprotected and simultaneously cleaved from the resin by treating with a cocktail solution of 95 / 5 TFA / TIPS for 2 h at room temperature. After filtration, the TFA was removed in vacuo and the peptide was precipitated by the addition of cold diethyl ether. The crude peptide purified by HPLC using a preparative column eluted with 19% acetonitrile in water with 0.1% TFA at a flow rate of 30 mL / min. The retention time was 11.1 min. The isolated yield was 24.2%. ESI-MS: calculated [M~i~2H]2+for C84H137N21O21 889.0; found [M+2H]2+889.1.Synthesis of HTK-A07017

[0130] Continuing from Fmoc-Pro-Hyp(rBu)-Gly-Cpg-Ser( / Bu)-D-Tic-Cpg-Resin, Fmoc-Arg(pbf)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Lys(Me2)-OH, Fmoc-Pip-OH, and DOTA-tris( / Bu)ester were coupled sequentially following described procedures. The peptide was deprotected and simultaneously cleaved from the resin by treating with a cocktail solution of 95 / 5 TFA'TIPS for 2 h at room temperature. After filtration, the TFA was removed in vacuo and the peptide was precipitated by the addition of cold diethyl ether. The crude peptide purified by HPLC using a preparative column eluted with 19% acetonitrile in water with 0.1% TFA at a flow rate of 30 mL / min. The retention time was 7.6 min. The isolated yield was 19.5%. ESI-MS: calculated [M+2H]2+for C82H133N21O21 875.0; found [M+2H]2+875.1.Synthesis of HTK-A07018

[0131] Continuing from Fmoc-Pro-Hyp( / Bu)-Gly-Cpg-Ser(rBu)-D-Tic-Cpg-Resin, Fmoc-Arg(pbf)-OH, Fmoc-Lys(Me2)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Pip-OH, and DOTA-tris( / Bu)ester were coupled sequentially following described procedures. The peptide was deprotected and simultaneously cleaved from the resin by treating with a cocktail solution of 95 / 5 TFA / TIPS for 2 h at room temperature. After filtration, the TFA was removed in vacuo and the peptide was precipitated by the addition of colddiethyl ether. The crude peptide purified by HPLC using a preparative column eluted with 20% acetonitrile in water with 0.1% TFA at a flow rate of 30 mL / min. The retention time was 8.2 min. The isolated yield was 27.7%. ESI-MS: calculated [M+2H]2+for C82H133N21021 875.0; found [M+2H]2+875.1.Synthesis of HTK-A07019

[0132] Continuing from Fmoc-Pro-Hyp( / Bu)-Gly-Cpg-Ser( / Bu)-D-Tic-Cpg-Resin, Fmoc-Arg(pbf)-OH, Fmoc-hCan(Boc)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Pip-OH, and DOTA-tris( / Bu)ester were coupled sequentially following described procedures. The peptide was deprotected and simultaneously cleaved from the resin by treating with a cocktail solution of 95 / 5 TFA / TIPS for 2 h at room temperature. After filtration, the TFA was removed in vacuo and the peptide was precipitated by the addition of cold diethyl ether. The crude peptide purified by HPLC using a preparative column eluted with 20% acetonitrile in water with 0.1% TFA at a flow rate of 30 mL / min. The retention time was 7.9 min. The isolated yield was 26.1%. ESI-MS: calculated [M+2H]2+for C79H127N21O22 862.0; found [M+2H]2+862.3.Synthesis of HTK-A07020

[0133] Continuing from Fmoc-Pro-Hyp(rBu)-Gly-Cpg-Ser( / Bu)-D-Tic-Cpg-Resin, Fmoc-Lys(iPr,Boc)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Pip-OH, and DOTA-tris( / Bu)ester were coupled sequentially following described procedures. The peptide was deprotected and simultaneously cleaved from the resin by treating with a cocktail solution of 95 / 5 TFA / TIPS for 2 h at room temperature. After filtration, the TFA wzas removed in vacuo and the peptide was precipitated by the addition of cold diethyl ether. The crude peptide purified by HPLC using a preparative column eluted with 19% acetonitrile in water with 0.1% TFA at a flow rate of 30 mL / min. The retention time was 7.7 min. The isolated yield was 31.4%. ESI-MS: calculated [M+2H]2+for C83H137N21O21 868.0; found [M+2H]2+868.2.Svnthesis of HTK-A07030

[0134] Continuing from Fmoc-Pro-Hyp(7Bu)-Gly-Cpg-Ser(rBu)-D-Tic-Cpg-Resin, Fmoc-Arg(pbf)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Lys(Boc)-OH, and DOTA- tris( / Bu)ester were coupled sequentially following described procedures. The peptide was deprotected and simultaneously cleaved from the resin by treating with a cocktail solution of 95 / 5 TFA / TIPS for 2 h at room temperature. After filtration, the TFA was removed in vacuo and the peptide was precipitated by the addition of cold diethyl ether. The crude peptide purified by HPLC using a semi-preparative column eluted with 24% acetonitrile in water with 0.1% TFA at a flow’ rate of 4.5 mL / min. The retention time was 11.0 min. The isolated yield wzas 17.7%. ESI-MS: calculated [M+2H]2" for C73H117N19O20 790.9; found [M+2H]2+791.1.Synthesis of HTK-A07031

[0135] Continuing from Fmoc-Pro-Hyp(rBu)-Gly-Cpg-Ser( / Bu)-D-Tic-Cpg-Resin, Fmoc-Arg(pbf)-OH, Fmoc-Lys(Boc)-OH, Fmoc-GABA-OH, and DOTA-tris(rBu)ester were coupled sequential ly following described procedures. The peptide was deprotected and simultaneously cleaved from the resin by treating with a cocktail solution of 95 / 5 TFA / TIPS for 2 h at room temperature. After filtration, the TFA was removed in vacuo and the peptide was precipitated by the addition of cold diethyl ether. The crude peptide purified by HPLC using a semi-preparative column eluted with 24% acetonitrile in water with 0.1% TFA at a flow rate of 4.5 mL / min. The retention time was 11.5 min. The isolated yield was 16.0%. EST-MS: calculated [M+2H]2+for C77H124N20O21 833.5; found [M+2H]2+833.5.Synthesis of AR01001

[0136] Continuing from Fmoc-Pro-Hyp(tBu)-Gly-Cpg-Ser(tBu)-D-Tic-Cpg-Resin, Fmoc-Arg(pbf)-OH, Fmoc-Lys(Me,Boc)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Pip-OH, and DOTA-tris(tBu)ester were coupled sequentially following described procedures. Thepeptide was deprotected and simultaneously cleaved from the resin by treating with a cocktail solution of 95 / 5 TFA / TIS for 2 h at room temperature. After filtration, the TFA was removed in vacuo and the peptide was precipitated by the addition of cold diethyl ether. The crude peptide purified by HPLC using a semi-preparative column eluted with 15-60% acetonitrile in water with 0.1% TFA in 20 min at a flow rate of 4.5 mL / min. The retention time was 10.3 min. ESI-MS: calculated [M+2H]2+ for C81H13IN21O21 868.0; found [M+2H]2+ 868.4.Synthesis of AR01002

[0137] Continuing from Fmoc-Pro-Hyp(tBu)-Giy-Cpg-Ser(tBu)-D-Tic-Cpg-Resin, Fmoc-Arg(pbf)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Lys(Me,Boc)-OH, Fmoc-Pip-OH, andDOTA-tris(tBu)ester were coupled sequentially following described procedures. The peptide was deprotected and simultaneously cleaved from the resin by treating with a cocktail solution of 95 / 5 TFA / TIS for 2 h at room temperature. After filtration, the TFA was removed in vacuo and the peptide was precipitated by the addition of cold diethyl ether. The crude peptide purified by HPLC using a semi-preparative column eluted with 25% acetonitrile in water with 0.1% TFA at a flow rate of 4.5 mL / min. The retention time was 8.4 min. The isolated yield was 3.5%. ESI-MS: calculated [M+2H]2+ for C81H131N21O21 868.0; found [M+2HJ2+ 868.3.Synthesis of AR01003

[0138] Continuing from Fmoc-Pro-Hyp(tBu)-Gly-Cpg-Ser(tBu)-D-Tic-Cpg-Resin,Fmoc-Arg(pbf)-OH, Fmoc-Lys(Me3)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Pip-OH, and DOTA-tris(tBu)ester were coupled sequentially following described procedures. The peptide was deprotected and simultaneously cleaved from the resin by treating with a cocktail solution of 95 / 5 TFA / TIS for 2 h at room temperature. After filtration, the TFA was removed in vacuo and the peptide was precipitated by the addition of cold diethyl ether. The crude peptide purified by HPLC using a semi-preparative column eluted with 23% acetonitrile in water with 0.1% TFA at a flow rate of 4.5 mL / min. The retention time was 14.1 min. The isolated yield wras 4.8%. ESI-MS: calculated [M+2H]2+ for C83H136N21O21 882.0; found [M+2H]2+ 882.2.Synthesis of AR01004

[0139] Continuing from Fmoc-Pro-Hyp(tBu)-Gly-Cpg-Ser(tBu)-D-Tic-Cpg-Resin, Fmoc-Arg(pbf)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Lys(Me3)-OH, Fmoc-Pip-OH, and DOTA-tris(tBu)ester were coupled sequentially following described procedures. The peptide was deprotected and simultaneously cleaved from the resin by treating with a cocktail solution of 95 / 5 TFA / TIS for 2 h at room temperature. After filtration, the TFA was removed in vacuo and the peptide was precipitated by the addition of cold diethyl ether. The crude peptide purified by HPLC using a semi-preparative column eluted with 25% acetonitrile in water with 0.1% TFA at a flow rate of 4.5 mL / min. The retention time was 8.2 min. The isolated yield was 6.0%. ESI-MS: calculated[M+2H]2+ for C83H136N21O21 882.0; found |M+2H]2+ 882.8.

[0140] Table 4 below shows the peptide sequences of each of the B1R targeting moieties. The chemical structures of (A) HTK-A07013, (B) HTK-A07015, (C) HTK- A07016, (D) HTK-A07017 and (E) HTK-A07018 are shown in Figure 1, the chemical structures of (A) HTK-A07019, (B) HTK-A07020, (C) HTK-AO7O3O and (D) HTK-A07031, are shown in Figure 2, and the chemical structures of (A) AR01001, (B) AR01002, (C) AR01003 and (D) AR01004 are shown in Figure 3.Table 4. Peptide sequences of B1R targeting peptides.General procedure for the preparation of nonradioactive Ga-complexed standards

[0141] A solution of the DOTA-conjugated precursor was incubated with GaCh (5 eq.) in sodium acetate (NaOAc) buffer (0.1 M, 500 pL, pH 4.2) at 80 °C for 15 min. The reaction mixture was purified by HPLC using a semi -preparative column at a flow rate of 4.5 mL / min. The HPLC solvents were H2O and CH3CN containing 0.1% TFA. The HPLC eluates containing the desired peptide were collected, pooled, and lyophilized. The HPLC conditions, retention times, isolated yields and mass spectrometry (MS) confirmations of the nonradioactive Ga-complexed standards are provided in T able 5 below.Table 5. HPLC purification conditions and MS characterizations of Ga-DOTA- conjugated B 1 R-targeting peptides.General procedure for radiolabeling of peptides with gallium-68 (6SGa)

[0142] 68GaCh (270.5-526.9 MBq) in 0.5 mL DI water was added to a solution of peptide (10 nmol) in 0.7 mL (4-(2-hydroxyethyI)-l-piperazineethandesulfonic acid (HEPES) buffer (2M, pH 5.0). The radiolabeling reaction was carried out under microwave heating (100°C) for 1 min. The reaction mixture was purified by HPLC using a semi-preparative column with flow rate 4.5 mL / min. The HPLC solvents were PBS and CH3CN. 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 (1 mL) and water (2 mL). The68Ga-Iabeled product was eluted off the cartridge with ethanol (0.4 mL) and diluted with phosphate-buffered saline (PBS) (with 0.1% ascorbic acid) for animal studies. Quality control was performed using the analytical column with flow rate 2 mL / min by using PBS and CHsCN as solvents. The HPLC conditions and retention times are provided in the Table5.68Ga-labeled BlR-targeting tracers were obtained in 15.1-36.1% decay-corrected radiochemical yields and > 93% radiochemical purity.Cell Culture

[0143] The HEK293T::hBlR cell line was generated in-house via lentiviral transduction (yee Lin et al., Cancer Res 2015;75(2);387-9). The cell line was cultured in a 5% CO2 atmosphere at 37°C in a humidified incubator with DMEM medium supplemented with 10% fetal bovine serum, 100 I.U. / mL penicillin, and 100 pg / mL streptomycin.Competition Binding Assays

[0144] The binding affinity of the B1R was measured as reported (Lin ef al.. CancerRes 2015;75(2);387-9) via competition binding assays using BIR-expressing CHO-K1 cell membranes and pH ][Leu9,des-Argi0]kallidin as the radio-ligand. Binding affinities of the B 1 R targeting peptides are shown in Table 6 below.Table 6. Binding affinity (Ki) of B1R targeting peptides.Animal Model

[0145] Animal experiments were performed in accordance with guidelines established by the Canadian Council on Animal Care and approved by the Animal Ethics Committee of the University of British Columbia. Male NOD.Cg-RaglftB7Afo® I12rg“’2" / Sz J (NRG) mice were obtained from an in-house breeding colony at the Animal Resource Centre of the BC Cancer Research Centre, Vancouver, Canada. Mice were subcutaneously inoculated with 5-10 x 106HEK293T::hBlR cells (100 pL; 1:1 ratio of PBS / Matrigel) on tire left flank. Tumors were grown for 2-3 weeks before in vivo experiments.PET / CT Imaging

[0146] PET / CT imaging followed previously published procedures. Tumor-bearing mice were briefly sedated with isoflurane (2-2.5% isoflurane in 2L / min Oa) for i.v. injection of6SGa-labeled peptides (4.2-8. 1 MBq). The animals were allowed to roam free during the uptake period. Mice were subsequently sedated and scanned on a Siemens Inveon microPET / CT with body temperature maintained by a heating pad. The CT scan was obtained for attenuation correction and anatomical localization (80 kV; 500 pA; 3 bed positions; 34% overlap; 220° continuous rotation) followed by a 10 min PET acquisition at 1 h post-injection (p.i.) of the radiotracer. PET data were acquired in list mode, reconstructed using 3-dimensional ordered-subsets expectation maximization (2 iterations) followed by a fast maximum a priori algorithm (18 iterations) with CT- based attenuation correction. Images were analyzed using the Inveon Research Workplace software (Siemens Healthineers).Biodistribution

[0147] Under isoflurane anesthesia (2-2.5% isoflurane in 2L / min O2), mice were injected intravenously with6sGa-labeled peptides (1.1-3.5 MBq) with or without co- injection of 100 pg Z02176 i.v.. Mice were euthanized by CO2 inhalation after anesthesia with isoflurane. Tissues were harvested, washed in PBS, patted dry, weighed, and then assayed radioactivity on a gamma counter. Counted radioactivities were converted to percentage injected dose per gram of tissue (%ID / g) using a calibration curve.

[0148] Figure 5 shows the biodistribution data (%ID / g) of [<58Ga]Ga-Z02176, [68Ga]Ga-HTK-A07013, [68Ga]Ga-HTK-A07015, [68Ga]Ga-HTK-A07016, and[68Ga]Ga-HTK-A07017 in HEK293T::hBlR tumor-bearing male mice at I h postinjection. Figure 6 shows the biodistribution data (%ID / g) of [68Ga]Ga-HTK-A07018, [68Ga]Ga-HTK-A07019, [68Ga]Ga-HTK-A07020, [68Ga]Ga-HTK-A07030, and HTK- A07031 in HEK293T::hBlR tumor-bearing male mice at 1 h post- injection.

[0149] From the biodistribution data, it can be seen that certain of the B1R targeting compounds exhibit marked improvements in tumor uptake, as well as a reduced accumulation in non-tumor tissue such as muscle, blood, and kidneys. For example, taking the compound Z02176 as the comparison compound, it can be seen that several of the compounds exhibit a distribution in tumor tissues that is close to that of the control (at 22 %ID / g), such as for example [b8Ga]Ga HTK-A07018, which provides a level of 17.1 %ID / g, as well as [68Ga]Ga-HTK-A07017 (18.3 %ID / g), [68Ga]Ga-HTK- A07031 (16.4 %ID / g) and [68Ga]Ga-HTK-A07013 (15.7 %ID / g). Several of the compounds also exhibit a ratio of tumor:kidney uptake that is as good or even much improved over Z02176, which had a tumorkidney uptake ratio of 0.22. For example, [68Ga]Ga-HTK-A07018 exhibited a tumorkidney uptake ratio of 1.04, meaning more of the compound was present in tumor cells / tumor tissue than in the kidneys. Other compounds with good tumorkidney uptake ratios were [68Ga]Ga-HTK-A07013 (1.3), [b8Ga]Ga-HTK-A07016 (3.68), [6SGa]Ga-HTK-A07017 (0.89), and [68Ga]Ga-HTK- A07019 (1.24). Benefits in terms of reduced accumulation in other cells / tissues (e.g. muscle, blood and others) were also exhibited by the compounds. Accordingly, depending on the disease state and application (diagnosis, treatment) that is intended, the B1R targeting compounds of the invention can be selected to provide targeted binding to B1R expressing cells / tissue of interest.

[0150] Figure 4 further shows the PET maximal intensity projections of68Ga-labeled peptides at 1 h post-injection in HEK293T::hBlR tumor-bearing male mice.

[0151] Table 7 below further shows the biodistribution data for co-injection of [58Ga]Ga-HTK-A07013, [b8Ga]Ga-HTK-A07017 and [6SGa]Ga-HTK-A07018, with die compound Z02176, demonstrating that administration of the known BlR-targetingcompound Z02176 effectively reduced uptake of the other compounds into B1R expressing tumors.Table 7. Biodistribution data (%ID / g) of [68Ga]Ga-HTK-A07013, [68Ga]Ga-HTK- A07017, and [6SGa]Ga-HTK-A07018 with co-injection of 100 pg Z02176 in HEK293T::hBlR tumor-bearing male mice at 1 h post-injection.

[0152] The disclosures of all patents, patent applications, publications and database entries referenced in this specification are hereby specifically incorporated by reference in their entirety to the same extent as if each such individual patent, patent application, publication and database entry were specifically and individually indicated to be incorporated by reference.

[0153] Although the invention has been described with reference to certain specific embodiments, various modifications thereof will be apparent to those skilled in the artwithout departing from the spirit and scope of the invention. All such modifications as would be apparent to one skilled in the art are intended to be included within tire scope of the following claims. References:1. Zhang, Z.: Amouroux, G.; Pan, J.; Jenni, S.; Zeisler, J.; Zhang, C.; Liu, Z.; Perrin, D.M.; Benard, F.; Lin, K.S. Radiolabeled B9958 Derivatives for Imaging Bradykinin Bl Receptor Expression with Positron Emission Tomography. Effect of the Radiolabel-Chelator Complex on Biodistribution and Tumor Uptake. Mol. Phcirm. 2016, 13, 2823-2832.2. Lin, K.S.; Amouroux, G.; Pan, I; Zhang, Z.; Jenni, S.; Lau, J ; Liu, Z.; Hundal- Jabai, N.; Colpo, N.; Benard, F. Comparative studies of three68Ga-labeled [Des-Arg10] kallidin derivatives for imaging bradykinin Bl receptor expression with PET. J. Nucl. Med. 2015, 56, 622-627. 3. Liu, Z.; Amouroux, G.; Zhang, Z.; Pan, J.; Hundal-Jabal, N.; Colpo, N.; Lau, X;Perrin, D.M.; Benard, F.; Lin, K.S.lsF-trifluoroborate derivatives of [DesArg1”] kallidin for imaging bradykinin Bl receptor expression with positron emission tomography. Mol. Pharm. 2015, 12, 974-982.4. Lin, K.S.; Benard, F.; Pan, J.; Mesak, F.; Zhang, Z. Compositions targeting bradykinin receptor Bl for medical imaging of cancer and other disorders. WO2014 / 040192 Al [filing date: 13 September 2013 j.

Claims

What is claimed is:

1. A bradykinin Bl receptor (B1R) targeting compound comprising general Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Xaa1- Xaa2-Xaa3- Pro4-Hyp5-Gly6-Cpg7-Sers-D-Tic9-Cpg10(I) wherein:Xaa1, Xaa2and Xaa3are independently a proteinogenic or non- proteinogenic amino acid, with the proviso that at least one of Xaa1, Xaa2and Xaa1is a non-proteinogenic amino acid.

2. The B1R targeting compound according to claim 1, wherein at least one of Xaa1, Xaa2and Xaa3is a proteinogenic or non-proteinogenic amino acid having a side chain R corresponding to Formula (HI) below:-CHi-CHs-X’-X2(III) whereX1is a bond or (-CH2-)n group, where n can be 1 to 3, andX2is selected from the group consisting of -NR’2, -NH-C(=NR’)-NRI2, and -O-NR’i, with each R1independently being any selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl and isobutyl.

3. The B1 R targeting compound according to claim 1 or 2 and comprising the general Formula (I), and with the proviso that at least one of Xaa1and Xaa2is other than Lys.

4. The B1R targeting compound according to any of claims 1-3 and comprising the general Formula (I), and with the proviso that Xaa3is other than Arg.

5. A bradykinin Bl receptor (B1R) targeting compound comprising general Formula (II) or a pharmaceutically acceptable salt or solvate thereof:B- L-Xaa1- Xaa2-Xaa2’- Pro4-Hyp:,-Gly6-Cpg7-Ser8-D-Tic9-Cpg10(II) wherein:B is selected from the group consisting of (i) radiolabelled moieties, (ii) radiometal chelating agents, (iii) moieties configured for19F. / !8F exchange, and (iv) boronate precursors that are capable of conversion to aniSF-labeled trifluoroborate:L is a linker; andXaa1, Xaa2and Xaa2’ are independently (i) a bond, or (ii) a proteinogenic or non- proteinogenic amino acid, with the proviso that either (1 ) at. least one of Xaa1, Xaa2and Xaa3is a bond or a non-proteinogenic amino acid, or (2) L is a bond, or a linking moiety that is other than 4-amino-(l- carboxymethyl)piperidine (Pip).

6. The B1R targeting compound according to claim 5, wherein each of Xaa', Xaa2and Xaa3comprise (i) a bond, or (ii) a proteinogenic or non-proteinogenic amino acid having a side chain R corresponding to Formula (III) below:-CH2-CH2-X1-X2(TIT) whereX1is a bond or (-CH2-)n group, where n can be I to 3, andX2is selected from the group consisting of -NR1?, -NH-C(=NRt)-NR12, and -O-NRb, with each R!independently being any selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, buty l and isobutyl.

7. The BIR targeting compound according to claim 5 or 6, with the proviso that at least one of Xaa1and Xaa2is other than Lys.

8. The B1R targeting compound according to any of claims 5-7, with the proviso that Xaa3is other than Arg.

9. The BIR targeting compound according to any of claims 5-8, wherein L is selected from the group consisting of a bond and a proteinogenic or non-proteinogenic amino acid.

10. The BIR targeting compound according to any of claims 5-8, wherein L is any selected from the group consisting of 4-amino-(l-carboxymethyl)piperidine (Pip), gamma-aminobutyric acid (GABA), and 9-amino-4,7-dioxanonanoic acid.

11. The BIR targeting compound according to any of claims 5-8, wherein L is a bond.

12. The BIR targeting compound according to any of claims 5-8, wherein L is Pip.

13. The BIR targeting compound according to any of claims 5-8, wherein L is GABA.

14. The BIR targeting compound according to any of claims 5-8, wherein L is 9- amino-4,7-dioxanonanoic acid.

15. The BIR targeting compound according to any of claims 2-4 and 6-14, wherein X1is -CH2-, -CH2-CH2- or -CH2-CH2-CH2-.

16. The B1R targeting compound according to any of claims 2-4 and 6-15, wherein X2is any selected from the group consisting of -NH2, -NHCH3, -N(CHs)2, -N(CH3)3, - NHCH(CH3)2, -NH-C(=NH)-NH2, -NH-C(=NCH3)-NH>, -NH-C(=NCH3)-NCH3, -NH- C(=NH)-N(CH3)2, and -O-NH2.

17. The B1R targeting compound according to any of claims 1-4 and 15-16, wherein Xaa1, Xaa2and Xaa3are any selected from the group consisting of Lys, N,N-E- dimethyl-lysine (Lys(Me)), N.N-c-dimethyl-lysine (Lys(Me2», N,N,N-e-trimethyl- lysine (Lys(Me3)), ornithine (Om), S-2-amino-5-(aminooxy)pentanoic acid (hCan), Arg, rV’-monometityl-L-arginine Arg(Me), asymmetric dimethylarginine Arg(Me2), symmetric dimethylarginine Arg(Me,Me), and N-s-isopropyl-lysine (Lys(iPr)), and optionally wherein two or more of Xaa1, Xaa2and Xaa ’ are non-proteinogenic amino acids.

18. The B1R targeting compound according to any of claims 5-16, wherein Xaa1, Xaa2and Xaa3are any selected from the group consisting of a bond, Lys, Lys(Me), N,N-s-dirnethyl-lysine (Lys(Me2)), Lys(Me3), ornithine (Om), S-2-amino-5- (aminooxy)pentanoic acid (hCan), Arg, Arg(Me), ArgtMez), Arg(Me,Me), and N-E- isopropyl-lysine (Lys(iPr)), and optionally wherein two or more of Xaa1. Xaa2and Xaa3are non-proteinogenic amino acids.

19. The B1R targeting compound according to any of claims 1-4 and 15-16, wherein at least one of Xaa1, Xaa2and Xaa3are any selected from the group consisting of Lys(Me2), Om, hCan, and Lys(iPr).

20. The B1R targeting compound according to any of claims 5-16 and 18, wherein at least one of Xaa1, Xaa2and Xaa3are any selected from the group consisting of abond, Lys(Me), Lys(Me2), Lys(Me.3), Om, hCan, Arg(Me), Arg(Mei), Arg(Me,Me), and Lys(iPr).

21. The B1R targeting compound according to any of claims 1-4, 15-16 and 19, wherein Xaa1is any selected from the group consisting of Lys and LysfAfe).

22. The B1R targeting compound according to any of claims 5-16, 18 and 20, wherein Xaa1is any selected from the group consisting of a bond, Lys, and LyslMe?.).

23. The B1R targeting compound according to any preceding claim, wherein Xaa2is any selected from the group consisting of Lys, Orn, Lys(Me2), and hCan.

24. The B1R targeting compound according to any preceding claim, wherein at least one of Xaa1and Xaa2is Lys(Me2), and optionally wherein both of Xaa1and Xaa2are Lys(Me2).

25. The B1R targeting compound according to any preceding claim, wherein Xaa’ is any selected from the group consisting of Arg and Lys(iPr).

26. The B1R targeting compound according to any of claims 1-2, 4-6, and 8-25, wherein Xaa1and Xaa2are Lys.

27. The B1R targeting compound according to any of claims 1-3, 5-7 and 8-26, wherein Xaa1is Lys and Xaa3is Arg.

28. The B1R targeting compound according to any of claims 1-3, 5-7 and 8-27, wherein Xaa2is Lys and Xaa3is Arg.

29. The B1R targeting compound according to any of claims 5-28, wherein B is a radiometal chelating agent that is selected from the group consisting of diethylenetriamine pentaacetic acid (DTPA), 1,4,7,10-tetraazacyclotetradecane-1.4.7.10-tetraacetic acid (DOTA), 1,4, 7, 10-tetraazacyclododececane,l -(glutaric acid)-4.7.10-triacetic acid (DOTAGA), ethylenediaminetetraacetic acid (EDTA), 1,4,7- triazacyclononane-triacetic acid (NOTA), 1,4,7-tiiazacyclononane-l -glutaric acid-4, 7- diacetic acid (NODAGA), I,8-N,N -bis-(carboxymethyl)-l,4,8,l 1- tetraazacyclotetradecane (TE2A), 3,6,9, 15-tetraazabicyclo[9.

3. l]pentadeca-1(15),1 l,13-triene-3,6,9-triacetic acid (PCTA), 1-substituted 1,4,7,-tricarboxymethyl-1.4.7.10-teraazacyclododecane triacetic acid (DO3A), DEDPA (6,6'-[l,2- etbanediylbis(iminomethylene)]bis(2-pyridinecaiboxylic acid), 1 ,4,8,11- tetraazacyclotetradecane-l,4,8,l l-tetraacetic acid (TETA), NODASA, CB-DO2A, 3p- C-DEPA, TCMC, DO3A, DTPA, DTPA analogues optionally selected from CHX-A”- DTPA and 1B4M-DTPA, TETA, NOPO, Me-3,2-HOPO, CB-TEIAIP, 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, Hzdedpa, Hmctapa, Hrpy4pa, EUPypa, Ehazapa, Hsdecapa, and other picolinic acid derivatives, tkCHXoctapa, Hkneunpa-p-Bn-NOz, CP256, PCTA, {4-[2-(bis-carboxymethylamino)- ethyl]-7-carboxymethyl-[l, 4, 7]triazonan-l-ylJ -acetic acid (NET A), C-NETA, C- NE3TA, HBED, BCPA, CP256, YMI03, desferrioxamine (DFO) and DFO derivatives, Hsphospa, a trithiol chelate, mercaptoacetyl, hydrazinonicotinamide, dimercaptosuccinic acid, 1,2-ethylenediylbis-L-cysteine diethyl ester, methylenediphosphonate, N, N0-bis(2-hydroxy-5-sulfobenzyl)-ethylenediamine-N, N — diacetic acid (SHBED), hexamethylpropyleneamineoxime, hexakis(methoxy isobutyl isonitrile), and 2,2',2",2'"-(l,i0-dioxa-4,7,13,16-tetTaazacyclooctadecane- 4,7,13,16-tetrayl)tetraacetic acid (CROWN) and derivatives thereof.

30. The B1R targeting compound according to claim 29, wherein B is any selected from the group consisting of DOTA, DOTAGA, NOTA and NOD AG AThe B1R targeting compound according to claim 30, wherein B is DOTA32. The B1R targeting compound according to any of claims 5-29, wherein B is a moiety configured forI9F / 18F exchange or a boronate precursor that is capable of conversion to a18F-labeled trifluoroborate.

33. The B1R targeting compound according to any of claims 5-29, wherein B is trifluoroborate.

34. The B1R targeting compound according to any of claims 1-4, 15-16, 19, 21, and 23-28, wherein the compound comprises any of the following:(1) Lys-Om-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in HTK-AO7O15)(2) LysfMez)- Lys(Me2)-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in HTK-A07016)(3) Lys(Me2)-Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in HTK-A07017)(4) Lys- Lys(Me2)-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in HTK-A07018)(5) Lys-hCan-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in HTK-A07019)(6) Lys- Lys-Lys(iPr)-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in HTK-A07020).

35. The B1R targeting compound of any of claims 1-4, 15-16, 19, 21, 23-28, and 34 wherein the compound consists essentially of that corresponding to general Formula (I).

36. The B1R targeting compound of any of claims 1-4, 15-16, 19, 21, 23-28 and 34- 35, wherein the compound consists of that corresponding to general Formula (I).

37. The B1R targeting compound according to any of claims 5-16, 18, 20 and 22- 33, wherein the B1R targeting compound comprises a B1R targeting moiety corresponding to any of those of claims 1-4, 15-16, 19, 21, 23-28 and 34-36.

38. The B1R targeting compound according to any of claims 5-16, 18, 20, 22-33 and 37, wherein the compound of Formula (II) comprises any of the following B1R targeting sequences:(1) Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in HTK-A07013)(2) Lys-Orn-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in HTK-A07015)(3) Lys(Me2)-Lys(Me2)-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in HTK-A07016)(4) Lys(Me?)-Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in HTK-A07017)(5) Lys-Lys(Me2)-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in HTK-A07018)(6) Lys-hCan-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in HTK-A07019)(7) Lys- Lys-Lys(iPr)-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in HTK-A07020)(8) Lys- Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in HTK-A07030)(9) Lys- Lys(Me)-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in ARO 1001)( 10) Lys(Me)- Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in ARO 1002)(11) Lys- Lys(Me3)-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in AR01003)(12) Lys(Me.0- Lys-Arg-Pro-Hyp-Gly-Cpg-Ser-DTic-Cpg (in AR01004).

39. The B1R targeting compound according of any of claims 5-16, 18, 20, 22-33 and 37-38, wherein the compound of Formula (II) corresponds to any of the following:« .A 6 * h a 1 1 u a T § "w40. The B1R targeting compound according to any of claims 5-16, 18, 20, 22-33 and 37-38, wherein the compound is radiolabelled with a radionuclide.

41. The B1R targeting compound according to claim 39, wherein the radionuclide is selected from the group consisting of68Ga,I8F,!23I,I31I,90Y,177Lu,61Cu,64Cu,67Cu,67Ga,11’In,44Sc,86Y,S9Zr,90Nb,! !7mSn,165Er,227Th,225Ac,213Bi,212Bi,72As,77As,2, 1At,203Pb,212Pb,47Sc,166HO,123I,;ssRe,ls6Re,149Pm,159Gd,105Rh,l09Pd,198Au,199Au,175Yb,142Pr,! !4mIn,94mTc,i49Tb,i52Tb,155Tb,i61Tb and99mTc.

42. The B1R targeting compound according to claim 41, wherein the compound is radiolabeled with a diagnostic radionuclide corresponding to any selected from the group consisting of123I, "mTc,inIn,6SGa,18F,44Sc,2O3Pb,64Cu,61Cu, and86Y.

43. The B1R targeting compound according to claim 41, wherein the compound is radiolabeled with a therapeutic radionuclide corresponding to any selected from the group consisting of177Lu,i i !In,90Y,225Ac,212Pb,213Bi,64Cu,57Cu,lS6Re and!**Re.

44. The B1R targeting compound according to claim 42, wherein the compound is radiolabeled with a radionuclide corresponding to68Ga.

45. The B1R targeting compound according to any of claims 5-16, 18, 20, 22-33,37-41 and 43, wherein the compound is a therapeutic compound.

46. The B1R targeting compound according to any of claims 5-16, 18, 20, 22-33,37-42 and 44, wherein the compound is a diagnostic compound.

47. The B1R targeting compound according to any of claims 5-16, 18, 20, 22-33, and 37-39 wherein the compound is unlabelled.

48. A pharmaceutical composition for diagnostic or therapeutic use, comprising the B1R targeting compound of any of claims 5-16, 18, 20, 22-33, and 37-47.

49. The pharmaceutical composition according to claim 48, wherein the composition is formulated for parenteral administration.

50. Use of the BIR targeting compound, or the pharmaceutical composition of any of claims 1 -49, for in vivo imaging of a tissue or cancer expressing or overexpressing BIR.

51. Use of the BIR targeting compound, or the pharmaceutical composition of any of claims 1-49, for radiotherapeutic treatment of a tissue or cancer expressing or overexpressing BIR.

52. A method for imaging a tissue or cancer expressing or overexpressing bradykinin Bl receptor (BIR) in a patient, comprising administering to the patient the BIR targeting compound, or the pharmaceutical composition of any of claims 1-49, with a radiolabel suitable for in vivo imaging.

53. A method for treating a tissue or cancer expressing or overexpressing bradykinin Bl receptor (BIR) in a patient, comprising administering to the patient the BIR targeting compound, or the pharmaceutical composition of any of claims 1-49, with a radiolabel suitable for radiotherapeutic treatment.

54. The use according to any of claims 50-51, or the method according to any of claims 52-53, wherein the cancer or tissue is a cancer associated with BIR overexpression.

55. The use according to any of claims 50-51 and 52, or the method according to any of claims 52-53 and 54, wherein the cancer is a breast cancer, prostate cancer, lung cancer, brain cancer, esophageal cancer, cervical cancer, gastric cancer, or renal cancer.

56. The use according to any of claims 50-51 and 54-55, or the method according to any of claims 52-53 and 54-55, wherein the cancer is an early stage breast or prostate cancer.

57. The use according to any of claims 50-51 and 54-56, or the method according to any of claims 52-53 and 54-56, wherein the cancer is primary or recurrent prostate cancer.

58. The use according to any of claims 50-51 and 54-57, or the method according to any of claims 52-53 and 54-57, wherein the tissue is damaged endovascular intima.

59. The use according to any of claims 50-51 and 54-58, or the method according to any of claims 52-53 and 54-58, wherein the damaged endovascular intima comprises a plaque.

60. The use according to any of claims 50-51 and 54-59, or the method according to any of claims 52-53 and 54-59, wherein the BLR compound or composition is administered parenterally.

61. The use according to any of claims 50-51 and 54-60, or the method according to any of claims 52-53 and 54-60, wherein the B1R compound or composition is administered to a mammal.

62. The use according to any of claims 49-50 and 53-60, or the method according to any of claims 52-53 and 54-61, wherein the BLR compound or composition is administered to a human.

63. The use according to any of claims 50-51 and 54-62, or the method according to any of claims 52-53 and 54-62, wherein the BLR compound or composition is administered to provide a diagnosis of cancer or other condition based on the expression of B1R.

64. The use according to any of claims 50-51 and 54-63, or the method according to any of claims 52-53 and 54-63, wherein the B1R compound or composition is administered to monitor a response to therapy for cancer or other condition that involves the expression of B1R.

65. The use according to any of claims 50-51 and 54-64, or the method according to any of claims 52-53 and 54-64, wherein the B1R compound or composition is administered to treat a metastasized cancer.

66. The use according to any of claims 50-51 and 54-65, or the method according to any of claims 52-53 and 54-65, wherein the B1R compound or composition isadministered to guide focal ablative treatment of a cancer or other condition that involves expression of B1R.

Images