Lat-1 targeting amino acid derivatives and uses thereof

Abstract

The present invention relates to diagnosing and treating malignancies, and more specifically to labeled small molecules for diagnosing and treating cancer. The present invention is directed to small-molecule therapeutics and diagnostic agents that can engage LAT1 to enable targeted diagnosis and therapy using a theragnostic approach. Thus, preferred embodiments of the present invention provide radiopharmaceuticals that can interact with LAT1 and provide a mechanism to bind and / or transport both diagnostic and therapeutic radionuclides to provide proof of target engagement, diagnostic capabilities and / or subsequent treatment.

Description

LAT-1 TARGETING AMINO ACID DERIVATIVES AND USES THEREOFTECHNICAL FIELD

[0001] The invention relates to diagnosing and treating malignancies, and more specifically to labeled small molecules for diagnosing and treating cancer.BACKGROUND OF THE ART

[0002] Solid and hematologic cancers together are a leading cause of death across the world across different geographies and populations. The worldwide incidence of cancer is approximately 20 million cases on a yearly basis in 2022, which is well over 50,000 cases per day.

[0003] Cancer cells are characterized by high proliferation. The increased proliferative activity of cancer cells has long been exploited via chemotherapy to differentially induce cellular damage and death in cancer cells. However, this is a one size fits all approach that does not work across all cancer types, let alone in many individual cancers.

[0004] The broad movement in medicine from population-based approaches which address average effects of therapy across a heterogenous population has shifted to a personalized approach to medicine to precisely deliver treatment while sparing normal tissues. In this vein, the LAT1 transporter has been proposed as a target of interest due to over expression in several tumor types, yet with relatively modest expression elsewhere in the body.

[0005] LAT1, the light subunit, forms a heterodimer with CD98 while the heavy subunit is a membrane glycoprotein h It is a key protein in cell growth and development and is highly expressed in the testis, bone marrow, placenta and blood brain barrier (BBB) to deliver essential amino acids.2,3Unique to the BBB, it is present on both apical and basolateral membranes and is a pH and Na+ independent transporter.1,4Aside from essential amino acids, it is able to transport thyroid hormones and other exogenous drugs.1The basic structural requirements for substrates of LAT1 are carboxylic acid and amino groups in addition to a large side group.1,5

[0006] LAT1 is overexpressed in several solid and hematologic tumor types due to the metabolic requirements for essential amino acids in proliferating cancer cells. Aside frommalignant gliomas, lung and breast cancers, LAT1 expression is increased in additional solid tumors including those originating from bladder, uterine cervix, esophagus, kidneys, lymphoma, multiple myeloma, among several others.6-9Early therapies under evaluation include non-selective LAT1 substrates, inhibitors, antibodies, and targeted nano-particle delivery systems.6For example, US publication 2022 / 0105125 discloses prodrugs and ligands for targeting a micelle to LATl. Some amino acid derivatives have been proposed as inhibitors of LAT1, for example in US patent no. 7,345,068.

[0007] LATl as a cancer target is best characterized by existing imaging data, central to which are radiopharmaceuticals suited to imaging the metabolism of essential amino acids. Using amino acid derivatives for imaging presents challenges related to the numerous metabolic pathways involving each amino acid, as shown in US publication 2019 / 0247527. O-(2-18F- fluoroethyl)-L-tyrosine (FET) is used in tumor imaging, for example as discussed in US patent no. 7,544,715. FET is well known in the art, as stated in US Patent no. 7,189,383. FET, however, presents unwanted off-target effects. FET in normal subjects has low generalized uptake throughout normal tissues with the highest accumulation in the urinary tract due to urinary excretion.10US Patent no. 9,839,701 proposes radiolabeled tyrosine derivatives having a linear chain extending from the phenyl group and terminating in a radioactive fluorine isotope. However, the disclosed compounds increase amino acid efflux from the cell, causing rapid excretion of the compound and being, accordingly, less suitable for delivering therapeutic agents.

[0008] Gliomas, particularly glioblastoma multiforme, have been most studied as a cancer target for amino acid-based diagnostics and therapeutics.11Studies have, however, shown that the effectiveness of such diagnostics and therapeutics to be very dependent on the molecule’s chemistry.13

[0009] While gliomas have been most studied, there is promising evidence suggesting target engagement in other tumors types such as lung cancer and breast cancer. In lung cancer, there is more than 6 times the expression of LATl mRNA in NSCLC compared to normal lung tissue.12Aggressive lung cancer with high cancer stem cell activity demonstrates high LATl mRNA expression and is associated with shorter overall survival.14LATl expression varies byNSCLC tumor type, most frequently expressed in squamous cell carcinomas (91%), large cell carcinomas (67%), and adenocarcinomas (29%), again associated with a worse prognosis.15Imaging biomarker proof of LAT1 target engagement has been demonstrated both via L-3- [18F]-Fluoro-a-methyl tyrosine (FAMT) and FET, both with a predilection for uptake in squamous cell histological subtypes.16, 17

[0010] In breast cancer, major unmet needs include the treatment of women with triplenegative breast cancer (TNBC) or those with advanced stage aggressive disease who are destined for a palliative care approach. It has been shown that 41% of TNBC patients express LAT1 which contributes to worse prognosis.18Another study has corroborated these findings while also demonstrating increased LAT1 expression in metastatic and invasive breast cancer across breast cancer subtypes including those expressing hormone receptors.19Imaging proof of target engagement has been demonstrated in human subjects with breast cancer.17

[0011] Therapeutic and diagnostic compounds according to the prior art present one or more disadvantages. Due to the instability of many radionuclide bonds, radionuclides are released from the compounds and thus either do not participate in the uptake by tumour cells, or are not excreted from the cell according to an intended metabolic and / or excretion pathway. Unbonded radionuclides may furthermore circulate in the body of a subject or be absorbed into healthy tissue, causing unwanted tissue damage.

[0012] Current treatment options for cancer include external beam radiotherapy and chemotherapy. These techniques, however, have known side effects significantly affecting the quality of life of the patient and may miss existing small and / or circulating tumor masses which may then cause a reoccurrence of cancer.

[0013] Therefore, there is a need for better small-molecule therapeutic and / or diagnostic agents to address at least some of the drawbacks of present technologies. In particular, improved agents are needed to treat solid and hematologic malignancies that are refractory or undertreated with current treatments.SUMMARY

[0014] The embodiments of the current invention are directed to novel small molecule therapeutics and diagnostics that take advantage of the LAT1 transporter. Preferred embodiments of the present invention target cellular proliferation through the LAT1 transporter. LAT1 uniquely allows the embodiments of the invention to treat and diagnose cancer, including but not limited to brain metastases, an area where many current therapeutics fail due to restricted access by the blood brain barrier.

[0015] The current invention is directed to the diagnosis and treatment of both solid and hematologic malignancies with radiolabeled small molecules that target the LAT1 transporter.

[0016] The embodiments of the present invention may also comprise small molecules labeled with non-radioactive halogens and radioactive halogens. In a preferred embodiment of the present invention, the radiolabelled small molecules may be labeled with radioactive halogens selected from the group consisting of18F,75Br,76Br,77Br,82Br,123I,124I,125I,131I,210At,211At and all other astatine isotopes.

[0017] The embodiments of the present invention may also comprise small molecules able to chelate radiometals. In a preferred embodiment of the present invention, the radiolabelled small molecules may be labeled with radiometals from a group comprising but not restricted to212Pb89Zr,44Sc,n iIn,90Y,66Ga,67Ga,68Ga,177Lu, "mTc,61Cu,62Cu,64Cu,67Cu,149Tb,152Tb,155Tb,161Tb,153Gd,155Gd,157Gd,213Bi,225Ac,230U,223Ra and165Er.

[0018] In general, the present invention provides compounds of Formulas (I), (III), (IV) and (V). The compound of Formula (I) can be described generally as having a phenylalanine or tyrosine backbone and having side groups Ri and R2 on the phenyl ring with a general formula NH2COOH(R7)-C(R5)(R6)-(CH2)n-PhRiR2. The compounds of Formula (III) can be described generally as having a tryptophan backbone and having side groups Ri and R2 on the phenyl ring with the general formula NH2COOH(R7)-C(R5)(R6)-(CH2)n-Pyr(R3,R4)PhRiR2.

[0019] Ri is one of a radionuclide, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl,amino, sulfhydryl, sulfonyl, aldehyde or ketone. In embodiments, Ri is substituted in an ortho, a meta or a para position on the phenyl ring. In embodiments, the phenyl ring is substituted to yield a heterocyclic ring.

[0020] R-2 is one of hydrogen, hydroxyl, a radionuclide, alkyl, halo-alkyl, alkenyl, halo- alkenyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo- aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde, ketone.

[0021] In embodiments, at least one of Ri and R2 is a side group of Formula (II), having a general formula 0-C(Rio)(Rii)-(CH2)n-PhRsR9. In embodiments, each of Rs and R9 is one of hydrogen, hydroxyl, a radionuclide, alkyl, halo-alkyl, alkenyl, halo-alkenyl, alkynyl, halo- alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde, ketone.

[0022] In embodiments, each one of R5, Re, R7, Rio and Rn is one of hydrogen, alkenyl, halo-alkenyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde and ketone.

[0023] In embodiments, “n” is between 0 and 20.

[0024] In embodiments, any one of Ri and R2 is O-halo-benzyl and a halogen atom in theO-halo-benzyl group is in one of a meta position and a para position on the O-halo-benzyl. In embodiments, the O-halo-benzyl is in one of a meta position and a para position on the compound of Formula (I) or (IV). In embodiments, the halogen atom is one of F, Br, I and At. In embodiments, the halogen atom is a radioactive isotope. In embodiments, any one of Ri and R2 is O-benzyl and Rs, R9 or both are the radionuclide comprising a radioactive halogen isotope.

[0025] In embodiments, Ri the side group of Formula (II), at least one of Rs and R9 is a first radionuclide, R2 is a second radionuclide, and the first and second radionuclides are isotopes of different atoms.

[0026] The compounds of Formulas (IV) and (V) have a general phenylalanine, tyrosine or tryptophan backbone as described above and have at least one chelating moiety as part of at least one side group Xi, X2 and / or X3. In embodiments, Xi is a chelating moiety. In embodiments, Xi is a chelating moiety substituted one of: hydroxyl, methoxyl, alkynyl, halo- alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde and ketone. In embodiments, each one of X2 and X3 is any one of hydrogen, halogen, hydroxyl, methoxyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde and ketone.

[0027] In embodiments, the chelating moiety comprises a heterocyclic group. In embodiments, the chelating moiety is of Formula (VI) having a general formula NHCO-CH2- C8N4(CH2COOH)3.

[0028] In embodiments, Xi is the chelating moiety substituted on one of methoxyl and O- benzyl. In embodiments the chelating moiety is substituted on O-benzyl in one of a meta position and a para position. In embodiments X2 and X3 are, each, a halogen atom in the meta position. In embodiments, the halogen atom is iodine. In embodiments the chelating moiety further comprises a metal atom chelated thereto. In embodiments the metal atom is a radioactive isotope. In embodiments, the radioactive isotope is one of a diagnostic isotope and a therapeutic isotope. In embodiments, the metal atom is lutetium or gallium, for example177Lu or68Ga.

[0029] In embodiments, the compounds comprise a plurality of chelating moieties, the plurality of chelating moieties having a plurality of radioactive metal isotopes chelated thereto. In embodiments, the plurality of radioactive metal isotopes comprises diagnostic radioactive metal isotopes, therapeutic radioactive metal isotopes, or combinations thereof.

[0030] The present invention provides methods for diagnosing comprising administering, to a subject, a diagnostically effective amount of the compounds described above, or pharmaceutically acceptable salts thereof, and detecting radioactive emissions from the subject.

[0031] The present invention provides methods of treating malignancies comprising administering, to a subject, a therapeutically effective amount of one or more of the compounds described above or pharmaceutically acceptable salts thereof. In embodiments the therapeutically effective amount is 0.00001 mg / kg to 100 mg / kg body weight, 0.001 mg / kg to 50 mg / kg body weight, or 0.01 mg / kg to 10 mg / kg body weight, administered in one or more doses. In embodiments, the treating further comprises administering, to the subject, one or more of external beam therapy and non-radioactive therapies. In embodiments, the one or more nonradioactive therapies comprise check-point inhibitors.

[0032] The present invention provides a pharmaceutical composition comprising one or more of the compounds described above, or pharmaceutically acceptable salts thereof, and one or more of pharmaceutically acceptable carriers, adjuvants, excipients, diluents, pharmaceutical auxiliaries, therapeutic ingredients and prophylactic ingredients. In embodiments, the adjuvants comprise one or more of ascorbic acid, probenecid, immunomodulators, checkpoint inhibitors, cytokines, DNA damage repair inhibitors, PARP inhibitors and PAR-2 inhibitors.

[0033] The present invention provides uses of the compounds described above for diagnosing and / or treating malignancies, optionally in conjunction with one or more of external beam therapy, immunomodulators, checkpoint inhibitors, cytokines, adjuvants, DNA damage repair inhibitors, PARP inhibitors and PAR-2 inhibitors.BRIEF DESCRIPTION OF THE DRAWINGS

[0034] This application does not presently include drawings.DETAILED DESCRIPTION

[0035] The description that follows, and the embodiments described therein, is provided by way of illustration of an example, or examples, of particular embodiments of the principles andaspects of the present invention. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the invention.

[0036] It should also be appreciated that the present invention can be implemented in numerous ways, including as a process, method, an apparatus, a system, a device, or a method. In this specification, these implementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention.

[0037] In this disclosure, a number of terms and abbreviations are used. The following definitions of such terms and abbreviations are provided. It will be understood by a person skilled in the relevant art that in different geographical regions and jurisdictions these terms and definitions used herein may be given different names but relate to the same respective systems.

[0038] Preferred embodiments of the present invention can be implemented in numerous configurations depending on implementation choices based upon the principles described herein. Various specific aspects are disclosed, which are illustrative embodiments not to be construed as limiting the scope of the disclosure. Although the present specification describes components and functions implemented in the embodiments with reference to standards and protocols known to a person skilled in the art, the present invention as well as the embodiments of the present invention are not limited to any specific standard or protocol.

[0039] As used herein, a person skilled in the relevant art may generally understand the term “comprising” to generally mean the presence of the stated features, steps, or components as referred to in the claims, but that it does not preclude the presence or addition of one or more other features, steps, components, or groups thereof.

[0040] The present invention is directed to small-molecule therapeutics and diagnostic agents that can engage LAT1 to enable targeted diagnosis and therapy using a theragnostic approach. Thus, preferred embodiments of the present invention provide radiopharmaceuticals that can interact with LAT1 and provide a mechanism to bind or transport both diagnostic and therapeutic radionuclides to provide proof of target engagement, diagnostic capabilities and / or subsequent treatment.

[0041] Without being bound by any theory of operation or mechanism of action, the embodiments disclosed herein are based in part, on an unpredicted / unexpected discovery that novel small molecule diagnostic agents and therapeutics provided herein may target cellular proliferation through the LAT1 transporter. While the compounds provided herein are useful for diagnosing and treating a variety of conditions, LAT1 uniquely positions the provided radiopharmaceuticals to treat brain metastases, an area where many current therapeutics fail due to restricted access by the blood brain barrier.

[0042] In preferred embodiments of the invention, radiopharmaceutically, therapeutically and diagnostically effective derivatives of amino acids have been designed to improve cellular uptake and retention thereof, while providing a mechanism to label the molecules with one or more labeling moieties, such as one or more halogens and / or one or more radionuclides, to enable target identification and treatment with radiopharmaceuticals, alone or in combination with a cocktail approach.

[0043] For example, proof of target engagement can be provided by a radiopharmaceutical labeled with a beta-emitting halogen such as, for example,18F,76Br,77Br,123I,124I,131I. Once the target is confirmed, a radiopharmaceutical can be used in the treatment or diagnosis of the patient. This may be a single therapeutic that is labeled with a beta emitting radionuclide such as131I or an alpha emitting radionuclide, such as123I,211At or82Br, or a radionuclide emitting other useful radiation, or combinations thereof. A cocktail of these radiopharmaceuticals in any ratio can be used to treat both gross and microscopic tumor volumes. Proof of target engagement may also be provided by radiometals, including but not limited to embodiments wherein molecules are radiolabeled via metal chelation. Diagnostic radionuclides include but are not limited to67Ga,68Ga,n iIn.

[0044] Throughout the present disclosure, references to and diagrams of aromatic or cyclic compounds include references to heterocyclic compounds having one or more nitrogen atoms substituted for a one or more corresponding carbon atoms.

[0045] Throughout the present disclosure, the terms “radiopharmaceutical”, “radiotherapeutic”, “radiodiagnostic”, “radiation-emitting compound” and similar terms may be used interchangeably without limiting its scope.

[0046] Throughout the present disclosure, reference to the compounds as described includes reference to pharmaceutically acceptable salts thereof.

[0047] Throughout the present disclosure, the terms “cancer”, “tumor” and “malignancy” may be used interchangeably without limiting its scope.

[0048] Throughout the present disclosure, the terms “patient” and “subject” may be used interchangeably without limiting the scope of the principles disclosed herein, and may include a human as well as an animal, such as a monkey, a cow, a horse, a cat, a dog. It is understood that the radiotherapeutics disclosed herein may be useful in treating both human and non-human cancers, with the necessary adaptations for dosage and toxicity as will be apparent to a skilled person.

[0049] While throughout the specification the compounds, methods, uses and compositions may be referred to as treating and / or diagnosing cancer, the present invention provides diagnostic and / or therapeutic compounds, methods, uses and compositions suitable for diagnosing and / or treating conditions that exhibit LAT1 overexpression and are not limited to cancer.

[0050] In one aspect of the present invention, a LAT1 -targeting amino acid derivative has the general Formula (I). The L-isomer form is used for the purpose of illustration only, and it is understood that other isomers of the compounds disclosed herein may be used.Formula (I)

[0051] Ri may be a radionuclide, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde or ketone, and may be substituted on any suitable atom in the aromatic ring. For example, the aromatic ring may instead be a heterocyclic ring comprising at least one nitrogen atom.

[0052] Ri may be a side group of Formula (II):Formula (II)

[0053] When Ri is a side group of Formula (II), each one of Rs and R9 may be any one of hydrogen, hydroxyl, a radionuclide, alkyl, halo-alkyl, alkenyl, halo-alkenyl, alkynyl, halo- alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde, ketone.

[0054] R2 may be any one of hydrogen, hydroxyl, a radionuclide, alkyl, halo-alkyl, alkenyl, halo-alkenyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde, ketone, or a side group of Formula (II).

[0055] Each one of R5, Re, R7, Rio and Rn may be any one of hydrogen, alkenyl, halo- alkenyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo- aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl,heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde and ketone.

[0056] In Formula (I) and Formula (II) “n” is between 0 and 20. For example, when the aminoacid derivative does not have a modified chain between the amino, acid and phenyl group, n is zero. The chain may be lengthened by between 1 and 20 CH2 groups. It is understood that other groups beyond CH2 may be used. In non-limiting examples, one or more CH2 groups may be replaced with alcohol groups, ketone groups, methylated groups, ethylene groups, glycol groups and others. The length, composition and structure of the chains adjacent one or more phenyl groups may be adapted to modulate the pharmacokinetics and other properties of the radiotherapeutic and / or radiodiagnostic compounds herein. In a non-limiting example, longer chains may be used to reduce molecular transport outside of a blood vessel or to reduce absorption by the intestine, so as to maintain a substantial portion of the compound in circulation within the system to which it was administered. In other examples, groups having different sizes and / or charges may be provided on the chain to modulate the shape of the compound of Formula (I), for example by increasing or decreasing an angle between functional groups. One or more chains may be at least partly PEGYlated for modulating bioavailability, pharmacodynamics and / or the pharmacokinetics of the compounds disclosed herein.

[0057] The compound of Formula (I) is a radiation-emitting compound and accordingly comprises at least one radionuclide. The radionuclide may emit alpha particles, beta particles, gamma radiation, or a combination thereof. The compound of Formula (I) may comprise more than one radionuclide. For example, the compound may comprise radionuclides each emitting a different type of radiation, and / or having differing half-lives and / or emission rates and / or emission intensities. When used diagnostically, the compound of Formula (I) comprises diagnostic-suitable radionuclides emitting radiation that is detectable outside the body of a subject. When used therapeutically, the compound of Formula (I) comprises radionuclides suitable for therapeutic use, for example radionuclides emitting alpha particles, beta particles and / or other radiation suitable for killing and / or damaging target cells.

[0058] Accordingly, the radiation emitted by radionuclides suitable for therapeutic use may be undetectable or partly detectable outside the body of a subject. Combinations ofradionuclides for therapeutic and diagnostic use are possible. The same radionuclide may be suitable for diagnostic and for therapeutic use. For example, the radionuclide decay chain may comprise both diagnostic and therapeutic radiation emission.

[0059] The radionuclide may be any suitable radionuclide. In some embodiments, the radionuclide is a radioactive halogen isotope, such as a fluorine, chlorine, bromine and / or astatine isotope. The radionuclide may be a radioactive metal isotope.

[0060] Ri, R2, Rs and / or R9 may be substituted on the phenyl and / or heterocyclic rings in any suitable position. In embodiments, Ri is a side group of Formula (II) substituted in the meta or para position on the phenyl ring of the compound of Formula (I). In a similar fashion, Rs and R9 may be one or more radionuclides or radionuclide-containing groups substituted in the meta and / or para position on the phenyl ring of Formula (II).

[0061] In embodiments, the compounds of the present invention comprise one or more of compounds A - S as shown. Reference letter “I” is omitted for clarity.(H) (J)

[0062] According to a broad aspect, a LAT1 -targeting aminoacid derivative is a compound of Formula (III):Formula (III)

[0063] The general principles outlined for the compound of Formula (I) apply, with the necessary adaptations, to the compound of Formula (III). Accordingly the cyclic portions of the compound of Formula (III) may be heterocyclic without departing from the principles disclosed herein. For example, the phenyl ring may be a pyridyl ring, or another appropriate heterocyclic ring.

[0064] Ri may be hydrogen, hydroxyl, a radionuclide, alkyl, halo-alkyl, alkenyl, halo- alkenyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo- aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde, ketone. R2 may be any one of hydrogen, hydroxyl, a radionuclide, alkyl, halo-alkyl, alkenyl, halo-alkenyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde, ketone.

[0065] Any one or both of Ri and R2 may be a side group of Formula (II) as described above and may comprise groups Rs and R9 as described above.

[0066] Each of R3, R4, Rs, Re, R7, Rio and Rn may be any one of alkenyl, halo-alkenyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde and ketone. “N” is between 0 and 20, as described above.

[0067] The compound of Formula (III) comprises one or more radionuclides substituted thereto. The one or more radionuclides may be substituted onto the side group of Formula (II) when present, onto the phenyl or indole ring of the compound of Formula (III), or onto combinations thereof.

[0068] In embodiments, the compounds of the present invention comprise one or more of the compounds A’ - L’. Reference letter “I” is omitted for clarity.

[0069] According to a broad aspect, a LAT1 -targeting amino acid derivative comprises a compound of Formula (IV) or a compound of Formula (V):

[0070] Xi may be any one of a chelating moiety, such as a chelating moiety substituted directly onto the phenyl ring, and a chelating moiety substituted on any one of hydroxyl, methoxyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde and ketone.

[0071] Each one of X2 and X3 may be any one of hydrogen, halogen, hydroxyl, methoxyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo- aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde and ketone. Each one of X2 and X3 may be a side group of Formula (II) as described above. Each one of X2 and X3 may comprise a radionuclide. For example, when X2 and / or X3 are halogen or O-halo-benzyl, one or more of the halogen atoms may be a radioactive isotope.

[0072] Each of R3, R4, Rs, Re, R7, Rio and Rn, when present, may be any one of alkenyl, halo-alkenyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde and ketone.

[0073] The chelating moiety may comprise a heterocyclic group. In embodiments, the chelating moiety may be a moiety of Formula (VI):Formula (VI)

[0074] The chelating moiety may comprise dodecane tetraacetic acid (DOTA), conjugates and / or derivatives thereof. In some embodiments, two or more chelating moieties may be provided on one aminoacid derivative, thereby allowing chelation of two or more radionuclides to the same derivative.

[0075] In the embodiment shown in Formula VI, the amino group is conjugated directly onto the aminoacid. One or more carbon atoms may be interposed between the amino group, or between the chelating moiety in general, and the aminoacid. For example, between 1 and 20 carbons may be interposed between the amino group of the chelating moiety of Formula VI and the aminoacid. Any one or more of the interposed carbons may comprise a group Rs, the group Rs being any one of hydrogen, hydroxyl, a radionuclide, alkyl, halo-alkyl, alkenyl, halo-alkenyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo- aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde, and ketone. If two or more carbons are interposed, it is understood that each one of the carbons may comprise one of the aforementioned groups and combinations thereof, such as but not limited to hydrogen on a first carbon and hydroxyl on a second carbon, arepossible. A non-limiting embodiment comprising interposed carbons is shown as Formula (Via). When m is zero, it is understood that no Rs group is conjugated thereto and that Formula (Via) corresponds to Formula (VI):Formula (Via)

[0076] It is understood that other chelators may be used instead of DOTA or in combination therewith, for example as a cocktail of aminoacid derivatives.

[0077] In embodiments, the chelating moiety is substituted on O-benzyl, being in any one of the meta or para position on the benzyl ring. The O-benzyl group may be substituted onto the phenyl ring of the compounds of Formula (IV) and (V) in any one of the meta and para position.

[0078] The compounds of Formula (IV) and (V) may comprise a plurality of chelating moieties appropriately substituted thereto. For example, a plurality of chelating moieties may be configured to deliver a higher radiotherapeutic payload per aminoacid derivative engaged to the LAT1 transporter on a cancer cell, or a combination of radiotherapeutic and radiodiagnostic isotopes. The plurality of chelating moieties may have isotopes of different atoms chelated thereto, as appropriate.

[0079] In embodiments, the compounds of the present invention comprise one or more of compounds A” - F ” :

[0080] It is understood that, in the compounds A”-F” iodine, when present, may be substituted with any appropriate halogen, or with a radionuclide, and the chelating moiety may be substituted on any of the meta positions or the para position on the benzyl group. In compounds A”-F”, the carbon atom between the amino group of the chelating moiety and the oxygen on the aminoacid, when present, may be omitted without departing from the present teachings.

[0081] Each chelating moiety is configured to receive an atom or an ion for transport to or into a cell. Accordingly, the LAT1 -targeting aminoacid derivative engages LAT1 on a target cell and is absorbed into the cell through the engaged transporter. The absorption brings the derivative and the chelated atom or ion into the cell. When the chelated atom is a radionuclide, the targeted engagement of the overexpressed LAT1 transporter on a cancer cell, whether it is part of a larger tumor mass, a smaller tumor mass or a circulating cancer cell, provides for the targeted delivery of radiotherapeutic compounds to the cancer cell.

[0082] The chelating moiety may chelate to any appropriate atom, including but not limited to89Zr,44Sc,n iIn,90Y,66Ga,67Ga,68Ga,177Lu, "mTc,61Cu,62Cu,64Cu,67Cu,149Tb,152Tb,155Tb,161Tb,153Gd,155Gd,157Gd,213Bi,225Ac,230U,223Ra,165Er,68Ga and177Lu. It is understood that any radioactive isotope may be used and the radioisotope may be selected according to one or more of activity, size, affinity for the chelating moiety, decay chain, half-life, and other factors.

[0083] It is understood that, while the compounds of Formulas (I), (III), (IV) and (V) may generally have a phenylalanine, tyrosine or tryptophan backbone, other aminoacid backbones suitable for engaging LAT1 for delivery of a radiotherapeutic or a radiodiagnostic to a cell may be used without departing from the present teachings. The principles outlined herein may be used with other suitable backbone aminoacids for targeted engagement of cancer cells. In general, an aminoacid having an affinity for a target receptor and / or transporter, including but not limited to LAT1, may be modified through the addition of radionuclide-containing side groups as shown herein, for bonding to the receptor and / or transporter and for further transport into the cell. As a non-limiting example, leucine, valine and / or cysteine may be used as a backbone for targeting cancers such as breast cancers.

[0084] It is understood that while the L-isomer form of the backbone aminoacids is shown throughout the present disclosure, this is done for illustration purposes only. Other isomeric forms, including D-aminoacids and / or one or more chiral side groups may be used to modulate the specificity, absorption and / or pharmacokinetics of the compounds. For example, it has been suggested that some diseased tissue may uptake D-aminoacids at a different rate than healthy tissue20. Other studies suggest D-aminoacids have a slower dietary uptake and / or depletion rate than L-aminoacids21. Accordingly, the compounds of the present invention may be used in an appropriate isomeric form or as a racemic mixture to modulate the uptake, conversion, depletion and / or excretion rates thereof.

[0085] In a non-limiting example, a D-form backbone having a slower uptake may be used for a radiodiagnostic for monitoring tumor mass presence, size or apoptosis following treatment. Having a slower uptake rate, a portion of the radiodiagnostic may be absorbed into a circulating tumor mass several hours following the administration of a rapidly absorbed therapeutic compound, at a time when treated cells may be expected to have undergone apoptosis. D-form radiodiagnostic accumulation may thus be indicative of residual, non-apoptotic tumor mass presence, suggesting the need for further treatment. Contemporaneous administration of two ormore compounds having different uptake rates thus avoids subjecting a patient to repeated administrations of different compounds, increasing patient comfort. Constraints on medical staff time may also be reduced, particularly in contexts where radiopharmaceutical handling procedures may require the use of special equipment, designated facilities and / or be limited to designated trained staff.

[0086] The present invention provides means for treating and / or diagnosing cancer and other conditions exhibiting LAT1 overexpression regardless of the target site size.

[0087] For example, a subject may exhibit early signs of cancer, such as changes in metabolites or other biomarkers in bloodwork or other analyses. Conventional diagnostic techniques such as X-ray, CT and MRI scans may prove inconclusive, or identify only a subset of the cancer growth sites. For example, these techniques may not detect circulating cancer cells and / or masses, thus complicating or preventing the delivery of conventional radiotherapy.

[0088] Such circulating, undetectable or smaller masses may be targeted by generalized chemotherapy, which is known to have side effects and to negatively affect both cancerous and healthy tissue, resulting in a reduced quality of life for the subject.

[0089] Targeted engagement of the overexpressed LAT1 transporter thus provides means for delivering radiodiagnostics and / or radiotherapeutics to cancer cells regardless of their location and regardless of mass size while generally sparing healthy tissue.

[0090] In general, the compounds of the present invention provide alkene, alkyne, aryl and / or other side groups to better bind and stabilize the radionuclide labels, including211At. This reduces the possibility of toxicity, for example of free131I or211At.

[0091] In general the compounds of the present invention provide improved target engagement and uptake of the radiopharmaceutical compounds by target cells. For example, it was surprisingly discovered that meta-substitution of a side group on the tyrosine phenyl ring, previously thought to inhibit the LAT1 transporter, may provide radiotherapeutic compounds that are absorbed into the target cell and may thus deliver a radionuclide payload.

[0092] Treatment of cancer using the compounds of the present invention may comprise administering one or more of said compounds to a subject in need thereof, optionally in combination with other compounds, therapeutic agents and / or other therapies. For example, treatment may comprise administering the compounds of the present invention in combination with radiotherapy. In a non-limiting example, a treatment may target both a principal cancerous mass through combined radiotherapy and LAT1 engagement, and target smaller or yet undetected metastases of said cancerous mass using LAT1 engagement as provided herein. Cancer recurrence, spread and / or deterioration is accordingly reduced while providing a better quality of life for the subject compared to aggressive radiotherapy, aggressive chemotherapy, or a combination of both.

[0093] Combination therapies comprising two or more radionuclides are possible. The two or more radionuclides may be bound or chelated to the same radiotherapeutic molecule, or a combination of radiotherapeutics, each having one or more different radionuclides bound or chelated thereto, may be provided. For example, when both gross tumor volumes and microdeposits and / or circulating cancer cells need treatment, a cocktail of radiotherapeutics emitting both beta radiation and alpha radiation may be provided. In general, beta radiation may penetrate several cells within the same gross tumor mass, while alpha radiation may damage individual cells from which, or from whose surface it is emitted. Accordingly, alpha radiation may be particularly suitable for treating circulating tumor cells and / or microdeposits to limit the radiation exposure of healthy tissue or cells in the surroundings. Any of the beta or alpha emitting radionuclides or their derivatives could be combined to formulate a treatment cocktail in any combination in a proportion of 0.1% to 99.9% of the active ingredients of the cocktail, or of the total radionuclide or radiotherapeutic content of the cocktail.

[0094] It is understood that combination treatment may comprise both chelating radiopharmaceuticals and halogenated compounds as discussed herein.

[0095] Methods comprising the compounds of the present invention, and uses thereof, may be combined with other therapies as appropriate. For example, administration of one or more compounds as disclosed herein may be accompanied by cytotoxic therapies, biologic therapies, or other treatments.

[0096] For example, uses of the compounds of the present invention may further comprise administering one or more of immunomodulators, checkpoint inhibitors, cytokines, adjuvants, DNA damage repair inhibitors, PARP inhibitors and / or PAR-2 inhibitors. Non-limiting examples of the foregoing include Atezolizumab, Avelumab, Cemiplimab, Dostarlimab, Durvalumab, Ipilimumab, Nivolumab, Pembrolizumab, Relatlimab, Retifanlimab, PD-L1, CTLA-4, Tremelimumab, Aldesleukin, granulocyte-macrophage colony-stimulating factor (GM-CSF), Interferon alfa-2a, Interferon alfa-2b, Peginterferon alfa-2b, Imiquimod, Poly ICLC (also sold as Hiltonol®), ascorbic acid, probenecid, Pexidartinib (Turalio™), olaparib, rucaparib, or niraparib.

[0097] The compounds of the present invention may be used and administered in combination with external beam radiation, for example for affecting and / or destroying additional portions of larger and / or stationary tumour masses. For example, external beam radiotherapy may be used on an existing larger tumour mass and the compounds of the present invention may be administered concurrently with the external beam radiotherapy to target circulating masses, circulating cells and / or metastases that may be too small for radiotherapy, or not yet detected.

[0098] The compounds and pharmaceutically acceptable salts thereof as described herein may be administered in therapeutically effective amounts according to one or more dosing regimens. In a preferred embodiment, the therapeutically effective amount may be about 0.00001 mg / kg body weight to about 100 mg / kg body weight, more preferably about 0.001 mg / kg body weight to about 50 mg / kg body weight, and / or even more preferably about 0.01 mg / kg body weight to about 10 mg / kg body weight. In a non-limiting example, the therapeutically effective amount may be administered between 1 and 8 administrations and / or administration cycles. The administrations and / or administration cycles may be separated by a predetermined period of time, for example between 1 day and about 8 weeks. For example, the predetermined period of time may be set according to one or more of the half-life of a radionuclide, an excretion rate of the radionuclide or decay derivatives thereof, or other factors as appropriate. The predetermined period of time may be between about 4 weeks and about 8 weeks.

[0099] It is understood that the dose may be adjusted up and / or down by 20-50% and the regimen may be adjusted based on subject response and toxicity arising from the prior doses.

[0100] In a preferred embodiment, the dosing regimen may be adjusted according to a dosing regimen for companion therapies. For example, a treatment comprising administration of the compounds as disclosed herein and one or more companion therapies, such as checkpoint inhibitor or other immunomodulator therapies, may comprise an interval between 0 and about 60 days between administrations of the compounds and the administration of the companion therapies. In a non-limiting example, the interval is from about 7 days to about 14 days.

[0101] When the companion therapies comprise immunomodulators having, as an effect, the inhibition of DNA and / or cell repair, such companion therapies may be administered simultaneously with the radiotherapeutics as disclosed herein, or administered prior to radiotherapeutic administration, for example, between 1 and 30 days prior. In such embodiments, a combination therapy may, first, inhibit cellular or DNA repair in a patient, thereby priming the patient’s cancer cells for sustaining maximum damage from the radiotherapeutic once the radiotherapeutic is administered.

[0102] Administration may comprise oral and / or parenteral administration, including but not limited to infusion and / or injection, for example intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbirtal, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulular, subcapsular, subarachnoid, intraspinal, and intrastemal.

[0103] It is understood that dosages as disclosed herein may be based on a predetermined dosing regimen (e.g. a one-size-fits-all regimen) or personalized to the subject according to suitable personalized medicine techniques. Adaptive dosing may comprise personalization through dosimetry. For example, patient-specific personalized dosages may be based on imaging studies of tracer accumulation in cancer and in target organs, e.g. those organs and / or tissues at risk for toxicity.

[0104] It is understood that combination therapies comprising the compounds disclosed herein are not limited to the examples above and may comprise other acceptable products and / or drugs according to the subject’s needs, including but not limited to anti -nausea, antiinflammatory, anti -coagulant and other therapies.

[0105] According to a broad aspect, a composition comprising the compounds as disclosed herein, or pharmaceutically acceptable salts thereof, also comprises any one or more of pharmaceutically acceptable carriers, adjuvants, excipients, diluents, pharmaceutical auxiliaries, therapeutic ingredients and prophylactic ingredients as will be apparent to a skilled person.

[0106] Methods of detecting and / or diagnosing cancer and / or other malignancies comprise administering, to a subject in need thereof, a diagnostically effective amount of the compounds disclosed herein, or pharmaceutically acceptable salts thereof, and detecting radioactive emissions from the subject. The detecting may comprise any acceptable detection and / or dosimetry technique. EXAMPLES

[0107] Compound D” was synthesized and assessed for structure, composition and purity.Compound D”

[0108] Radiosynthesis of compound D” with177Lu and68Ga yielded compounds of Formula (VII) and Formula (VIII).Formula (VIII)

[0109] The compound of Formula (VII) was assessed at >99% purity and showed high specific activity. The compound of Formula (VIII) was assessed at >98% purity and at >92% non-decay -corrected radiochemical yield.

[0110] The compounds of Formulas (VII) and (VIII) provide a useful radioactive payload for delivery to a target. For example, the compound of Formula (VIII) retained 92% and aboveof the original total activity of68Ga prior to synthesis. Elevated radiochemical yields allow for efficient synthesis of radiolabeled or radio-chelated compounds from valuable radioisotope feeds while reducing the overall radioactivity of waste and post-processing streams, as more of the original radioactivity is retained and may be provided as a treatment or a diagnostic.

[0111] The efficacy, toxicity, dosage and other factors related to the medical use of the compounds disclosed herein may be tested using one or more acceptable testing techniques as known to the skilled person. The prophetic examples disclosed herein are not meant to be limiting.

[0112] In one example, the targeting of cancer cells by the LAT1 -targeting radiotherapeutics of the present invention includes exposing a culture of human or animal cancer cells to a solution comprising between 1 nanogram and 10 milligrams of one or more radiotherapeutics for a predetermined time, such as between 1 minute and 6 hours. The culture may then be washed to remove excess radiotherapeutic. The uptake may be measured by detecting and / or quantifying radioactive emissions from the washed culture. The radiotherapeutic may also be labeled, for example fluorescently or immunologically labeled, and the uptake may be detected and / or measured by appropriate fluorescence and / or immunoassay techniques. For example, between about 10% and about 99.99% or all of the cancer cells may exhibit radiotherapeutic uptake.

[0113] In another example, the washed culture may be lysed, homogenized or otherwise appropriately destroyed by causing the rupture and / or disintegration of substantially all cell membranes within the culture, and the lysate / homogenate may be assayed for radiotherapeutic content, radioactive decay products or immunoassayed according to acceptable methods.

[0114] In another example, a comparative uptake study comprising both cancer and noncancer human or animal cells may indicate a comparatively stronger uptake of the radiotherapeutic by cancer cells compared to healthy cells. Similarly to the above, a mixed culture of healthy and cancer cells may be exposed to the radiotherapeutic. The cells may be labeled appropriately, for example by staining, by fluorescence or by immuno-labeling for distinguishing between cancer and healthy cells. Alternatively, the culture may be separated whereby the cancer cells and the healthy cells each occupy an area substantially free of theother. The comparative uptake test may indicate at least 5% higher radiotherapeutic uptake by the cancer cells compared to the healthy cells.

[0115] The in-vitro model described above may be used to detect and / or quantify cell death in response to radiotherapeutic exposure. Detection and / or quantification of cell death may be performed by acceptable methods such as visually or by measuring the content of a biomarker associated with cell death. In a non-limiting example, a comparative cell death study may comprise cancer cells having a labeling or staining compound whose presence, for example in a wash fluid, indicates rupture of the cell membrane or cell death. The healthy cells may also be appropriately labeled with a compound, and the comparative quantities of the compound in the wash fluid indicate the relative rate of cell death of the cancer cells compared to the healthy cells. The radiotherapeutic may cause at least 5% more cell death in the cancer cells than in healthy cells.

[0116] In-vivo tests may comprise a mammal model, such as a mouse, a rat or a primate. For example, the in-vivo model may be an OncoMouse™ or another animal having a predisposition for developing tumors. Alternatively, an animal model may be provided with a tumor mass or a tumor culture. The animal model may then be exposed the radiotherapeutic, for example by injection. The injected dosage may be between 1 nanogram and 10 milligrams per kilogram of body weight. Uptake of the radiotherapeutic may be measured according to acceptable techniques, including dosimetry. The radiotherapeutic may be suitably labeled for detection and / or quantification in tissues and organs by acceptable scanning techniques such as CT and NMR scanning.

[0117] The animal model may also be used to detect and / or quantify cell death. Cell death may be measured by comparing tumor mass growth rates, or size, before and after exposure to a radiotherapeutic, or by measuring circulating tumor concentration in a bodily fluid of the animal model. The exposure to the radiotherapeutic may mimic exposure patterns in an intended patient population, for example by providing one or more doses of the radiotherapeutic according to the dosing regimens described above. The radiotherapeutic may substantially reduce or eliminate tumor growth, for example by reducing growth and / or proliferation by 20% or more compared to untreated tumors. The radiotherapeutic may also reduce the size of tumorsfollowing partial exposure or an exposure to the radiotherapeutic corresponding to a treatment cycle, for example by at least 5%.

[0118] Preclinical animal models may also be used to study target engagement, normal biodistribution, toxicity, and therapeutic effect in different cancers and animal models selected to study that specific cancer. Accordingly, the cancers mentioned above may be specific cancers, e.g. liver cancer, lung cancer, pancreatic cancer, stomach cancer, and other cancers.

[0119] In human trials, the radiotherapeutic may be administered at the dosages and at the regimens described above. Uptake may be measured by detecting radiation from the body of the subject and / or by measuring excreted radiotherapeutic content, with the necessary corrections for radioactive decay and other factors. In human tests, the radiotherapeutic may show a reduction in tumor growth by at least 20%, a reduction in tumor mass size or circulating tumor concentration by at least 5%. The incidence and / or severity of side effects associated with radiotherapy and / or chemotherapy may be reduced, for example by at least 5%.

[0120] The embodiments described above are intended to be exemplary only. The practice of the principles disclosed herein by skilled persons may provide other useful embodiments and uses without departing from the present teachings.REFERENCESE Scalise M, Galluccio M, Console L, Pochini L, Indiveri C. The Human SLC7A5 (LAT1): The Intriguing Histidine / Large Neutral Amino Acid Transporter and Its Relevance to Human Health. Front Chem. 2018;6:243. doi: 10.3389 / fchem.2018.002432. Prasad PD, Wang H, Huang W, et al. Human LAT1, a subunit of system L amino acid transporter: molecular cloning and transport function. Biochem Biophys Res Commun. Feb 16 1999;255(2):283-8. doi: 10.1006 / bbrc.1999.02063. Singh N, Gupta M, Trivedi CM, Singh MK, Li L, Epstein JA. Murine craniofacial development requires Hdac3 -mediated repression of Msx gene expression. Dev Biol. May 15 2013;377(2):333-44. doi: 10.1016 / j.ydbio.2013.03.0084. Duelli R, Enerson BE, Gerhart DZ, Drewes LR. Expression of large amino acid transporter LAT1 in rat brain endothelium. J Cereb Blood Flow Metab. Nov 2000;20(l 1): 1557- 62. doi : 10.1097 / 00004647-200011000-000055. Kongpracha P, Nagamori S, Wiriyasermkul P, et al. Structure-activity relationship of a novel series of inhibitors for cancer type transporter L-type amino acid transporter 1 (LAT1). J Pharmacol Sci. Feb 2017;133(2):96-102. doi: 10.1016 / j.jphs.2017.01.0066. Hafliger P, Charles RP. The L-Type Amino Acid Transporter LATl-An Emerging Target in Cancer. IntJMol Sci. May 16 2019;20(10)doi: 10.3390 / ijms201024287. Czyz J, Malkowski B, Jurczyszyn A, et al. (18)F-fluoro-ethyl-tyrosine ((18)F-FET) PET / CT as a potential new diagnostic tool in multiple myeloma: a preliminary study. Contemp Oncol (Pozn). 2019;23(l):23-31. doi: 10.5114 / wo.2019.833428. Kaneda-Nakashima et al. a-Emitting cancer therapy using 211At-AAMT targeting LAT1, Cancer Sci. 2021;112: 1132-1140.9. Jigjidkhorloo N, Kanekura K, Matsubayashi J, et al. Expression of L-type amino acid transporter 1 is a poor prognostic factor for Non-Hodgkin's lymphoma. Sci Rep. Nov 4 2021; 11(1):21638. doi : 10.1038 / s41598-021-00811 -810. Pauleit D, Floeth F, Herzog H, et al. Whole-body distribution and dosimetry of O-(2- [18F]fluoroethyl)-L-tyrosine. Eur J Nucl Med Mol Imaging. Apr 2003;30(4):519-24. doi : 10.1007 / s00259-003- 1118-011. Singnurkar A, Poon R, Detsky J. 18F-FET-PET imaging in high-grade gliomas and brain metastases: a systematic review and meta-analysis. J Neurooncol. Jan 2023; 161(1): 1-12. doi : 10.1007 / s 11060-022-04201 -612. Takeuchi K, Ogata S, Nakanishi K, et al. LAT1 expression in non-small-cell lung carcinomas: analyses by semiquantitative reverse transcript! on-PCR (237 cases) and immunohistochemistry (295 cases). Lung Cancer. Apr 2010;68(l):58-65. doi: 10.1016 / j. lungcan.2009.05.02013. Augustyn et al. LAT-1 activity of meta-substituted phenylalanine and tyrosine analogs, Bioorganic & Medicinal Chemistry Letters 26 (2016), 2616-2621.14. Liu YH, Li YL, Shen HT, et al. L-Type Amino Acid Transporter 1 Regulates Cancer Sternness and the Expression of Programmed Cell Death 1 Ligand 1 in Lung Cancer Cells. Int JMolSci. Oct 11 2021;22(20)doi: 10.3390 / ijms22201095515. Kaira K, Oriuchi N, Imai H, et al. Prognostic significance of L-type amino acid transporter 1 expression in resectable stage I-III nonsmall cell lung cancer. Br J Cancer. Feb 26 2008;98(4):742-8. doi: 10.1038 / sj .bjc.660423516. Theodoropoulos AS, Gkiozos I, Kontopyrgias G, et al. Modern radiopharmaceuticals for lung cancer imaging with positron emission tomography / computed tomography scan: A systematic review. SAGE Open Med. 2020;8:2050312120961594. doi: 10.1177 / 205031212096159417. Pauleit D, Stoffels G, Schaden W, et al. PET with O-(2-18F-Fluoroethyl)-L-Tyrosine in peripheral tumors: first clinical results. J Nucl Med. Mar 2005;46(3):411-6.18. Furuya M, Horiguchi J, Nakajima H, Kanai Y, Oyama T. Correlation of L-type amino acid transporter 1 and CD98 expression with triple negative breast cancer prognosis. Cancer Sci. Feb 2012;103(2):382-9. doi: 10.1111 / j .1349-7006.2011.02151.x19. Ichinoe M, Mikami T, Yanagisawa N, et al. Prognostic values of L-type amino acid transporter 1 and CD98hc expression in breast cancer. J Clin Pathol. Sep 2021;74(9):589-595. doi : 10.1136 / j clinpath-2020-20645720. Bastings J, van Eijk H, Olde Damink S, Rensen S. d-amino Acids in Health and Disease: A Focus on Cancer. Nutrients. Sep 2019; 11(9):2205. doi: 10.3390 / nul 1092205.21. Friedman, M, Levin, CE Nutritional and medicinal aspects of D-amino acids. Amino Acids 2012;42: 1553-1582. doi: 10.1007 / s00726-011-0915-1.

Claims

What is claimed is:

1. A compound of Formula (I),Formula (I) wherein Ri is a radionuclide, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo- cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo- heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde, ketone, or a side group of Formula (II) :RFormula (II) wherein R2 is hydrogen, hydroxyl, a radionuclide, alkyl, halo-alkyl, alkenyl, halo- alkenyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo- aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde, ketone, or a side group of Formula (II); wherein each one of Rs and R9 is any one of hydrogen, hydroxyl, a radionuclide, alkyl, halo-alkyl, alkenyl, halo-alkenyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo- cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo- heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde, ketone; wherein each one of R5, Re, R7, Rio and Rn is any one of hydrogen, alkyl, alkenyl, halo- alkenyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo- aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo- cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde and ketone; wherein n is between 0 and 20; and wherein the compound of Formula (I) comprises at least one radionuclide.

2. The compound of claim 1, wherein any one of Ri and R2 is O-halo-benzyl and wherein a halogen atom in the O-halo-benzyl group is in one of a meta position and a para position on the O-halo-benzyl.

3. The compound of claim 2, wherein the O-halo-benzyl is in one of a meta position and a para position on the compound of Formula (I).

4. The compound of claim 2, wherein the halogen atom is one of F, Br, I and At.

5. The compound of claim 4, wherein the halogen atom is a radioactive isotope.

6. The compound of claim 1, wherein any one of Ri and R2 is O-benzyl and wherein Rs, R9 or both are the radionuclide comprising a radioactive halogen isotope.

7. A compound of Formula (III):Formula (III) wherein Ri is hydrogen, hydroxyl, a radionuclide, alkyl, halo-alkyl, alkenyl, halo- alkenyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo- aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo- cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde, ketone, or a side group of Formula (II) :Formula (II) wherein R2 is hydrogen, hydroxyl, a radionuclide, alkyl, halo-alkyl, alkenyl, halo- alkenyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo- aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo- cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde, ketone, or a side group of Formula (II);wherein each one of Rs and R9 is any one of hydrogen, hydroxyl, a radionuclide, alkyl, halo-alkyl, alkenyl, halo-alkenyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo- cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo- heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde and ketone; wherein each one of R3, R4, Rs, Re, R7, Rio and Rn is any one of alkenyl, halo-alkenyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo- aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde and ketone; wherein n is between 0 and 20; and wherein the compound of Formula (III) comprises at least one radionuclide.

8. The compound of claim 7, wherein:(a) Ri is the side group of Formula (II) and at least one of Rs and R9 is a radionuclide;(b) Ri is O-benzyl and R2 is a radionuclide; or(c) Ri is the side group of Formula (II), at least one of Rs and R9 is a radionuclide, and R2 is a radionuclide.

9. The compound of claim 7, wherein Ri the side group of Formula (II), at least one of Rs and R9 is a first radionuclide, R2 is a second radionuclide, and the first and second radionuclides are isotopes of different atoms.

10. A compound of Formula (IV)Formula (IV) wherein Xi is one of: a chelating moiety; and a chelating moiety substituted on one of: hydroxyl, methoxyl, alkynyl, halo-alkynyl, O- benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde and ketone; wherein each one of X2 and X3 is any one of hydrogen, halogen, hydroxyl, methoxyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo- aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde and ketone; wherein each one of R5, Re and R7 is any one of alkenyl, halo-alkenyl, alkyl, alkynyl, halo- alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl,heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde and ketone; and wherein n is between 0 and 20.

11. The compound of claim 10, wherein the chelating moiety comprises a heterocyclic group.

12. The compound of claim 11, wherein the chelating moiety is of Formula (Via) :Formula (Via) wherein m is between 0 and 20; and wherein Rs is any one of hydrogen, hydroxyl, a radionuclide, alkyl, halo-alkyl, alkenyl, halo-alkenyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo- aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo- cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde, and ketone.

13. The compound of claim 12, wherein Xi is the chelating moiety substituted on one of methoxyl and O-benzyl.

14. The compound of claim 13, wherein the chelating moiety is substituted on O-benzyl in one of a meta position and a para position.

15. The compound of claim 14, wherein X2 and X3 are, each, a halogen atom in the meta position.

16. The compound of claim 15, wherein the halogen atom is iodine.

17. The compound of claim 12, wherein the chelating moiety further comprises a metal atom chelated thereto.

18. The compound of claim 17, wherein the metal atom is a radioactive isotope.

19. The compound of claim 18, wherein the radioactive isotope is one of a diagnostic isotope and a therapeutic isotope.

20. The compound of claim 12, comprising a plurality of chelating moieties, wherein the plurality of chelating moieties have a plurality of radioactive metal isotopes chelated thereto.

21. The compound of claim 20, wherein the plurality of radioactive metal isotopes comprises diagnostic radioactive metal isotopes, therapeutic radioactive metal isotopes, or combinations thereof.

22. A compound of Formula (V)Formula (V)wherein Xi is one of: a chelating moiety; and a chelating moiety substituted on one of: hydroxyl, methoxyl, alkynyl, halo-alkynyl, O- benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde and ketone; wherein each one of X2 and X3 is any one of hydrogen, halogen, hydroxyl, methoxyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo- aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde and ketone; wherein each one of R3, R4, Rs, Re and R7 is any one of alkenyl, halo-alkenyl, alkyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo-aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo-cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde and ketone; and wherein n is between 0 and 20.

23. The compound of claim 22, wherein the chelating moiety comprises a heterocyclic group.

24. The compound of claim 23, wherein the chelating moiety is of Formula (Via) :(C)m — RsFormula (Via) wherein m is between 0 and 20; and wherein Rs is any one of hydrogen, hydroxyl, a radionuclide, alkyl, halo-alkyl, alkenyl, halo-alkenyl, alkynyl, halo-alkynyl, O-benzyl, O-halo-benzyl, aralkyl, aralkynyl, halo- aralkyl, halo-aralkynyl, cycloalkylalkyl, cycloalkynyl, halo-cycloalkylalkyl, halo- cycloalkynyl, heterocyclylalkyl, heterocyclylalkynyl, halo-heterocyclylalkyalkynyl, amino, sulfhydryl, sulfonyl, aldehyde, and ketone.

25. The compound of claim 24, wherein Xi is the chelating moiety substituted on one of methoxyl and O-benzyl.

26. The compound of claim 25, wherein the chelating moiety is substituted on O-benzyl in one of a meta position and a para position.

27. The compound of claim 26, wherein X2 and X3 are, each, a halogen atom.

28. The compound of claim 27, wherein the halogen atom is iodine.

29. The compound of claim 24, wherein the chelating moiety further comprises a metal atom chelated thereto.

30. The compound of claim 29, wherein the metal atom is a radioactive isotope.

31. The compound of claim 30, wherein the radioactive isotope is one of a diagnostic isotope and a therapeutic isotope.

32. The compound of claim 24, comprising a plurality of chelating moieties, wherein the plurality of chelating moieties have a plurality of radioactive metal isotopes chelated thereto.

33. The compound of claim 32, wherein the plurality of radioactive metal isotopes comprises diagnostic radioactive metal isotopes, therapeutic radioactive metal isotopes, or combinations thereof.

34. A method of diagnosing malignancies, comprising administering, to a subject, a diagnostically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof and detecting radioactive emissions from the subject.

35. A method of diagnosing malignancies, comprising administering, to a subject, a diagnostically effective amount of the compound of claim 7 or a pharmaceutically acceptable salt thereof and detecting radioactive emissions from the subject.

36. A method of diagnosing malignancies, comprising administering, to a subject, a diagnostically effective amount of the compound of claim 10 or a pharmaceutically acceptable salt thereof and detecting radioactive emissions from the subject.

37. A method of diagnosing malignancies, comprising administering, to a subject, a diagnostically effective amount of the compound of claim 22 or a pharmaceutically acceptable salt thereof and detecting radioactive emissions from the subject.

38. A method of treating malignancies, comprising administering, to a subject, a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

39. The method of claim 38, wherein the therapeutically effective amount is 0.00001 mg / kg to 100 mg / kg body weight, preferably from 0.001 to 50 mg / kg body weight, and most preferably 0.01 to 10 mg / kg body weight administered in one or more doses.

40. The method of claim 39, further comprising administering, to the subject, one or more of external beam therapy and non-radioactive therapies.

41. The method of claim 40, wherein the one or more non-radioactive therapies comprise check-point inhibitors.

42. A method of treating malignancies, comprising administering, to a subject, a therapeutically effective amount of the compound of claim 7 or a pharmaceutically acceptable salt thereof.

43. The method of claim 42, wherein the therapeutically effective amount is 0.00001 mg / kg to 100 mg / kg body weight, preferably from 0.001 to 50 mg / kg body weight, and most preferably 0.01 to 10 mg / kg body weight administered in one or more doses.

44. The method of claim 43, further comprising administering, to the subject, one or more of external beam therapy and non-radioactive therapies.

45. The method of claim 44, wherein the one or more non-radioactive therapies comprise check-point inhibitors.

46. A method of treating malignancies, comprising administering, to a subject, a therapeutically effective amount of the compound of claim 10 or a pharmaceutically acceptable salt thereof.

47. The method of claim 45, wherein the therapeutically effective amount is 0.00001 mg / kg to 100 mg / kg body weight, preferably from 0.001 to 50 mg / kg body weight, and most preferably 0.01 to 10 mg / kg body weight administered in one or more doses.

48. The method of claim 47, further comprising administering, to the subject, one or more of external beam therapy and non-radioactive therapies.

49. The method of claim 48, wherein the one or more non-radioactive therapies comprise check-point inhibitors.

50. A method of treating malignancies, comprising administering, to a subject, a therapeutically effective amount of the compound of claim 22 or a pharmaceutically acceptable salt thereof.

51. The method of claim 50, wherein the therapeutically effective amount is 0.00001 mg / kg to 100 mg / kg body weight, preferably from 0.001 to 50 mg / kg body weight, and most preferably 0.01 to 10 mg / kg body weight administered in one or more doses.

52. The method of claim 51, further comprising administering, to the subject, one or more of external beam therapy and non-radioactive therapies.

53. The method of claim 52, wherein the one or more non-radioactive therapies comprise check-point inhibitors.

54. A composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and one or more of: pharmaceutically acceptable carriers, adjuvants, excipients, diluents, pharmaceutical auxiliaries, therapeutic ingredients and prophylactic ingredients.

55. The composition of claim 54, wherein the adjuvants comprise one or more of ascorbic acid, probenecid, immunomodulators, checkpoint inhibitors, cytokines, DNA damage repair inhibitors, PARP inhibitors and PAR-2 inhibitors.

56. A composition comprising the compound of claim 7 or a pharmaceutically acceptable salt thereof and one or more of: pharmaceutically acceptable carriers, adjuvants, excipients, diluents, pharmaceutical auxiliaries, therapeutic ingredients and prophylactic ingredients.

57. The composition of claim 56, wherein the adjuvants comprise one or more of ascorbic acid, probenecid, immunomodulators, checkpoint inhibitors, cytokines, DNA damage repair inhibitors, PARP inhibitors and PAR-2 inhibitors.

58. A composition comprising the compound of claim 10 or a pharmaceutically acceptable salt thereof and one or more of: pharmaceutically acceptable carriers, adjuvants, excipients, diluents, pharmaceutical auxiliaries, therapeutic ingredients and prophylactic ingredients.

59. The composition of claim 58, wherein the adjuvants comprise one or more of ascorbic acid, probenecid, immunomodulators, checkpoint inhibitors, cytokines, DNA damage repair inhibitors, PARP inhibitors and PAR-2 inhibitors.

60. A composition comprising the compound of claim 22 or a pharmaceutically acceptable salt thereof and one or more of: pharmaceutically acceptable carriers, adjuvants, excipients, diluents, pharmaceutical auxiliaries, therapeutic ingredients and prophylactic ingredients.

61. The composition of claim 60, wherein the adjuvants comprise one or more of ascorbic acid, probenecid, immunomodulators, checkpoint inhibitors, cytokines, DNA damage repair inhibitors, PARP inhibitors and PAR-2 inhibitors.

62. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for diagnosing malignancies.

63. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for treating malignancies.

64. The use of claim 63, wherein the compound is for administration in one or more doses and in a total amount of 0.00001 mg / kg to 100 mg / kg body weight, preferably from 0.001 to 50 mg / kg body weight, and most preferably 0.01 to 10 mg / kg body weight.

65. The use of claim 63 in conjunction with one or more of external beam therapy, immunomodulators, checkpoint inhibitors, cytokines, adjuvants, DNA damage repair inhibitors, PARP inhibitors and / or PAR-2 inhibitors.

66. Use of the compound of claim 7 or a pharmaceutically acceptable salt thereof for diagnosing malignancies.

67. Use of the compound of claim 7 or a pharmaceutically acceptable salt thereof for treating malignancies.

68. The use of claim 67, wherein the compound is for administration in one or more doses and in a total amount of 0.00001 mg / kg to 100 mg / kg body weight, preferably from 0.001 to 50 mg / kg body weight, and most preferably 0.01 to 10 mg / kg body weight.

69. The use of claim 67 in conjunction with one or more of external beam therapy, immunomodulators, checkpoint inhibitors, cytokines, adjuvants, DNA damage repair inhibitors, PARP inhibitors and / or PAR-2 inhibitors.

70. Use of the compound of claim 10 or a pharmaceutically acceptable salt thereof for diagnosing malignancies.

71. Use of the compound of claim 10 or a pharmaceutically acceptable salt thereof for treating malignancies.

72. The use of claim 71, wherein the compound is for administration in one or more doses and in a total amount of 0.00001 mg / kg to 100 mg / kg body weight, preferably from 0.001 to 50 mg / kg body weight, and most preferably 0.01 to 10 mg / kg body weight.

73. The use of claim 71 in conjunction with one or more of external beam therapy, immunomodulators, checkpoint inhibitors, cytokines, adjuvants, DNA damage repair inhibitors, PARP inhibitors and PAR-2 inhibitors.

74. Use of the compound of claim 22 or a pharmaceutically acceptable salt thereof for diagnosing malignancies.

75. Use of the compound of claim 22 or a pharmaceutically acceptable salt thereof for treating malignancies.

76. The use of claim 75, wherein the compound is for administration in one or more doses and in a total amount of 0.00001 mg / kg to 100 mg / kg body weight, preferably from 0.001 to 50 mg / kg body weight, and most preferably 0.01 to 10 mg / kg body weight.

77. The use of claim 75 in conjunction with one or more of external beam therapy, immunomodulators, checkpoint inhibitors, cytokines, adjuvants, DNA damage repair inhibitors, PARP inhibitors and PAR-2 inhibitors.

78. The compound of claim 16, wherein the chelating moiety further comprises one of Lu and Ga chelated thereto79. The compound of claim 16, wherein the chelating moiety further comprises one of177Lu and68Ga chelated thereto.

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