Radiolabeled compounds targeting prostate-specific membrane antigen - Patents.com

Abstract

A compound of formula (I) or a salt or solvate thereof, comprising a prostate specific membrane antigen (PSMA) targeting moiety: 1 -R 1a R 1b - where R 1a is absent, -CH2-, -O-, or -S-, and R 1b is -CH2- or -CHF-. 2 is -(CH2)3-O-, -(CH2)3-, -(CH2)4-, -CH2-O-(CH2)2-, or -CH2-S-(CH2)2. 3 is ethylene fused to a tricyclic fused ring. 1 , L 2 , L 3 , L 4 , L 5b , L 5c , L 6 , and L 7 is a linkage (e.g., a peptide bond). X br is a branched atom. R rad is a radioactive metal chelating agent. alb is an albumin binder. n1, n2, n3, n4, and n5 are integers. When the PSMA targeting moiety is linked to a radiolabeling group, the compound may be used as an imaging agent or a therapeutic agent for a PSMA-expressing disease / condition. TIFF2025507971000122.tif54150

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 316,595, filed March 4, 2022, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

[0002] FIELD OF THEINVENTION The present invention relates to radiolabeled compounds for the treatment of diseases or conditions characterized by expression of prostate specific membrane antigen, particularly compounds that have low uptake in the salivary glands and / or kidneys. [Background technology]

[0003] Prostate-specific membrane antigen (PSMA) is a transmembrane protein that catalyzes the hydrolysis of N-acetyl-aspartylglutamate to glutamate and N-acetylaspartate.PSMA is selectively overexpressed in certain diseases and conditions compared to most normal tissues.For example, PSMA is overexpressed up to 1,000-fold in prostate tumors and metastases.Due to its pathological expression pattern, various radiolabeled PSMA targeting constructs have been designed and evaluated for imaging of PSMA-expressing tissues and / or for therapy of diseases or conditions characterized by PSMA expression.

[0004] 18 F-DCFBC, 18 F-DCFPyL, 68 Ga-PSMA-HBED-CC, 68 Ga-PSMA-617, 68 Ga-PSMA I and T (see FIG. 1 ), as well as alpha emitters ( 225 Ac, etc.) or beta emitters ( 177 Lu or 90 Several radiolabeled PSMA-targeted derivatives of Lys-urea-glutamic acid (Lys-ureido-Glu) have been developed, including the previously mentioned versions labeled with cysteine ​​(e.g., Y).

[0005] In clinical trials, 177 Lu and 225 PSMA-617 radiolabeled with therapeutic radionuclides such as Ac has shown promise as an effective systemic treatment for metastatic castration-resistant prostate cancer (mCRPC). However, dry mouth (xerostomia), taste changes, and renal adverse events are common side effects of this treatment, due to high accumulation of the radiotracer in the salivary glands and kidneys (Hofman et al.,2018 The Lancet 16(6):825-833; Rathke et al.2019 Eur J Nucl Med Mol Imaging 46(1):139-147; Sathekge et al.2019 Eur J Nucl Med Mol Imaging 46(1):129-138). Accumulation of the radiotracer in the kidneys and salivary glands is therefore a limiting factor that reduces the maximum cumulative dose that can be safely given to a patient, thereby limiting the potential therapeutic efficacy of Lys-Urea-Glu-based radiopharmaceuticals (Violet et al. 2019 J Nucl Med. 60(4):517-523). Thus, there is a need for new radiolabeled PSMA-targeted compounds, specifically compounds that accumulate less in the salivary glands and / or kidneys.

[0006] No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention. Summary of the Invention

[0007] The present disclosure relates to PSMA-targeting compounds that bind to PSMA using a Lys-ureido-Glu moiety or a derivative thereof, a radioactive metal chelator, and an albumin binder. Both the location of the radioactive metal chelator and the location of the albumin binder relative to the PSMA binding moiety result in novel compounds with useful delivery of radiation to tumor sites and improved side effects (e.g., low uptake in the kidney and / or salivary glands). Without wishing to be bound by theory, the disclosed compounds can minimize structural disorders. [Brief description of the drawings]

[0008] The features of the present invention will become apparent from the following description taken in conjunction with the accompanying drawings.

[0009] [Figure 1] 1 shows examples of prior art PSMA-targeted compounds for prostate cancer imaging.

[0010] [Figure 2A] Representative in vitro competitive PSMA binding assay curves using LNCaP cells with CCZ02009 (left panel) and HTK03170 (right panel) are shown. [Figure 2B] PET images of 68Ga-CCZ02009 in LNCaP tumor-bearing NRG mice at 1 hour (left panel) and 3 hours (right panel) post-injection are shown.

[0011] [Diagram 3] Representative in vitro competitive PSMA binding assay curves using LNCaP cells with CCZ02060 (left panel) and CCZ02059 (right panel) are shown.

[0012] [Figure 4] SPECT / CT images of 177Lu-CCZ02017 in LNCaP tumor-bearing NRG mice at 3, 24, 72, 144, and 240 hours post-injection are shown.

[0013] [Diagram 5] A representative in vitro competitive PSMA binding assay curve using LNCaP cells with CCZ02008 is shown.

[0014] [Figure 6] A representative in vitro competitive PSMA binding assay curve using LNCaP cells with CCZ02025 is shown.

[0015] [Figure 7] A representative in vitro competitive PSMA binding assay curve using LNCaP cells with CCZ02024 is shown.

[0016] [Figure 8] A representative in vitro competitive PSMA binding assay curve using LNCaP cells with CCZ02015 is shown.

[0017] [Figure 9] Representative in vitro competitive PSMA binding assay curves using LNCaP cells with CCZ02012 (Figure 9A) and CCZ02013 (Figure 9B) are shown.

[0018] [Figure 10] Representative in vitro competitive PSMA binding assay curves using LNCaP cells with CCZ02021 (Figure 10A) and CCZ02022 (Figure 10B) are shown.

[0019] [Figure 11] A representative in vitro competitive PSMA binding assay curve using LNCaP cells with CCZ02034 is shown.

[0020] [Figure 12] A representative in vitro competitive PSMA binding assay curve using LNCaP cells with CCZ02005 is shown.

[0021] [Figure 13] A representative in vitro competitive PSMA binding assay curve using LNCaP cells with CCZ02061 is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] All publications, patents, and patent applications (including any drawings and appendices therein) are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, and patent application, drawing, or appendix was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

[0023] As used herein, the terms "comprising," "having," "including," and "containing," as well as grammatical variations thereof, are inclusive and open-ended and do not exclude additional unrecited elements and / or features / components defined as being part of the specified feature(s) / component(s), even if those features / components consist or consist essentially of the specified feature(s) / component(s). When used herein in the context of a compound, composition, use, or method, the term "consisting essentially of" means that additional elements and / or method steps may be present, but that these additions do not substantially affect the manner in which the recited compound, composition, method, or use functions. When used herein in the context of a composition, use, or method feature, the term "consisting of" excludes the presence of additional elements and / or method steps in that feature. A compound, composition, use, or method described herein as comprising certain elements and / or steps may, in certain embodiments, consist essentially of those elements and / or steps, and in other embodiments, consist of those elements and / or steps (whether or not those embodiments are specifically mentioned). Uses or methods described herein as including certain elements and / or steps may in certain embodiments consist essentially of those elements and / or steps, and in other embodiments consist of those elements and / or steps (regardless of whether those embodiments are specifically referred to).

[0024] Reference to an element with the indefinite article "a" does not exclude the possibility that more than one element is present, unless the context clearly requires that only one element is present. The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. When used herein in conjunction with the term "comprising," the use of the words "a" or "an" can mean "one," but is also consistent with the meanings of "one or more," "at least one," and "one or more."

[0025] In this disclosure, the recitation of numerical ranges by endpoints includes all numbers subsumed within that range, including all whole numbers, integers, and, where appropriate, all intermediate fractions (e.g., 1 to 5 can include 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5, etc.).

[0026] Unless otherwise specified, "certain particular embodiment," "various embodiments," "an embodiment," and similar terms include the particular feature(s) described for that embodiment, either alone or in combination with any other embodiment(s) described herein, whether other embodiments are referenced directly or indirectly, and whether the feature or embodiment is described in the context of a method, product, use, composition, compound, etc.

[0027] As used herein, the terms "treat," "treatment," "therapeutic," and the like include amelioration of symptoms, reduction in disease progression, improved prognosis, and reduction in recurrence.

[0028] The term "subject" refers to an animal (e.g., a mammal or a non-mammal). The subject may be a human or a non-human primate. The subject may be a laboratory mammal (e.g., a mouse, rat, rabbit, hamster, etc.). The subject may be a farm animal (e.g., a horse, sheep, cow, pig, camelid, etc.) or a domestic animal (e.g., a dog, cat, etc.). In some embodiments, the subject is a human.

[0029] The compounds disclosed herein may also include their free base forms, salts, or pharma- ceutically acceptable salts.Unless otherwise specified, the compounds claimed and described herein are intended to include all racemic mixtures and all individual enantiomers or combinations thereof, whether or not expressly represented herein.

[0030] The compounds disclosed herein may be shown as having one or more charged groups, may be shown with the ionizable groups in an uncharged (e.g., protonated) state, or may be shown without specifying a formal charge. As will be understood by those skilled in the art, the ionization state of a particular group in a compound (e.g., but not limited to, CO2H, PO3H2, SO2H, SO3H, SO4H, OPO3H2, etc.) will depend, among other things, on the pKa of the group and the pH of its location. By way of example and not limitation, it will be understood that a carboxylic acid group (i.e., COOH) will generally be deprotonated (and negatively charged) at neutral pH and up to physiological pH values, unless the protonation state is stabilized. Similarly, OSO3H (i.e., SO4H), SO2H, SO3H, OPO3H2 (i.e., PO4H2), and PO3H groups will generally be deprotonated (and negatively charged) at neutral and physiological pH values.

[0031] As used herein, the terms "salt" and "solvate" have their usual meaning in chemistry. Thus, when a compound is a salt or solvate, it is associated with a suitable counterion. Methods of preparing salts or exchanging counterions are well known in the art. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g., but not limited to, Na, Ca, Mg, or K hydroxides, carbonates, bicarbonates, etc.) or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or in an organic solvent, or in a mixture of the two. The counterion may be changed by ion exchange techniques, such as, for example, ion exchange chromatography. All zwitterions, salts, solvates, and counterions are intended unless a particular form is specifically indicated.

[0032] In certain embodiments, the salt or counterion may be pharma- ceutical acceptable for administration to a subject. More generally, with respect to any pharmaceutical composition disclosed herein, non-limiting examples of suitable additives include any suitable buffer, stabilizer, salt, antioxidant, complexing agent, isotonicity agent, cryoprotectant, lyoprotectant, suspending agent, emulsifying agent, antimicrobial agent, preservative, chelating agent, binder, surfactant, wetting agent, non-aqueous vehicle such as fixed oil, or sustained or controlled release polymer. See, for example, Berge et al. 1977. (J.Pharm Sci. 66:1-19), or Remington-The Science and Practice of Pharmacy, 21st edition (Gennaro et al editors. Lippincott Williams & Wilkins Philadelphia), each of which is incorporated by reference in its entirety.

[0033] As used herein, "C nThe phrase "where n is an integer (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.) or n is defined as an integer range (e.g., 1-20, 1-18, 2-15, 3-20, etc.)" refers to the number of carbons in a compound, R group, L group, or substituent, or the number of carbons and heteroatoms in a compound, R group, L group, or substituent. An integer range includes all integers within that range, for example, the range 1-20 includes the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. Unless otherwise defined, heteroatoms may include any, some, or all of the possible heteroatoms. For example, in some embodiments, the heteroatoms may be selected from N, O, S, P, and Se. In some embodiments, the heteroatoms are selected from N, S, or O. Such embodiments are non-limiting. "Cy-Cz," where y and z are integers (e.g., C3-C 15 An alternative expression of "C n " (where n is an integer range from y to z).

[0034] The terms "alkyl", "alkylenyl", "alkenylenyl" and "alkylenyl" have their usual meanings in organic chemistry. For example, "alkenylenyl" has at least one carbon-carbon double bond and may have any number of carbon-carbon single bonds. Similarly, "alkynylenyl" has at least one carbon-carbon triple bond and may have any number of carbon-carbon single bonds. The terms "alkylenyl, alkenylenyl, and / or alkynylenyl" and "alkylenyl, alkenylenyl, or alkynylenyl" are intended to be equivalent and each include a hydrocarbon chain that may have any reasonable number of carbon-carbon single bonds, double bonds, and triple bonds, or combinations thereof. These hydrocarbon chains may be linear, branched, cyclic, or any combination of linear and branched, linear and cyclic, cyclic and branched, branched and cyclic, or linear, branched, and cyclic. Cyclic hydrocarbons may be non-aromatic, partially aromatic, or aromatic. Unless otherwise specified, the term "cyclic" includes single rings, multiple non-fused rings, fused rings, bridged rings, and combinations thereof.

[0035] The phrase "any carbon... is optionally and independently replaced by N, S, or O" and other similar phrases include a defined hydrocarbon (e.g., "alkyl", "alkylenyl", "alkenylenyl", or "alkynylenyl") containing zero, one, two or more heteroatoms, or any rational combination of two or more heteroatoms selected from N, S, and O. Thus, the above phrases expand the defined hydrocarbon to additionally include heteroalkyl, heteroalkylenyl, heteroalkenylenyl, and heteroalkynylenyl, etc. One of ordinary skill in the art will appreciate that various combinations of different heteroatoms may be used. The phrase "any carbon bonded to two other carbons is optionally and independently replaced by N, S, or O" and other similar phrases mean that any carbon in the defined hydrocarbon that is bonded to two other carbons (e.g., the underlined carbon in -CCC-) may be a heteroatom, whether those bonds are single, double, or triple bonds, but excludes heteroatoms bonded to other heteroatoms (e.g., excludes -CNS-, -SSN-, -NSC-, etc.).

[0036] Various R groups (e.g., R 1 , R 2 , R 3 etc.) and L groups (e.g., L 1 , L 2 , L 3 etc.) are defined in the present disclosure. L groups generally include linkages (e.g., -S-, -NH-C(O)-, -C(O)-NH-, -N(alkyl)-C(O)-, -C(O)-N(alkyl)-, -NH-C(O)-NH-, -NH-C(S)-NH-, [ka] )

[0037] If not specified, the size of the R or L group is that which would be considered reasonable by one of ordinary skill in the art. By way of example and not limitation, if not specified, the size of the alkyl group may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 108, 109, 110, 111, , 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or more than 100 carbon lengths. Further, without being limited, if not specified, the size of the heteroalkyl may be any of the following, according to common general knowledge to one of ordinary skill in the art: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 109, 108, 109, 109, 109, 110, 1 The carbon and heteroatom length may be 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, or greater than 100. In connection with the expressions "alkyl, alkenyl, or alkynyl" and similar expressions, "alkyl" will be understood to be a saturated alkyl and "alkenyl" and "alkynyl" will be understood to be unsaturated.

[0038] As used herein, in the context of alkyl / heteroalkyl groups of a compound, the term "linear" may be used as commonly understood by one of ordinary skill in the art and generally refers to a chemical entity that includes a backbone or main chain that is not divided into two or more continuous chains. Non-limiting examples of linear alkyls include methyl, ethyl, n-propyl, and n-butyl.

[0039] As used herein, the term "branched" may be used as commonly understood by those of skill in the art and generally refers to a chemical entity that includes a backbone or main chain that is divided into two or more continuous chains. The portion of the backbone or main chain that is divided in two or more directions may be linear, cyclic, or any combination thereof. Non-limiting examples of branched alkyl groups include tert-butyl and isopropyl.

[0040] The term "alkylenyl" refers to the divalent analog of an alkyl group. In connection with the expressions "alkylenyl, alkenylenyl, and / or alkynylenyl" and similar expressions, "alkylenyl" will be understood to be saturated alkylenyl, and "alkenylenyl" and "alkynylenyl" will be understood to be unsaturated. The term "heteroalkylenyl" refers to the divalent analog of a heteroalkyl group. The term "heteroalkenylenyl" refers to the divalent analog of a heteroalkenyl group. The term "heteroalkynylenyl" refers to the divalent analog of a heteroalkynyl group.

[0041] As used herein, the term "saturated" when referring to a chemical entity may be used as commonly understood by one of ordinary skill in the art and generally refers to a chemical entity that contains only single bonds and may contain linear, branched, and / or cyclic groups. Saturated C1-C 20Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, sec-pentyl, t-pentyl, n-hexyl, i-hexyl, 1,2-dimethylpropyl, 2-ethylpropyl, 1-methyl-2-ethylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1,2-triethylpropyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 2-ethylbutyl, 1 , 3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, sec-hexyl, t-hexyl, n-heptyl, i-heptyl, sec-heptyl, t-heptyl, n-octyl, i-octyl, sec-octyl, t-octyl, n-nonyl, i-nonyl, sec-nonyl, t-nonyl, n-decyl, i-decyl, sec-decyl, t-decyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, cyclooctanyl, cyclononanyl, cyclodecanyl, and the like. Thus, unless otherwise specified, C1-C 20 Alkylenyl includes, but is not limited to, all divalent analogs of the above saturated alkyl groups.

[0042] As used herein, the term "unsaturated" when referring to a chemical entity may be used as commonly understood by one of ordinary skill in the art and generally refers to a chemical entity that contains at least one double or triple bond and may contain linear, branched, and / or cyclic groups. 20 Non-limiting examples of alkenyl groups include vinyl, allyl, isopropenyl, 1-propen-2-yl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 2-buten-1-yl, 2-buten-2-yl, octenyl, decenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononanenyl, cyclodecanenyl, and the like. Thus, unless otherwise specified, C1-C 20Alkenylenyl includes, but is not limited to, all divalent analogs of the above alkenyl groups. 20 Non-limiting examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. Thus, unless otherwise specified, C1-C 20 Alkynylenyl includes, but is not limited to, all divalent analogs of the above alkynyl groups.

[0043] Non-limiting examples of non-aromatic cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Non-limiting examples of non-aromatic heterocyclic groups include aziridinyl, azetidinyl, diazetidinyl, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, imidazolinyl, pyrazolidinyl, imidazolidinyl, phthalimidyl, succinimidyl, oxiranyl, tetrahydropyranyl, oxetanyl, dioxanyl, thietanyl, thiepinyl, morpholinyl, oxathiolanyl, etc.

[0044] Unless further specified, "aryl" groups include both aromatic monocyclic and fused rings containing at least one aromatic ring. 20 Non-limiting examples of aryl groups include phenyl (Ph), pentalenyl, indenyl, naphthyl, and azulenyl.Non-limiting examples of aromatic heterocyclic groups of similar size include pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, acridinyl, indolyl, isoindolyl, indolizinyl, purinyl, carbazolyl, indazolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, phenanthridinyl, phenazinyl, phenanthrolinyl, perimidinyl, furyl, dibenzofuryl, xanthenyl, benzofuryl, thiophenyl, thianthrenyl, benzothiophenyl, phosphorinyl, phosphinolinyl, phosphindolyl, thiazolyl, oxazolyl, isoxazolyl, and the like.

[0045] As used herein, the term "substituted" is used as would be commonly understood by one skilled in the art, and generally refers to a compound or chemical entity having one chemical group replaced with a different chemical group. Unless otherwise specified, a substituted alkyl, alkylenyl, alkenylenyl, or alkynylenyl has one or more hydrogen atoms independently replaced with a non-hydrogen atom. For example, chloromethyl is a non-limiting example of a substituted alkyl, and more specifically, an example of a substituted methyl. Aminoethyl is another non-limiting example of a substituted alkyl, and more specifically, an example of a substituted ethyl. Unless otherwise specified, a substituted compound or group (e.g., an R group or an L group) may be substituted with any chemical group reasonable to one skilled in the art. By way of example and not limitation, a hydrogen bonded to a carbon or heteroatom (e.g., N) may be substituted with a halide (e.g., F, I, Br, Cl), amine, amide, oxo, hydroxyl, thiol, phosphate, phosphonate, sulfate, SO2H, SO3H, alkyl, heteroalkyl, aryl, heteroaryl, ketone, carboxaldehyde, carboxylate, carboxamide, nitrile, monohalomethyl, dihalomethyl, or trihalomethyl. In some embodiments, each carbon may be independently substituted with an oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphoric acid, or may be unsubstituted. In some embodiments, the amide substituent is -C(O)-NH2.

[0046] As used herein, the term "unsubstituted" is used as would be commonly understood by one of ordinary skill in the art. Non-limiting examples of unsubstituted alkyl include methyl, ethyl, tert-butyl, pentyl, etc. The term "optionally substituted" is used interchangeably with the term "unsubstituted or substituted." The term "optionally substituted" means that each position may or may not be substituted, and if substituted, each substituent may be the same or different.

[0047] In the structures provided herein, hydrogen may or may not be shown. In some embodiments, hydrogen (whether shown or implied) is replaced by protium (i.e., 1 H), and deuterium (i.e., 2 H) 1 H and 2 It may be in combination with H. 1 H 2 Methods for exchanging with H are well known in the art. In the case of solvent exchangeable hydrogen, 1 H and 2 Exchange with H occurs readily in the presence of a suitable deuterium source without a catalyst. The use of acids, bases, or metal catalysts, coupled with elevated temperature and pressure conditions, can facilitate the exchange of non-exchangeable hydrogen atoms, generally resulting in the exchange of all hydrogen atoms in the molecule. 1 From H 2 This results in an exchange for H.

[0048] The compounds disclosed herein may be synthesized (at least in part) using peptide synthesis methods. Each amino acid residue in a peptide or peptide region has both an amino group and a carboxylic acid group, either or both of which may be used for covalent attachment. When attached to the remainder of the compound, the amino and / or carboxylic acid groups may be converted to amide or other structures, for example, when the carboxylic acid group of a first amino acid is attached to the amino group of a second amino acid (i.e., a peptide bond). Thus, an amino acid residue may be represented by the formula -N(R a )-R b -C(O)-(wherein, R a and R b is an R group. ais typically hydrogen or methyl (or different alkyl). The amino acid residues of the peptide may contain typical peptide (amide) bonds and may further contain bonds between the side chain functional group and the side chain or main chain functional group of another amino acid. For example, the side chain carboxylic acid of one amino acid residue (e.g., Asp, Glu, etc.) in the peptide or peptide region may be bonded to the amine of another amino acid residue (e.g., Dap, Dab, Orn, Lys) in the peptide or peptide region. Further details are provided below. Unless otherwise indicated, the amino acid may be any amino acid, including proteinogenic and non-proteinogenic amino acids, alpha amino acids, beta amino acids, or any other amino acid.Non-limiting examples of non-proteinogenic amino acids are provided in Table 1, including, but not limited to, D-amino acids, including any D-form of the following amino acids: ornithine (Orn), 3-(1-naphthyl)alanine (Nal), 3-(2-naphthyl)alanine (2-Nal), α-aminobutyric acid, norvaline, norleucine (Nle), homonorleucine, beta-(1,2,3-triazol-4-yl)-L-alanine, 1,2,4-triazol-3-yl ... Alanine, Phe(4-F), Phe(4-Cl), Phe(4-Br), Phe(4-I), Phe(4-NH2), Phe(4-NO2), homoarginine (hArg), 2-amino-4-guanidinobutyric acid (Agb), 2-amino-3-guanidinopropionic acid (Agp), β-alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 7-aminoheptanoic acid, 8-aminooctanoic acid, 9-aminononanoic acid, 10-aminodecanoic acid, 2-aminooctanoic acid, 2-amino -3-(anthracen-2-yl)propanoic acid, 2-amino-3-(anthracen-9-yl)propanoic acid, 2-amino-3-(pyren-1-yl)propanoic acid, Trp(5-Br), Trp(5-OCH3), Trp(6-F), Trp(5-OH), or Trp(CHO), 2-aminoadipic acid (2-Aad), 3-aminoadipic acid (3-Aad), propargylglycine (Pra), homopropargylglycine (Hpg), beta-homopropargylglycine (Bpg), 2 ,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), azidolysine (Lys(N3)), azido-ornithine (Orn(N3)), 2-amino-4-azidobutanoic acid Dab(N3), Dap(N3), 2-(5'-azidopentyl)alanine, 2-(6'-azidohexyl)alanine, 4-amino-1-carboxymethyl-piperidine (Pip), 4-(2-aminoethyl)-1-carboxymethyl-piperazine (Acp), and tranexamic acid. When not specified as an L-amino acid or a D-amino acid, an amino acid should be understood to include both L-amino acids and D-amino acids.

[0049] [Table 1]

[0050] Definition L of the chemical formula (e.g., Formula I) 1 , R 3 , L 2 , L 3 , and R alb ) through the bond or at the end of the bond [ka] The symbols are intended to define the groups on one side of the wavy line without modifying the definition of the structure on the other side of the line. When an R or L group is attached on more than one side, any atoms shown outside the wavy line are intended to clarify the orientation of the defined group. Thus, only the atoms between the two wavy lines constitute the definition of the R or L group. If an atom is not shown outside the wavy line (e.g., L 1 ), or in the case of a chemical group shown without a wavy line but with bonds on multiple sides (such as, for example, -C(O)NH-), the chemical group should be read from left to right, consistent with the orientation in the formula to which the group relates, e.g., the formula -R a -R b -R c -, R as -C(O)NH- b The definition of -R a -NHC(O)-R c -R instead of - a -C(O)NH-R c will be incorporated into the formula as -.

[0051] In various aspects, compounds are disclosed having formula I (defined below) or a salt or solvate of formula I, [ka] During the ceremony, R 1 -R 1a R 1b - where R 1a is absent, -CH2-, -O-, or -S-, and R1b is -CH2- or -CHF-, R 2 is -(CH2)3-O-, -(CH2)3-, -(CH2)4-, -CH2-O-(CH2)2-, or -CH2-S-(CH2)2-, L 1 -S-, -N(R L1a )-C(O)-, -C(O)-N(R L1a )-, -NH-C(O)-NH-, -NH-C(S)-NH-, [ka] where R L1a is H, methyl, ethyl, or a benzyl group having 0 to 4 substituents independently selected from halogen, OMe, or SMe; R 3 is substituted with 0 to 4 substituents independently selected from C1-C4 alkyl, halogen, OMe, SMe, NH2, NO2, CN, or OH; [ka] where 0 to 4 ring carbons are replaced by nitrogen; L 2 -S-, -N(R L2a )-C(O)-, -C(O)-N(R L2a )-, -NH-C(O)-NH-, -NH-C(S)-NH-, [ka] where R L2a is H, methyl, or ethyl; n1 and n2 each represent 0 to 2; Ring A has 0 to 3 double bonds and is bonded at the meta or para position; L 3 , L 4 , L 5b , L 5c , L 6 , and L 7 are each independently -S-, -N(R L3a)-C(O)-, -C(O)-N(R L3a )-, -NH-C(O)-NH-, -NH-C(S)-NH-, [ka] where each R L3a is independently H, methyl, or ethyl; n3, n4, and n5 each independently represent 0 to 4; Each R 4 are independently linear, branched, and / or cyclic C n6 alkylenyl, alkenylenyl, and / or alkynylenyl, where each n6 is independently 1 to 20, and any carbon bonded to two other carbons is optionally and independently replaced by N, S, or O, and carbons are optionally and independently substituted with oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphate; R 5a -X br (R 5c )-R 5b is linear, branched and / or cyclic C n7 forming alkylenyl, alkenylenyl, and / or alkynylenyl, where n7 is 1-20, and any carbon bonded to two other carbons is optionally and independently replaced by N, S, or O, and carbons are optionally and independently replaced by oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphate; R 5a , R 5b , and R 5c One, two, or three of are optionally absent, and X br is C, CH, or N, and X br is at least 4 atoms away from ring A, Each R 6 and each R 7 are independently linear, branched, and / or cyclic C n8alkylenyl, alkenylenyl, and / or alkynylenyl, where each n8 is independently 1 to 20, and any carbon bonded to two other carbons is optionally and independently replaced by N, S, or O, and carbons are optionally and independently substituted with oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphate; R rad is a radiometal chelator, optionally bound by a radiometal, where R rad is at least 7 atoms away from ring A, R alb is an albumin binder, the albumin binder comprising: -(CH2) n9 -CH3 (wherein n9 is 8 to 20); -(CH2) n10 -C(O)OH (wherein n10 is 8 to 20), or [ka] (wherein n11 is 1 to 4, and R 8 is I, Br, F, Cl, H, OH, OCH3, NH2, NO2, or CH3; R alb is at least 7 atoms away from ring A.

[0052] In some embodiments, the compound (of formula I) has formula II: [ka] or a salt or solvate of formula II, wherein R 1 , R 2 , R 3 , R L3a , R 5b , R 5c , R 6 , R 7 , R rad , R alb , L 1 , L 2 , L 5b, L 5c , L 6 , L 7 , ring A, n1, n2, n4, and n5 are as defined in formula I or as defined in any other embodiment defined herein. In some of these embodiments, R 1 is -CH-CH- or -CHF-. In certain of these embodiments, R 2 In some of these embodiments, L is -(CH2)4-. 1 is -NH-C(O)-. In certain of these embodiments, R 3 teeth, [ka] and optionally, R 3 teeth, [ka] In some of these embodiments, L 2 In some of these embodiments, n1 is 0, ring A has 0 double bonds and is attached at the para position, and optionally ring A is [ka] In some of these embodiments, n2 is 0 or 1. In some of these embodiments, each R L3a is H. In some of these embodiments, X br is N or CH. In certain of these embodiments, R 5b is -(CH2)4-, and R 5c does not exist or R 5c is -(CH2)4-, and R 5b In some of these embodiments, L 5b In some of these embodiments, L is -NH-C(O)-. 5c In some of these embodiments, L is -NH-C(O)-.5b In some of these embodiments, n4 is 0 or 1 and R 6 is methylene, if present. In some of these embodiments, n5 is 0 or 1 and R 7 When present, L is methylene. In certain of these embodiments, L 6 When present, L is -NH-C(O)-. In certain of these embodiments, L 7 When present, R is -NH-C(O)-. In certain of these embodiments, R alb teeth, [ka] where n11 is 3 and R 8 is OCH3 or NO2. In some of these embodiments, R rad is DOTA or a DOTA derivative.

[0053] In some embodiments, R 1 -R 1a R 1b - where R 1a is absent or is -CH-, and R 1b is -CH2- or -CHF, R 2 is -(CH2)3-O-, -(CH2)3-, -(CH2)4-, or -CH2-O-(CH2)2-, L 1 is -N(R L1a )-C(O)-, -C(O)-N(R L1a )-, or -NH-C(O)-NH-, where R L1a is H or methyl, R 3 teeth, [ka] and L 2 is -N(R L2a )-C(O)-, -C(O)-N(RL2a )-, -NH-C(O)-NH-, where R L2a is H or methyl, n1 and n2 each represent 0 to 2; Ring A has 0 bonds and is bonded at the meta or para position; L 3 , L 4 , L 5b , L 5c , L 6 , and L 7 Each independently represents -N(R L3a )-C(O)-, -C(O)-N(R L3a )-, or -NH-C(O)-NH-, where each R L3a is independently H, methyl, or ethyl; n3, n4, and n5 each independently represent 0 to 4; Each R 4 are independently linear C 1- C 10 is alkylenyl, R 5a -X br (R 5c )-R 5b is linear, branched and / or cyclic C 1- C 20 forming alkylenyl, alkenylenyl, and / or alkynylenyl, where any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted with oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphate; 5a , R 5b , and R 5c One, two, or three of are optionally absent, and X br is N or CH, and X br is at least 4 atoms away from ring A, Each R 6 and each R 7 are independently linear, branched, and / or cyclic C 1- C 20alkylenyl, alkenylenyl, and / or alkynylenyl, where any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted with oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphate; R rad is a radiometal chelator, optionally bound by a radiometal, where R rad is at least 7 atoms away from ring A, R alb teeth, [ka] where n11 is 1 to 4, and R 8 is I, Br, F, Cl, H, OH, OCH3, NH2, NO2, or CH3.

[0054] In another embodiment, R 2 is -(CH2)3- or -(CH2)4-, L 1 is -N(R L1a )-C(O)- or -C(O)-N(R L1a )-, where R L1a is H or methyl, R 3 teeth, [ka] and L 2 is -N(R L2a )-C(O)- or -C(O)-N(R L2a )-, where R L2a is H or methyl, n1 and n2 each represent 0 to 1; L 3 , L 4 , L 5b , L 5c , L 6 , and L 7Each independently represents -N(R L3a )-C(O)- or -C(O)-N(R L3a )-and Here, each R L3a is independently H or methyl; Each R 4 are independently linear C 1- C 10 is alkylenyl, R 5a -X br (R 5c )-R 5b is linear, branched and / or cyclic C 1- C 10 alkylenyl, where any carbon bonded to two other carbons is optionally and independently replaced by O, and carbons are optionally and independently replaced by oxo, hydroxyl, amine, amide, or carboxylic acid; R 5a , R 5b , and R 5c One, two, or three of are optionally absent, and X br is N or CH, and X br is at least 4 atoms away from ring A, Each R 6 and each R 7 are independently linear, branched, and / or cyclic C 1- C 10 alkylenyl, where any carbon bonded to two other carbons is optionally and independently replaced by N, S, or O, and carbons are optionally and independently substituted with oxo, hydroxyl, amine, amide, urea, carboxylic acid; R alb teeth, [ka] where n11 is 1 to 4, and R 8 is OCH3 or NO2.

[0055] In another specific embodiment, L 3 In another specific embodiment, L 4is -NHC(O)-. In another specific embodiment, R 4 is methylene. In another specific embodiment, n3 is 1 to 4. In another specific embodiment, n3 is 1 to 2. In another specific embodiment, n3 is 1. In another specific embodiment, n2 is 0 to 1. In another specific embodiment, n2 is 1. In another specific embodiment, R 5a In another specific embodiment, R 5a is methylene.

[0056] In some embodiments, R 1a is absent. In some embodiments, R 1a is -CH-. In some embodiments, R 1a In some embodiments, R 1a is -S-.

[0057] In some embodiments, R 1b is -CH-. In some embodiments, R 1b is -CHF-.

[0058] In some embodiments, R 1 is -CH-. In some embodiments, R 1 In some embodiments, R 1 is -CH-CH-. In some embodiments, R 1 is -CH-CHF-. In some embodiments, R 1 is -O-CH-. In some embodiments, R 1 In some embodiments, R 1 is -S-CH-. In some embodiments, R 1 is -S-CHF-.

[0059] In some embodiments, R 2 is -(CH2)3-O-. In some embodiments, R 2is -(CH2)3-. In some embodiments, R 2 is -(CH2)4-. In some embodiments, R 2 is -CH-O-(CH)-. In some embodiments, R 2 is -CH2-S-(CH2)2-.

[0060] In some embodiments, L 1 is -N(R L1a )-C(O)- or -C(O)-N(R L1a )-, where R L1a is as defined in formula I. In some such embodiments, R L1a is H. In other such embodiments, R L1a In other such embodiments, R L1a In yet other such embodiments, R L1a is a benzyl group having 0-4 substituents independently selected from halogen, OMe, or SMe. L1a is a benzyl group. In some embodiments, L 1 is -N(R L1a )-C(O)- or -C(O)-N(R L1a )-, where L 1a is H or methyl. In some embodiments, L 1 is -NHC(O)-. In some embodiments, L 1 is -C(O)-NH-.

[0061] In some embodiments, R 5a -X br (R 5c )-R 5b is a linear or branched C 1- C 20 alkylenyl, where any carbon bonded to two other carbons is optionally and independently replaced by O, and carbons are optionally and independently replaced by oxo, hydroxyl, amine, amide, or carboxylic acid; R 5a , R 5b , and R5c One, two, or three of are optionally absent, and X br is N or CH, and X br is at least 4 atoms away from ring A. In another specific embodiment, R 5a -X br (R 5c )-R 5b is a linear or branched C 1- C 10 Forms an alkylenyl, where any carbon bonded to two other carbons is optionally and independently replaced by O. In another particular embodiment, 1, 2, 3, or 4 carbons are replaced by O.

[0062] In some embodiments, L 1 In some embodiments, L 1 is -NH-C(O)-NH-. In some embodiments, L 1 is -NH-C(S)-NH-. In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] It is.

[0063] In some embodiments, R 3 is substituted with 0 to 4 substituents independently selected from C1-C4 alkyl, halogen, OMe, SMe, NH2, NO2, CN, or OH; [ka] where 0-4 ring carbons are replaced with nitrogen, and in some such embodiments, the ring is unsubstituted and has a single nitrogen. 3 is substituted with 0 to 4 substituents independently selected from C1-C4 alkyl, halogen, OMe, SMe, NH2, NO2, CN, or OH; [ka] where 0-4 ring carbons are replaced with nitrogen, and in some such embodiments, the ring is unsubstituted and has a single nitrogen. 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] It is.

[0064] In some embodiments, L 2 is -N(R L2a )-C(O)- or -C(O)-N(R L2a )-, where R L2a is as defined in formula I. In some such embodiments, R L2a is H. In other such embodiments, R L2a In other such embodiments, R L2aIn yet other such embodiments, R L2a is a benzyl group having 0-4 substituents independently selected from halogen, OMe, or SMe. L2a is a benzyl group. In some embodiments, L 2 is -N(R L2a )-C(O)- or -C(O)-N(R L2a )-, where L 2a is H or methyl. In some embodiments, L 2 is -NHC(O)-. In some embodiments, L 2 is -C(O)-NH-.

[0065] In some embodiments, L 2 In some embodiments, L 2 is -NH-C(O)-NH-. In some embodiments, L 2 is -NH-C(S)-NH-. In some embodiments, L 2 teeth, [ka] In some embodiments, L 2 teeth, [ka] In some embodiments, L 2 teeth, [ka] In some embodiments, L 2 teeth, [ka] It is.

[0066] In some embodiments, n1 is 0. In some embodiments, n1 is 1. In some embodiments, n1 is 2.

[0067] In some embodiments, ring A has zero double bonds (i.e., all single bonds). In some embodiments, ring A has one double bond. In some embodiments, ring A has two double bonds. In some embodiments, ring A has three double bonds. In some embodiments, ring A is bonded at the meta position. In some embodiments, ring A is bonded at the para position. In some embodiments, ring A has zero double bonds and is bonded at the para position. In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] It is.

[0068] In some embodiments, n2 is 0. In some embodiments, n2 is 1. In some embodiments, n2 is 2.

[0069] In some embodiments, L 3 is -N(R L3a )-C(O)- or -C(O)-N(R L3a )-, where R L3a is as defined in formula I. In some such embodiments, R L3a is H. In other such embodiments, R L3a In other such embodiments, R L3a is ethyl. In some embodiments, L 3 is -N(R L3a )-C(O)- or -C(O)-N(R L3a )-, where R L3a is H or methyl. In some embodiments, L 3 is -NHC(O)-. In some embodiments, L 3 is -C(O)-NH-. In some embodiments, L3 In some embodiments, L 3 is -NH-C(O)-NH-. In some embodiments, L 3 is -NH-C(S)-NH-. In some embodiments, L 3 teeth, [ka] In some embodiments, L 3 teeth, [ka] In some embodiments, L 3 teeth, [ka] In some embodiments, L 3 teeth, [ka] It is.

[0070] In some embodiments, R 1 is -CH2-CH2-, and R 2 In some such embodiments, L 1 is -NH-C(O)-. In some such embodiments, R 3 teeth, [ka] and optionally, R 3 teeth, [ka] In some such embodiments, L 2 In some such embodiments, n1 is 0, ring A has 0 double bonds and is attached at the para position, and optionally ring A is [ka] In some such embodiments, n2 is 0 or 1. In some such embodiments, L 3 is -NHC(O)-.

[0071] In some embodiments, n3 is 0. In some embodiments, n3 is 1. In some embodiments, n3 is 2. In some embodiments, n3 is 3. In some embodiments, n3 is 4.

[0072] In embodiments where n3 is not 0, each R 4 are independently linear, branched, and / or cyclic C n6 Alkylenyl, alkenylenyl, and / or alkynylenyl, where any carbon bonded to two other carbons is optionally and independently replaced by N, S, or O, and the carbons are optionally and independently substituted. In some embodiments, each n6 is independently 1 to 15 or 1 to 10. In alternative embodiments, each n6 is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, each R 4 is independent, C n6 alkylenyl, where any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and the carbons are optionally independently substituted, and in some such embodiments, n3 is 1. In some embodiments, n3 is 1 and R 4 is C1-C5 alkylenyl, optionally methylene. In some embodiments, each R 4 are independent of each other, -C(R aa )H-, where each R aa is independently a side chain of a proteinogenic amino acid or a side chain of an alpha amino acid from Table 1. In some embodiments, each R 4 is independently a proteinogenic amino acid or an amino acid from Table 1 omitting the backbone amino and carboxylic acid groups of the amino acid.

[0073] In some embodiments where n3 is not 0, each L 4 are independent, -N(R L4a )-C(O)- or -C(O)-N(R L4a )-, where each R L4a is independently H, methyl, or ethyl. In other such embodiments, each R L4a is independently H or methyl. In other such embodiments, at least one R L4a is ethyl. In some embodiments, each L 4 is independently -NHC(O)- or -C(O)-NH-. In some embodiments, each L 4 is -NHC(O)-. In some embodiments, at least one L 4 In some embodiments, at least one L 4 In some embodiments, at least one L 4 In some embodiments, at least one L 4 but, [ka] In some embodiments, at least one L 4 but, [ka] In some embodiments, at least one L 4 but, [ka] In some embodiments, at least one L 4 but, [ka] It is.

[0074] In some embodiments, n3 is 1 and R 4is methylene, L 4 In some such embodiments, L 3 is -NHC(O)-. In some such embodiments, n2 is 1.

[0075] In some embodiments where n3 is not 0, each L 4 are independent, -N(R L3a )-C(O)- or -C(O)-N(R L3a )-, where each R L3a is independently H, methyl, or ethyl. In other such embodiments, each R L4a is independently H or methyl. In other such embodiments, at least one R L3a is ethyl.

[0076] X br is the branching atom, i.e., the linker branches from one chain to two chains, R rad and R alb In some embodiments, X is a point that connects both br is N, C, or CH. In some embodiments, X br is CH. In other embodiments, X br is N.

[0077] In some embodiments, X br is at least 4 ms, at least 5 atoms, at least 6 atoms, at least 7 atoms, at least 8 atoms, at least 9 atoms, or at least 10 atoms away from ring A. br is at least [a few] atoms away from ring A" means that X br is the number of atoms that form a continuous chain by the shortest path between X and ring A, and br and ring A atoms are excluded from the number of atoms. The phrase "by the shortest path" in this context refers to the number of atoms in a continuous chain of X, such that there are two or more non-equivalent paths for counting atoms. brThe possibility that the atoms separating ring A and ring B contain rings is referred to as the possibility that the shortest paths are counted in such a situation. br The number of atoms separating X from ring A does not include hydrogen and does not include any non-hydrogen atoms branching off from the shortest path. For example, in structure CCZ02017 (see examples for its chemical structure), X br The number of atoms separating ring A is six, excluding the two amide oxygens and all of the hydrogens.

[0078] In some embodiments, X br is 6 atoms away from ring A. In some embodiments, X br is separated from ring A by 5 atoms. br is four atoms away from ring A.

[0079] As defined by formula I, R 5a -X br (R 5c )-R 5b is C n7 In some embodiments, R 1 is an alkylene group, an alkenylenyl group, and / or an alkynylenyl group, where n7 is 1 to 20 (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20), and any carbon bonded to two other carbons may be independently replaced by an N, S, or O heteroatom. 5a -X br (R 5c )-R 5b is C n7In some embodiments, n7 is 1-15 or 1-10. In some embodiments, one carbon is replaced by N, S, or O. In other embodiments, two, three, four, or five carbons are each independently replaced by N, S, or O. In some embodiments, the carbons are unsubstituted. In other embodiments, one carbon is substituted. In other embodiments, two or three carbons are independently substituted. The substitutions are as defined in Formula I. In some embodiments, the substitutions are independently selected from one or more of hydroxyl, sulfhydryl, amine, guanidino, and / or carboxylic acid. In some embodiments, R 5a is absent. In some embodiments, R 5b is absent. In some embodiments, R 5c is absent. In some embodiments, R 5a and R 5b is absent. In some embodiments, R 5a and R 5c is absent. In some embodiments, R 5b and R 5c is absent. In some embodiments, R 5a , R5 b , and R 5c In some embodiments, R 5a is C1-C6 alkylenyl, optionally -(CH2) 1-4 In some embodiments, R 5b is C1-C6 alkylenyl, optionally -(CH2) 1-4 In some embodiments, R 5c is C1-C6 alkylenyl, optionally -(CH2) 1-4 -It is.

[0080] In some embodiments, R 5a is absent or C1-C6 alkylenyl, optionally -(CH2) 1-4 - and R 5b is absent or C1-C6 alkylenyl, optionally -(CH2)1-4 - and R 5c is absent or C1-C6 alkylenyl, optionally -(CH2) 1-4 - and X br is N, C, or CH, where R 5a , R 5b , or R 5c In some embodiments, R 5a -X br (R 5c )-R 5b teeth, [ka] where n12a, n12b, and n12c are each independently 0 to 4. In some embodiments, R 5a -X br (R 5c )-R 5b teeth, [ka] It is.

[0081] In some embodiments, L 5b is -N(R L5b )-C(O)- or -C(O)-N(R L5b )-, where R L5b is H, methyl, or ethyl. In some such embodiments, R L5b is H. In other such embodiments, R L5b In other such embodiments, R L5b is ethyl. In some embodiments, L 5b is -NHC(O)-. In some embodiments, L 5b is -C(O)-NH-. In some embodiments, L 5b is -S-.

[0082] In some embodiments, L 5b is -N(R L3a )-C(O)- or -C(O)-N(R L3a)-, where R L3a is H, methyl, or ethyl. In some such embodiments, R L3a is H. In other such embodiments, R L3a In other such embodiments, R L3a is ethyl. In some embodiments, L 5b is -NHC(O)-.

[0083] In some embodiments, L 5b is -NH-C(O)-NH-. In some embodiments, L 5b is -NH-C(S)-NH-. In some embodiments, L 5b teeth, [ka] In some embodiments, L 5b teeth, [ka] In some embodiments, L 5b teeth, [ka] In some embodiments, L 5b teeth, [ka] It is.

[0084] In some embodiments, L 5c is -N(R L5c )-C(O)- or -C(O)-N(R L5c )-, where R L5c is H, methyl, or ethyl. In other such embodiments, R L5c In other such embodiments, R L5c is ethyl. In some embodiments, L 5c is -NHC(O)-. In some embodiments, L5c is -C(O)-NH-. In some embodiments, L 5c is -S-.

[0085] In some embodiments, L 5c is -N(R L3a )-C(O)- or -C(O)-N(R L3a )-, where R L3a is H, methyl, or ethyl. In other such embodiments, R L3a In other such embodiments, R L3a is ethyl. In some embodiments, L 5c is -NHC(O)-. In some embodiments, L 5c is -C(O)-NH-. In some embodiments, L 5c In some embodiments, L 5c is -NH-C(O)-NH-.

[0086] In some embodiments, L 5c is -NH-C(O)-NH-. In some embodiments, L 5c is -NH-C(S)-NH-.

[0087] In some embodiments, L 5c teeth, [ka] In some embodiments, L 5c teeth, [ka] In some embodiments, L 5c teeth, [ka] In some embodiments, L 5c teeth, [ka] It is.

[0088] In some embodiments, n3 is 0 and R 5a is methylene, and X br is N or CH, R 5b is -(CH2)4-, and R 5c does not exist or R 5c is -(CH2)4-, and R 5b In some such embodiments, L 5b In some such embodiments, L 5c is -NHC(O)-. 5b and L 5c may each be -NHC(O)-.

[0089] In some embodiments, n4 is 0. In some embodiments, n4 is 1. In some embodiments, n4 is 2. In some embodiments, n4 is 3. In some embodiments, n4 is 4.

[0090] In embodiments where n4 is not 0, each R 6 are independently linear, branched, and / or cyclic C n8a Alkylenyl, alkenylenyl, and / or alkynylenyl, where each n8a is independently 1-20, any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and the carbons are optionally independently substituted. In some embodiments, each n8a is independently 1-15 or 1-10. In alternative embodiments, each n8a is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, each R 6 is independent, C n8aalkylenyl, where any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and the carbons are optionally independently substituted, and in some such embodiments, n4 is 1. In some embodiments, n4 is 1 and R 6 is C1-C5 alkylenyl, optionally methylene or -(CH2) 1-4 In some embodiments, each R 6 are independent of each other, -C(R aa )H-, where each R aa is independently a side chain of a proteinogenic amino acid or a side chain of an alpha amino acid from Table 1. In some embodiments, each R 6 is independently a proteinogenic amino acid or an amino acid from Table 1 omitting the backbone amino and carboxylic acid groups of the amino acid.

[0091] In some embodiments where n4 is not 0, each L 6 are independent, -N(R L6a )-C(O)- or -C(O)-N(R L6a )-, where each R L6a is independently H, methyl, or ethyl. In other such embodiments, each R L6a is independently H or methyl. In some embodiments where n4 is not 0, each L 6 are independent, -N(R L3a )-C(O)- or -C(O)-N(R L3a )-, where each R L3a is independently H, methyl, or ethyl. In other such embodiments, each R L3a is independently H or methyl. In other such embodiments, at least one R L6a is ethyl. In some embodiments, each L 6 is independently -NHC(O)- or -C(O)-NH-. In some embodiments, each L 6 is -NHC(O)-. In some embodiments, at least one L 6 In some embodiments, at least one L 6is -NH-C(O)-NH-. In some embodiments, L 6 is -NH-C(S)-NH-. In some embodiments, at least one L 6 but, [ka] In some embodiments, at least one L 6 but, [ka] In some embodiments, at least one L 6 but, [ka] In some embodiments, at least one L 6 but, [ka] It is.

[0092] In some embodiments, n5 is 0. In some embodiments, n5 is 1. In some embodiments, n5 is 2. In some embodiments, n5 is 3. In some embodiments, n5 is 4.

[0093] In embodiments where n5 is not 0, each R 7 are independently linear, branched, and / or cyclic C n8b Alkylenyl, alkenylenyl, and / or alkynylenyl, where each n8b is independently 1 to 20, any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and the carbons are optionally independently substituted. In some embodiments, each n8b is independently 1 to 15 or 1 to 10. In alternative embodiments, each n8b is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, each R 7is independent, C n8b alkylenyl, where any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and the carbons are optionally independently substituted, and in some such embodiments, n5 is 1. In some embodiments, n5 is 1 and R 7 is C1-C5 alkylenyl, optionally methylene or -(CH2) 1-4 In some embodiments, each R 7 are independent of each other, -C(R aa )H-, where each R aa is independently a side chain of a proteinogenic amino acid or a side chain of an alpha amino acid from Table 1. In some embodiments, each R 6 is independently a proteinogenic amino acid or an amino acid from Table 1 omitting the backbone amino and carboxylic acid groups of the amino acid.

[0094] In some embodiments where n5 is not 0, each L 7 are independent, -N(R L7a )-C(O)- or -C(O)-N(R L7a )-, where each R L7a is independently H, methyl, or ethyl. In other such embodiments, each R L7a is independently H or methyl. In other such embodiments, at least one R L7a is ethyl. In some embodiments, each L 7 is independently -NHC(O)- or -C(O)-NH-. In some embodiments, each L 7 In some embodiments where n5 is not 0, each L 7 are independent, -N(R L3a )-C(O)- or -C(O)-N(R L3a )-, where each R L3a is independently H, methyl, or ethyl. In other such embodiments, each R L3a is independently H or methyl. In other such embodiments, at least one R L3a is ethyl. In some embodiments, each L7 is independently -NHC(O)- or -C(O)-NH-. In some embodiments, each L 7 is -NHC(O)-. In some embodiments, at least one L 7 is -S-. In some embodiments, L 7 is -NH-C(O)-NH.

[0095] In some embodiments, L 7 is -NH-C(S)-NH-. In some embodiments, at least one L 7 but, [ka] In some embodiments, at least one L 7 but, [ka] In some embodiments, at least one L 7 but, [ka] In some embodiments, at least one L 7 but, [ka] It is.

[0096] R rad is a radioactive metal chelator that is at least 7 atoms away from ring A. rad is at least [a few] atoms away from ring A" means that R rad is the number of atoms that form a continuous chain by the shortest path between ring A and ring B, and R rad and ring A atoms are excluded from the number of atoms. The phrase "by the shortest path" in this context refers to the number of atoms in a continuous chain such that there are two or more non-equivalent paths for counting atoms in the chain. radThe probability that the atoms separating A and B contain a ring is referred to as the probability that the ring is included in the atoms separating A and B. In such a situation, the shortest paths are counted. rad The number of atoms separating R from ring A does not include hydrogens and does not include any non-hydrogen atoms branching off from the shortest path. For example, in structure CCZ02017 (see examples for chemical structure), R rad The number of atoms separating R and ring A is 13 (including the amide bond to DOTA), excluding the three amide oxygens. alb In some embodiments, R rad is separated from ring A by at least 7 atoms, at least 8 atoms, at least 9 atoms, at least 10 atoms, at least 11 atoms, at least 12 atoms, at least 13 atoms, at least 14 atoms, or at least 15 atoms. rad is 7 to 18 atoms (e.g., 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 atoms) away from ring A. rad is bound by a radioactive metal. In some embodiments, the radioactive metal is R rad is not bound to

[0097] If desired, the various embodiments described herein can be combined to form more specific embodiments. For example, in specific embodiments, ring A is [ka] and R 2 is -(CH2)4-, and R 3 teeth [ka] where n1 is 0 and L 1 -N(R L1a )-C(O)- or -C(O)-N(R L1a )-, where R L1a is H and L 2 -N(R L2a)-C(O)- or -C(O)-N(R L2a )-, where R L2a is H and R 1 -R 1a R 1b - where R 1a is -CH2- and R 1b is -CH2- or -CHF-.

[0098] In another specific embodiment, R 5c does not exist, and L 5c -N(R L3a )-C(O)- or -C(O)-N(R L3a )-, where R L3a is H and R 7 is methylene, L 7 -N(R L3a )-C(O)- or -C(O)-N(R L3a )-, where R L3a is H, n5 is 1, and R alb but [ka] where n11 is 3 and R 8 is OCH3 or NO2.

[0099] In another specific embodiment, n2 is 0 or 1, and L 3 -N(R L3a )-C(O)- or -C(O)-N(R L3a )-, where R L3a is H and R 4 is methylene, L 4 -N(R L3a )-C(O)- or -C(O)-N(R L3a )-, where R L3a is H, n3 is 1, and R 5a does not exist, and X br is CH.

[0100] In another specific embodiment, R 5b is a linear C1- C6 alkylenyl, L 5b -N(R L3a )-C(O)- or -C(O)-N(R L3a )-, where R L3a is H and R 6 is methylene, L 6 -N(R L3a )-C(O)- or -C(O)-N(R L3a )-, where R L3a is H and n4 is 0 to 2.

[0101] In some embodiments, R rad is selected from Table 2, where R rad is optionally bound by a radioactive metal.

[0102] The radiometal chelator may be any radiometal chelator suitable for binding to a radiometal and functionalized for binding to an amino group. Many suitable radiometal chelators are known, for example as reviewed in Price and Orvig, Chem. Soc. Rev., 2014, 43, 260-290, which is incorporated by reference in its entirety. Non-limiting examples of radiometal chelators include DOTA and derivatives; DOTAGA; NOTA; NODAGA; NODASA; CB-DO2A; 3p-C-DEPA; TCMC; DO3A; DTPA and DTPA analogs optionally selected from CHX-A″-DTPA and 1B4M-DTPA; TETA; NOPO; Me-3,2-HOPO; CB-TE1A1P; CB-TE2P; MM-TE2A; DM-TE2A; sarcofagin and sarcofagin derivatives optionally selected from SarAr, SarAr-NCS, diamSar, AmBaSar, and BaBaSar; TRAP; AAZTA; DATA and DATA derivatives; H2-macropa or derivatives thereof; H2dedpa, H4octapa, H4py4pa, H4Pypa, H2azapa, H 5decapa, and other picolinic acid derivatives; CP256; PCTA; C-NETA; C-NE3TA; HBED; SHBED; BCPA; CP256; YM103; desferrioxamine (DFO) and DFO derivatives; and H6phospa. Illustrative non-limiting examples of radiometal chelators and examples of radioisotopes chelated by these chelators are shown in Table 2. In Table 2, the functional groups for linking are shown in their unlinked form, and one of ordinary skill in the art will understand that these linking functional groups will be modified when linked to the compounds disclosed herein (e.g., COOH or NH2 in the chelator will become an amide bond when reacted with NH2 or COOH in the linker, respectively). R rad When counting the atoms separating R from ring A, the linking atom (or link-forming functional group in Table 2) is not included in the atom count. radcomprises a radiometal chelator selected from those listed above or in Table 2 linked via a linking functional group (e.g., COOH, NH, SH, etc.) One of skill in the art can substitute another chelator for any of the chelators listed herein.

[0103] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7]

[0104] In some embodiments, the chelator is DOTA or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is CB-DO2A or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is TCMC or a derivative thereof linked through an amide (e.g., formed from one of the -CONH2 groups shown in Table 2). In some embodiments, the chelator is 3p-C-DEPA or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is p-NH2-Bn-Oxo-DO3A or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is TETA or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is CB-TE2A or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is Diamsar or a derivative thereof linked through an amide (e.g., formed from one of the amino groups shown in Table 2). In some embodiments, the chelator is NOTA or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is NETA or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is HxTSE or a derivative thereof linked through an amide (e.g., formed from one of the amino groups shown in Table 2). In some embodiments, the chelator is P2N2Ph2 or a derivative thereof linked through an amide (e.g., formed from one of the amino groups shown in Table 2).In some embodiments, the chelator is DTPA or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is CHX-A00-DTPA or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is H2dedpa or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is H2azapa or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is H4octapa or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is H6phospa or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is H4CHXoctapa or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is H5decapa or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is H4neunpa-p-Bn-NO2 or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is SHBED or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is BPCA or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is PCTA or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2).In some embodiments, the chelator is H2-MACROPA or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2). In some embodiments, the chelator is crown or a derivative thereof linked through an amide (e.g., formed from one of the carboxyl groups shown in Table 2).

[0105] In some embodiments, the radiometal chelator is a derivative of a radiometal chelator shown in Table 2. Derivatives may include, for example, (1) modification of a functional group of the chelator (e.g., a carboxyl group, an amino group, etc.) or (2) attachment of a new functional group (e.g., attachment of an R group to the ethylene carbon located between the two nitrogen atoms, where the R group is a functional group fused to a spacer). In some embodiments, the carboxyl functional group shown in Table 2 is replaced with azidopropylethylacetamide (e.g., azido-mono-amide-DOTA), butynylacetamide (e.g., butyne-DOTA), thioethylacetamide (e.g., DO3A-thiol), maleimidoethylacetamide (e.g., maleimido-mono-amide-DOTA), or N-hydroxysuccinimide ester (e.g., DOTA-NHS-ester). When linked, these derivative chelators may be linked via an amide (formed from the remaining carboxyl group) or via a -C(O)-NH-(CH2) 2-3 -(triazole) or -C(O)-NH-(CH2) 2-3 In other embodiments, a backbone carbon in the chelator ring (e.g., in an ethylene located between two backbone nitrogen atoms) is fused to an R group bearing a functional group, optionally the R group being -(CH2) 1-3 -(phenyl)-N=C=S or -(CH2) 1-3-(phenyl)-N=C=O, optionally 1,4-isothiocyanatobenzyl, such as p-SCN-Bn-DOTA (S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid), p-SCN-Bn-NOTA (2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid), etc. When linked, these derivatives can form urea bonds (formed from isocyanates) or thiourea bonds (formed from isothiocyanates).

[0106] In some embodiments, the radiometal chelator is conjugated to a radioisotope (i.e., a radiometal). The conjugated radioisotope is 165 Er, 212 Bi, 166 Ho, 149 Pm, 159 Gd, 105 Rh, 109 Pd, 198 Au, 199 Au, 175 Yb, 142 Pr, 177 Lu, 111 In, 213 Bi, 212 Pb, 47 Sc, 90 Y, 225 Ac, 117m Sn, 153 Sm, 149 Tb, 161 Tb, 224 Ra, 227 Th, 223 Ra, 64 Cu, 67 In some embodiments, the chelator is a chelator of Table 2 and the conjugated radioisotope is a radioisotope shown in Table 2 as the binding agent for the particular chelator.

[0107] In some embodiments, the chelating agent is optionally 177 Lu, 111 In, 213 Bi,212 Pb, 47 Sc, 90 Y, 225 Ac, 117m Sn, 153 Sm, 149 Tb, 161 Tb, 165 Er, 224 Ra, 212 Bi, 227 Th, 223 Ra, 64 Cu, or 67 DOTA or a derivative thereof conjugated with Cu, optionally 225 Ac, 227 Th, or 177 Crown conjugated with Lu, optionally 225 H2-MACROPA conjugated with Ac, optionally 227 Me-3,2-HOPO conjugated with Th, optionally 225 H4py4pa conjugated with Ac, optionally 177 H4pypa conjugated with Lu, or optionally 111 It is DTPA conjugated with In.

[0108] In some embodiments, the chelator is selected from the group consisting of TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), SarAr (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexazabicyclo[6.6.6]-eicosane-1,8-diamine), NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), TRAP (1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid), HBED (N,N'-biphenyl)-1,4,7-triphenylphosphine), 1,4,7-triphenylphosphine, ... The picolinic acid derivatives are N,N'-bis(2-hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid), 2,3-HOPO (3-hydroxypyridin-2-one), PCTA (3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid), DFO (desferrioxamine), DTPA (diethylenetriaminepentaacetic acid), OCTAPA (N,N'-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N'-diacetic acid), or another picolinic acid derivative.

[0109] In some embodiments, the radioactive metal chelator is mercaptoacetyl, hydrazinonicotinamide, dimercaptosuccinic acid, 1,2-ethylenediylbis-L-cysteine ​​diethyl ester, methylene diphosphonate, hexamethylpropyleneamine oxime, or hexakis(methoxyisobutylisonitrile). In some of these embodiments, the chelator is bound by a radioisotope. In some such embodiments, the radioisotope is 186 Re or 188 Re. In some embodiments, the chelator is not bound by a radioisotope.

[0110] R alb is an albumin binder. In some embodiments, R alb is -(CH2) n9 In some embodiments, R is -CH3, where n9 is 8 to 20, and in alternative embodiments, n9 is 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.alb is -(CH2) n10 In some embodiments, R is -C(O)OH, where n10 is 8 to 20, and in alternative embodiments, n10 is 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. alb teeth, [ka] where n11 is 1 to 4, and R 8 is I, Br, F, Cl, H, OH, OCH3, NH2, NO2, or CH3, and in alternative embodiments, n11 is 1, 2, 3, or 4. In some embodiments, n11 is 3. In some embodiments, R 8 is OCH or NO. In some embodiments, R alb teeth, [ka] It is.

[0111] R alb is separated from ring A by at least 7 atoms. alb is separated from ring A by at least 4 atoms, at least 5 atoms, at least 6 atoms, at least 7 atoms, at least 8 atoms, at least 9 atoms, or at least 10 atoms. alb is at least [a few] atoms away from ring A" means that R alb is the number of atoms that form a continuous chain by the shortest path between ring A and ring B, and R alb and ring A atoms are excluded from the number of atoms. The phrase "by the shortest path" in this context refers to the number of atoms in a continuous chain such that there are two or more non-equivalent paths for counting atoms in the chain. alb The probability that the atoms separating A and B contain a ring is referred to as the probability that the ring is included in the atoms separating A and B. In such a situation, the shortest paths are counted. albThe number of atoms separating R from ring A does not include hydrogens and does not include any non-hydrogen atoms branching off from the shortest path. For example, in structure CCZ02017 (see examples for chemical structure), R alb The number of atoms separating ring A and ring B is 12, excluding the four amide oxygens, R rad The branch of the linker connecting the is removed, and all hydrogens are removed.

[0112] In some embodiments, R alb is 7 to 18 atoms away from ring A, and R rad is separated from ring A by 7 to 18 atoms. alb and R rad are each separated from ring A by 10 to 11 atoms. br is separated from ring A by 4 to 6 atoms, optionally 6 atoms.

[0113] In some embodiments, the compound (of formula I) has formula II: [ka] or a salt or solvate of formula II, wherein R 1 , R 2 , R 3 , R L3a , R 5b , R 5c , R 6 , R 7 , R rad , R alb , L 1 , L 2 , L 5b , L 5c , L 6 , L 7 , ring A, n1, n2, n4, and n5 are as defined in formula I or as defined in any other embodiment defined herein. In some of these embodiments, R 1 is -CH-CH- or -CHF-. In certain of these embodiments, R 2In some of these embodiments, L is -(CH2)4-. 1 is -NH-C(O)-. In certain of these embodiments, R 3 teeth, [ka] and optionally, R 3 teeth, [ka] In some of these embodiments, L 2 In some of these embodiments, n1 is 0, ring A has 0 double bonds and is attached at the para position, and optionally ring A is [ka] In some of these embodiments, n2 is 0 or 1. In some of these embodiments, each R L3a is H. In some of these embodiments, X br is N, C, or CH. In certain of these embodiments, R 5b is -(CH2)4-, and R 5c does not exist or R 5c is -(CH2)4-, and R 5b In some of these embodiments, L 5b In some of these embodiments, L is -NH-C(O)-. 5c In some of these embodiments, L is -NH-C(O)-. 5b In some of these embodiments, n4 is 0 or 1 and R 6 is methylene, if present. In some of these embodiments, n5 is 0 or 1 and R 7 When present, L is methylene. In certain of these embodiments, L 6When present, L is -NH-C(O)-. In certain of these embodiments, L 7 When present, R is -NH-C(O)-. In certain of these embodiments, R alb teeth, [ka] where n11 is 3 and R 8 is OCH3 or NO2. In some of these embodiments, R rad is DOTA or a DOTA derivative.

[0114] In some embodiments, the compound optionally comprises 177 Lu, 111 In, 213 Bi, 212 Pb, 47 Sc, 90 Y, 225 Ac, 117m Sn, 153 Sm, 149 Tb, 161 Tb, 165 Er, 224 Ra, 212 Bi, 227 Th, 223 Ra, 64 Cu, or 67 CCZ02009, CCZ02017, CCZ02008, CCZ02025, CCZ02024, CCZ02015, CCZ02019, CCZ02012, or CCZ02013 (see Examples for chemical structures) conjugated with Cu, or a salt or solvate thereof.

[0115] In some embodiments, the compound optionally comprises 177 Lu, 111 In, 213 Bi, 212 Pb, 47 Sc, 90 Y, 225 Ac, 117m Sn, 153 Sm, 149 Tb, 161Tb, 165 Er, 224 Ra, 212 Bi, 227 Th, 223 Ra, 64 Cu, or 67 CCZ02009, CCZ02017, CCZ02008, CCZ02025, CCZ02024, CCZ02015, CCZ02019, CCZ02012, CCZ02005, CCZ02021, CCZ02022, CCZ02059, CCZ02060, CCZ02034, CCZ02061, or CCZ02013 (see examples for chemical structures) conjugated with Cu, or a salt or solvate thereof.

[0116] In some embodiments, the compound optionally comprises 177 Lu, 111 In, 213 Bi, 212 Pb, 47 Sc, 90 Y, 225 Ac, 117m Sn, 153 Sm, 149 Tb, 161 Tb, 165 Er, 224 Ra, 212 Bi, 227 Th, 223 Ra, 64 Cu, or 67 CCZ02005, CCZ02021, CCZ02022, CCZ02059, CCZ02060, CCZ02034, CCZ02061, or a salt or solvate thereof, conjugated with Cu.

[0117] The radiometal chelator is used to bind therapeutic radioisotopes, e.g. 165 Er, 212 Bi, 166 Ho, 149 Pm, 159 Gd, 105 Rh, 109 Pd, 198 Au, 199 Au, 175 Yb, 142 Pr,177 Lu, 111 In, 213 Bi, 212 Pb, 47 Sc, 90 Y, 225 Ac, 117m Sn, 153 Sm, 149 Tb, 161 Tb, 224 Ra, 227 Th, 223 Ra, 64 Cu, 67 Disclosed is the use of certain embodiments of the compound (or pharmaceutical composition thereof) when conjugated with a PSMA-expressing condition or disease (such as, for example, a tumor) in a subject. Accordingly, provided is the use of the compound in the preparation of a medicament for treating a PSMA-expressing condition or disease in a subject. Also provided is a method of treating a PSMA-expressing disease in a subject, comprising administering to the subject a composition comprising the compound and a pharma- ceutical acceptable excipient. By way of example and not limitation, the disease may be a PSMA-expressing tumor or a PSMA-expressing cancer.

[0118] PSMA expression has been detected in various cancers (e.g., Rowe et al., 2015, Annals of Nuclear Medicine 29:877-882; Sathekge et al., 2015, Eur J Nucl Med Mol Imaging 42:1482-1483; Verburg et al., 2015, Eur J Nucl Med Mol Imaging 42:1622-1623; and Pyka et al., J Nucl Med November 19, 2015 jnumed.115.164442). Thus, the PSMA-expressing cancer can be, but is not limited to, prostate cancer, renal cancer, breast cancer, thyroid cancer, gastric cancer, colorectal cancer, bladder cancer, pancreatic cancer, lung cancer, liver cancer, brain tumor, melanoma, neuroendocrine tumor, ovarian cancer, or sarcoma. In some embodiments, the cancer is prostate cancer.

[0119] The compounds presented herein incorporate peptides that may be synthesized by any of a variety of methods established in the art, including, but not limited to, solution and solid phase peptide synthesis using 9-fluorenylmethoxycarbonyl (Fmoc) and / or t-butyloxycarbonyl (Boc) chemistry, and / or other synthetic approaches.

[0120] Solid phase peptide synthesis methods and techniques are well established in the art. For example, a peptide can be synthesized by sequentially incorporating the desired amino acid residues one by one. In such methods, peptide synthesis typically begins with coupling the C-terminal amino acid of the peptide of interest to a suitable resin. Prior to this, the reactive side chain and alpha amino group of the amino acid are protected from reaction by suitable protecting groups, allowing only the alpha carboxyl group to react with functional groups such as amine groups, hydroxyl groups, or halogenated alkyl groups on the solid support. After coupling the C-terminal amino acid to the support, the protecting groups on the side chain and / or alpha amino group of the amino acid are selectively removed to allow coupling of the next amino acid of interest. This process is repeated until the desired peptide is fully synthesized, at which point it can be cleaved from the support and purified. A non-limiting example of an instrument for solid phase peptide synthesis is the Aapptec Endeavor 90 peptide synthesizer.

[0121] To allow for the coupling of additional amino acids, the Fmoc protecting group may be removed from the amino acid on the solid support under mildly basic conditions, such as piperidine (20-50% v / v) in DMF. The amino acid to be added must also be activated for coupling (e.g., with an alpha carboxylate). Non-limiting examples of activating reagents include, but are not limited to, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP). Racemization is minimized by using triazoles such as 1-hydroxy-benzotriazole (HOBt) and 1-hydroxy-7-aza-benzotriazole (HOAt). Coupling may be carried out in the presence of a suitable base such as N,N-diisopropylethylamine (DIPEA / DIEA). For long peptides or if desired, peptide synthesis and ligation may be used.

[0122] Apart from the formation of a typical peptide bond to extend a peptide, the peptide can be extended in a branched manner by coupling to a side chain functional group (e.g., a carboxylic acid or amino group) either side chain to side chain or side chain to backbone amino or carboxylate. Coupling to amino acid side chains may be performed by any known method and may be performed on-resin or off-resin. Non-limiting examples include forming amides between an amino acid side chain containing a carboxyl group (e.g., Asp, D-Asp, Glu, D-Glu, etc.) and either an amino acid side chain containing an amino group (e.g., Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, etc.) or the peptide N-terminus; forming amides between an amino acid side chain containing an amino group (e.g., Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, etc.) and either an amino acid side chain containing a carboxyl group (e.g., Asp, D-Asp, Glu, D-Glu, etc.) or the peptide C-terminus; and forming 1,2,3-triazoles via click chemistry between an amino acid side chain containing an azide group (e.g., Lys(N3), D-Lys(N3), etc.) and either an amino acid side chain containing an alkyne group (e.g., Pra, D-Pra, etc.). While the protecting groups on the appropriate functional groups must be selectively removed prior to amide bond formation, the reaction between alkyne and azide groups via the click reaction to form 1,2,3-triazoles does not require selective deprotection. Non-limiting examples of selectively removable protecting groups include 2-phenylisopropyl ester (O-2-PhiPr) (e.g., on Asp / Glu), as well as 4-methyltrityl (Mtt), allyloxycarbonyl (alloc), 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene))ethyl (Dde), and 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl (ivDde) ​​(e.g., on Lys / Orn / Dab / Dap). The O-2-PhiPr and Mtt protecting groups can be selectively deprotected under mildly acidic conditions, such as 2.5% trifluoroacetic acid (TFA) in DCM.The Alloc protecting group can be selectively deprotected using tetrakis(triphenylphosphine)palladium(0) and phenylsilane in DCM. The Dde and ivDde protecting groups can be selectively deprotected using 2-5% hydrazine in DMF. The deprotected side chains of Asp / Glu (L or D form) and Lys / Orn / Dab / Dap (L or D form) can then be coupled, for example, by using the coupling reaction conditions described above.

[0123] The peptide backbone amide may be N-methylated (i.e., alpha aminomethylated) or N-alkylated. This may be accomplished by directly using Fmoc-N-methylated amino acids (or Fmoc-N-alkylated amino acids) during peptide synthesis. Alternatively, N-methylation (or N-alkylation) under Mitsunobu conditions may be performed. First, the free primary amine group is protected using 4-nitrobenzenesulfonyl chloride (Ns-Cl) and 2,4,6-trimethylpyridine (collidine) in NMP. N-methylation may then be achieved in the presence of triphenylphosphine, diisopropyl azodicarboxylate (DIAD), and methanol. N-deprotection may then be performed using mercaptoethanol and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in NMP. HATU, HOAt, and DIEA may be used to couple the protected amino acid to the N-methylated alpha amino group.

[0124] PSMA binding moieties (e.g., Lys-ureido-Glu, Lys-ureido-Aad, etc.) can be constructed on the solid phase by the formation of a ureido bond between the amino groups of two amino acids. This can be done by coupling an Fmoc-protected amino acid (e.g., Fmoc-Lys(ivDde)-OH) to Wang resin using a standard activation / coupling strategy (e.g., Fmoc-protected amino acid (4 equivalents), HATU (4 equivalents), and N,N-diisopropylethylamine (7 equivalents) in N,N-dimethylformamide). The Fmoc protecting group is then removed with 20% piperidine in N,N-dimethylformamide. To form the ureido bond, the free amino group of the solid phase-bound amino acid is reacted with a second amino acid whose carboxylic acid group is protected with a t-butyl group and whose amino group is activated, converting it to an isocyanate group (-N=C=O). Activation and conversion of the amino group to an isocyanate group can be achieved by reacting the amino group with phosgene or triphosgene. After formation of the ureido bond, the side chain functionality of the amino acid (e.g., ivDde on Lys) can be removed and then a linker, albumin binding motif, and / or radiolabel group (e.g., a radiometal chelator, etc.) can be coupled to the PSMA binding moiety.

[0125] Thioether (-S-) bond formation (e.g., L 1 , L 2 , L 3etc.) can be accomplished either on the solid phase or in solution phase. For example, the formation of a thioether (-S-) bond can be achieved by coupling a thiol-containing compound (such as a thiol group on a cysteine ​​side chain) with an alkyl halide (such as 3-(Fmoc-amino)propyl bromide) in the presence of a base (such as N,N-diisopropylethylamine) in a suitable solvent (such as N,N-dimethylformamide). When the reaction is carried out in solution phase, the reactants used are preferably in equivalent molar ratios (1:1), and the desired product can be purified by flash column chromatography or high performance liquid chromatography (HPLC). When the reaction is carried out on the solid phase, i.e., one reactant is bound to the solid phase, the other reactant is usually used in excess (3 or more equivalents of the reactant bound to the solid phase). After the reaction, excess unreacted reactants and reagents can be removed by sequentially washing the solid phase (resin) using a combination of solvents such as, for example, N,N-dimethylformamide, methanol, and dichloromethane.

[0126] Formation of a bond between a thiol group and a maleimide group (e.g., L 1 , L 2 , L 3 etc.) can be carried out using the conditions described above for the formation of thioether (-S-) bonds, simply by replacing the alkyl halide with a maleimide-containing compound. Similarly, this reaction can be carried out on solid phase or in solution phase. When the reaction is carried out in solution phase, the reactants used are preferably in equivalent molar ratios (1:1), and the desired product can be purified by flash column chromatography or high performance liquid chromatography (HPLC). When the reaction is carried out on solid phase, i.e., one reactant is bound to the solid phase, the other reactant is usually used in excess (3 or more equivalents of the reactant bound to the solid phase). After the reaction, excess unreacted reactants and reagents can be removed by sequentially washing the solid phase (resin) using a combination of solvents such as, for example, N,N-dimethylformamide, methanol, and dichloromethane.

[0127] Urea or thiourea linkages can be created by reacting an amine group with isocyanate or isothiocyanate, respectively, which are common functional groups on radiometal chelators. An isothiocyanate functional group can be added to a radiometal chelator by reacting an amino group on the chelator with thiophosgene [i.e., C(S)Cl2]. Similarly, an isocyanate functional group can be added to a radiometal chelator by reacting an amino group on the chelator with phosgene [i.e., C(O)Cl2].

[0128] Non-peptide moieties (e.g., radioactive metal chelating groups, albumin binding groups, and / or linkers) can be coupled to the peptide N-terminus while the peptide is attached to the solid support. This is facilitated if the non-peptide moiety contains an activated carboxylate (and optionally a protecting group), allowing the coupling to be performed on the resin. By way of example and not limitation, a bifunctional chelator such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) tris(tert-butyl ester) can be activated in the presence of N-hydroxysuccinimide (NHS) and N,N'-dicyclohexylcarbodiimide (DCC) and coupled to the peptide. Alternatively, the non-peptide moiety may be incorporated into the compound via a copper-catalyzed click reaction under either solution- or solid-phase conditions. The copper-catalyzed click reaction is well established in the art. For example, 2-azidoacetic acid is first activated and coupled to the peptide by NHS and DCC. The alkyne-containing non-peptide moiety can then be coupled to the peptide by the addition of Cu. 2+ and sodium ascorbate in the presence of water and organic solvents, such as acetonitrile (ACN) and DMF solutions. Non-peptide moieties may also be added in the solution phase, which is routinely done.

[0129] The synthesis of radioactive metal chelators is well known, and many chelators are commercially available (e.g., from Sigma-Aldrich™ / Milipore Sigma™, etc.). Protocols for conjugation of radioactive metals to chelators are also well known (e.g., see the Examples below).

[0130] Once the peptide is fully synthesized on the solid support, the desired peptide may be cleaved from the solid support using a suitable reagent such as TFA, triisopropylsilane (TIS), and water. Side chain protecting groups such as Boc, pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), trityl (Trt), and tert-butyl (tBu) are simultaneously removed (i.e., deprotected). The crude peptide may be precipitated and collected from the solution by adding cold ether, followed by centrifugation. Purification and characterization of the peptide may be performed by standard separation techniques such as high performance liquid chromatography (HPLC) based on the size, charge, and polarity of the peptide. The identity of the purified peptide may be confirmed by mass spectrometry or other similar approaches.

[0131] The present invention is further illustrated in the following examples. EXAMPLES

[0132] Common methods

[0133] All chemicals and solvents were obtained from commercial sources and used without further purification. PSMA targeting peptides were synthesized using a solid-phase approach on an AAPPTec (Louisville, KY) Endeavor 90 peptide synthesizer. Purification and quality control of cold radiolabeled peptides were performed on an Agilent HPLC system equipped with a model 1200 quaternary pump, a model 1200 UV absorbance detector (set at 220 nm), and a Bioscan (Washington, DC) NaI scintillation detector. Agilent ChemStation software was used to control the operation of the Agilent HPLC system. The HPLC columns used were a semi-preparative (Luna C18, 5μ, 250×10 mm) and an analytical (Luna C18, 5μ, 250×4.6 mm) column purchased from Phenomenex (Torrance, CA). The HPLC solvents were A: H2O containing 0.1% TFA, and B: CH3CN containing 0.1% TFA. The collected HPLC eluate containing the desired peptide was lyophilized using a Labconco (Kansas City, MO) FreeZone 4.5 Plus freeze dryer. Mass spectrometry was performed using a Waters (Milford, Massachusetts) LC-MS equipped with an ESI ion source, QDa mass detector. C18 Sep-Pak cartridges (1 cm 3 , 50 mg) was obtained from Waters (Milford, Mass.). 68 Ga was eluted from an iThemba Labs (Somerset West, South Africa) generator and purified using a DGA resin column from Eichrom Technologies LLC (Lisle, IL). 68 Ga or 177 The radioactivity of Lu-labeled peptides was measured using a Capintec (Ramsey, NJ) CRC®-25R / W dose calibrator, and the radioactivity of mouse tissues collected from the biodistribution study was counted using a Perkin Elmer (Waltham, MA) Wizard2 2480 automated gamma counter.

[0134] General synthesis of PSMA targeting molecules

[0135] The peptidomimetic PSMA targeting Lys-ureido-Glu moiety was synthesized by solid-phase peptide chemistry. Fmoc-Lys(ivDde)-Wang resin was swollen in CHCl, followed by Fmoc removal by treating the resin with 20% piperidine in DMF. To generate the isocyanate of the H-Glu(OtBu)-OtBu moiety, a solution of H-Glu(OtBu)-OtBu and diisopropylethylamine in CHCl was cooled to −78°C in a dry ice / acetone bath. Triphosgene was dissolved in CHCl and the resulting solution was added dropwise to the reaction at −78°C. The reaction was then allowed to warm to room temperature and stirred for 30 min. The isocyanate of the H-Glu(OtBu)-OtBu solution was then added to the lysine-immobilized resin and allowed to react for 16 h. After washing the resin with DMF, the ivDde protecting group was removed with 2% hydrazine in DMF. Then, Fmoc-protected amino acids were coupled to the side chain of Lys in the presence of HATU and N,N-diisopropylethylamine. Finally, DOTA-tris(t-bu) ester (2-(4,7,10-tris(2-(t-butoxy)-2-oxoethyl)-1,4,7,10)-tetraazacyclododecan-1-yl)acetic acid) was coupled. The peptide was then deprotected and simultaneously cleaved from the resin by treatment with 95 / 5 trifluoroacetic acid (TFA) / triisopropylsilane (TIS) at room temperature for 3-4 h. After filtration, the peptide was precipitated by adding the TFA solution to cold diethyl ether. The crude peptide was purified by HPLC using a preparative column. The eluates containing the desired peptide were collected, pooled, and lyophilized.

[0136] General synthesis of Ga or Lu labeled standards

[0137] To prepare Ga- or Lu-labeled standards, a solution of each precursor was incubated with GaCl3 or LuCl3 (5 equiv.) in NaOAc buffer (0.1 M, 500 μL, pH 4.2) at 80-90 °C for 15 min. The reaction mixture was then purified by HPLC using a semi-preparative column, and the HPLC eluate containing the desired peptide was collected, pooled, and lyophilized.

[0138] 68 Ga, 177 Lu, and 225 Ac radiolabel

[0139] 68 Ga, with 5 mL of 0.05 M HCl 68 The product was eluted from the Ge generator, collected in 2.5 mL of 12 M HCl, and captured on DGA resin. The resin was then washed with 3 mL of 5 M HCl and purified. 68 Ga] 3+ was eluted. 177 Lu and 225 Ac was purchased from ITM (Germany). 68 Ga, 177 Lu, or 225 Ac was added to 700 μL of 2 M HEPES buffer containing 15-25 nmol of peptide, and the reaction mixture was then either heated at 85-90° C. for 15-30 min or microwaved for 1 min. 68 Ga labeling and 177 For Lu labeling, each solution was purified by semi-preparative HPLC followed by C18 Sep-pak purification. Radiochemical purity of >95% as determined by analytical HPLC was required for animal studies. 225 For Ac labeling, only Sep-pak purification was performed. Radiochemical purity of >95% as determined by radio-TLC was required for animal studies.

[0140] Cell culture and tumor inoculation

[0141] The LNCaP cell line was obtained from ATCC (LNCaP clone FGC, CRL-1740). It was established from a metastatic site in the left supraclavicular lymph node of a human prostate adenocarcinoma. Cells were cultured at 37 °C in PRMI 1640 medium supplemented with 10% FBS, penicillin (100 U / mL), and streptomycin (100 μg / mL) in a humidified incubator containing 5% CO2. Cells grown to 80–90% confluence were then washed with sterile phosphate-buffered saline (1× PBS pH 7.4) and trypsinized. The number of collected cells was counted with a Hausser Scientific (Horsham, PA) hemocytometer. Approximately 10 million LNCaP cells were inoculated into the left dorsal flank of immune-containing NRG mice. Tumors were allowed to grow for 4–6 weeks and reach a size of 200–600 mm 3 When the volume reached 100 μg / ml, it was used for imaging and biodistribution studies.

[0142] In vitro PSMA competitive binding assay and human serum albumin binding assay

[0143] The inhibition constant (Ki) for PSMA was calculated as 18 F]DCFPyL was measured by an in vitro competitive binding assay using DCFPyL as the radioligand. LNCaP cells (400,000 / well) were plated on 24-well poly-D-lysine coated plates for 48 h. Growth medium was removed and replaced with HEPES buffered saline (50 mM HEPES, pH 7.5, 0.9% sodium chloride). After 1 h, [ 18 [F]DCFPyL (0.1 nM) was added (in triplicate) to each well containing various concentrations (0.5 mM-0.05 nM) of test compound. The assay mixture was incubated at 37 °C for 1 h with gentle agitation, followed by washing twice with cold HEPES-buffered saline. Then, trypsin solution (0.25%, 400 μL) was added to each well to harvest the cells. Radioactivity was measured by gamma counting, and Ki values ​​were calculated using the "one-site fitted Ki" built-in model in Prism 8 (GraphPad).

[0144] Human serum albumin binding assays were performed using the Transil HSA binding kit (Sovicell) according to the manufacturer's recommended procedures.

[0145] PET / CT Imaging, SPECT / CT, and Biodistribution

[0146] PET imaging experiments were performed using a Siemens Inveon microPET / CT scanner. SPECT imaging experiments were performed using a MILabs microSPECT / CT scanner. Each tumor-bearing mouse was injected with 4–6 MBq of CT-T cells. 68 Ga or 18.5MBq 177 Lu-labeled tracers were injected via the tail vein under anesthesia (2% isoflurane in oxygen). Mice were allowed to recover and roam freely in their cages. At the designated time points, mice were re-sedated with 2% isoflurane inhalation in oxygen and placed in the scanner. A 10-min CT scan was first performed for localization, followed by post-segmentation attenuation correction for reconstruction of PET or SPECT images. This was followed by 10 min of static PET imaging or 1 h (30 min × 2 frames) of static SPECT scanning to determine uptake in the tumor and other organs. Mice were kept warm with a heating pad during acquisition.

[0147] For biodistribution studies, mice were injected with radiotracer as described above. Mice were anesthetized with 2% isoflurane inhalation and euthanized by CO2 inhalation. Blood was immediately drawn from the heart and organs / tissues of interest were harvested. Collected organs / tissues were weighed and counted using a Perkin Elmer (Waltham, MA) Wizard2 2480 gamma counter. Uptake in each organ / tissue was normalized to injected dose (radioactivity) using a standard curve and expressed as percentage of injected dose per gram of tissue (ID% / g).

[0148] Example 1: Synthesis and evaluation of CCZ02009 compared to HTK03170 without a GLY spacer

[0149] The chemical structure of CCZ02009 is: [ka]

[0150] The synthesis of CCZ02009 follows the general synthetic procedure described above, except that CCZ02009 is based on the Lys-ureido-Aad moiety. To generate the isocyanate of the 2-aminoadipyl moiety, a solution of L-2-aminoadipic acid (Aad) di-tert-butyl ester hydrochloride and diisopropylethylamine in CHCl was cooled to −78° C. in a dry ice / acetone bath. Triphosgene was dissolved in CHCl and the resulting solution was added dropwise to the reaction at −78° C. The reaction was then allowed to warm to room temperature and stirred for 30 minutes to give a solution of the isocyanate of the 2-aminoadipyl moiety. After urea formation on the Lys side chain and ivDde deprotection, Fmoc-Ala(9-anth)-OH, Fmoc-tranexamic acid, Fmoc-Gly-OH, Fmoc-Lys(ivDde)-OH, Fmoc-Gly-OH, and 4-(p-methoxyphenyl)butyric acid were sequentially coupled. The ivDde group was then deprotected and finally DOTA-tris(t-bu) ester was coupled. CCZ02009 was then purified by HPLC. Calculated mass [M+2H] 2+ =762.9, actual value 763.0.

[0151] The chemical structure of HTK03170 is shown below. [ka]

[0152] For comparison, HTK03170 was synthesized, which lacks the glycine spacer between the PSMA-binding moiety and the albumin-binding moiety shown in CCZ02009. Calculated mass [M+2H] 2+ =734.4, actual value 734.7.

[0153] Table 3 shows that with a Gly spacer between the PSMA-binding and albumin-binding moieties, the PSMA-binding affinity increased from 1.53±0.33 nM to 0.12±0.02 nM, and the albumin-binding affinity increased from 70.1±3.2 μM to 64.9±2.2 μM. Figure 2A shows representative binding affinity curves for CCZ02009 (left panel) and HTK03170 (right panel). Figure 2B and Table 4 show the binding affinity curves in LNCaP tumor-bearing NRG mice at 1 hour (left panel of Figure 2B) and 3 hours (right panel of Figure 2B) post-injection (pi). 68 PET imaging and biodistribution results using Ga-CCZ02009 are shown. High overall persistent blood radioactivity was observed at both time points, indicating strong albumin binding of CCZ02009.

[0154] Table 3. PSMA and human albumin binding affinities of CCZ02009 and HTK03170 (n=3). [Table 3]

[0155] Table 4. At 1 and 3 hours after injection 68 Biodistribution results in LNCaP tumor-bearing NRG mice treated with Ga-CCZ02009. Values ​​are percent injected dose per gram of tissue (ID% / g). [Table 4]

[0156] Example 2: Synthesis and evaluation of CCZ02060 and CCZ02059 with additional Gly spacers

[0157] The chemical structures of CCZ02060 and CCZ02059 are shown below. [ka]

[0158] The synthesis of CCZ02060 and CCZ02059 follows the procedure for the synthesis of CCZ02009 described above, except that CCZ02060 contains two Gly spacers and CCZ02059 contains four Gly spacers. For CCZ02060, the calculated mass [M+2H] 2+ = 791.4, measured value 791.5. For CCZ02059, calculated mass [M+2H] 2+ =848.4, actual value 848.5.

[0159] CCZ02060 and CCZ02059 bind to PSMA with an affinity (Ki) of 1.09±0.19 nM and 10.84±3.28 nM (n=2), respectively. Figure 3 shows representative binding affinity curves for CCZ02060 (left panel) and CCZ02059 (right panel). The number of Gly spacers affects PSMA binding affinity, i.e., the most favorable binding affinity was observed with a single Gly spacer (CCZ02009), followed by two Gly spacers (CCZ02060) and four Gly spacers (CCZ02059).

[0160] Example 3: Synthesis and evaluation of CCZ02017 compared to HTK03170 without a GLY spacer

[0161] The chemical structure of CCZ02017 is shown below. [ka]

[0162] The synthesis of CCZ02017 follows the synthesis procedure of CCZ02009 described above, except for the albumin binder in CCZ02017, which is 4-(p-nitrophenyl)butyric acid. 4-(p-nitrophenyl)butyric acid is substantially weaker than 4-(p-methoxyphenyl)butyric acid (Reference: Kuo et al. J Nucl Med. 2021 Apr;62(4):521-527). Figure 4 shows the CD40-dependent cytotoxicity of LNCaP tumors in NRG mice bearing LNCaP tumors at 3, 24, 72, 144, and 240 hours after injection. 177Table 5 shows SPECT / CT images of Lu-CCZ02017 in NRG mice bearing LNCaP tumors at 3, 24, 72, 144, and 240 hours after injection. 177 The biodistribution of Lu-CCZ02017 is shown. 177 Lu-HTK03170 was administered at 24 and 72 hours post-injection. 177 It shows similar blood ID% / g values ​​(see Table 4) as Lu-CCZ02017 (see Table 6). As CCZ02017 is a weaker albumin binder, the data indicates that the introduction of a Gly spacer improves albumin binding. 177 LNCaP tumor uptake of Lu-CCZ02017 was 177 Substantial improvement compared to Lu-HTK03170.

[0163] Table 5. Results at 3, 24, 72, 144, and 240 hours after injection. 177 Biodistribution results in LNCaP tumor-bearing NRG mice treated with Lu-CCZ02017. Values ​​are in ID% / g. [Table 5]

[0164] Table 6. Results at 24 and 72 hours after injection 177 Biodistribution results in LNCaP tumor-bearing NRG mice treated with Lu-HTK03170. Values ​​are in ID% / g. [Table 6]

[0165] Table 7. Results at 3, 24, 72, 144, and 240 hours after injection. 225 Biodistribution results in LNCaP tumor-bearing NRG mice treated with Ac-CCZ02017. Values ​​are in ID% / g. [Table 7]

[0166] Example 4: Synthesis and evaluation of CCZ02008

[0167] The chemical structure of CCZ02008 is shown below. [ka]

[0168] The synthesis of CCZ02008 follows the procedure for the synthesis of CCZ02009 described above, incorporating 4R-F-Glu in place of Aad. Calculated mass [M+2H] 2+ = 764.9, observed value 765.2. CCZ02008 binds to PSMA with high affinity Ki = 0.48 ± 0.1 nM (n = 3). See Figure 5 and Table 8. Table 8. Results at 4, 24, 72, and 120 hours post-injection 177 Biodistribution results in LNCaP tumor-bearing NRG mice treated with Lu-CCZ02008. Values ​​are in ID% / g. [Table 8]

[0169] Example 5: Synthesis and Evaluation of CCZ02025

[0170] The chemical structure of CCZ02025 is shown below. [ka]

[0171] The synthesis of CCZ02025 follows the synthesis procedure for CCZ02009 described above, incorporating 4R-F-Glu in place of Aad and 4-(p-nitrophenyl)butyric acid in place of 4-(p-methoxyphenyl)butyric acid. Calculated mass [M+2H] 2+ = 772.4, actual value 772.6. CCZ02025 bound to PSMA with high affinity Ki = 0.59 nM (Figure 6, n = 1). 68Ga-CCZ02025 shows good tumor uptake and overall background tissue clearance (Table 9).

[0172] Table 9. Results at 1 and 3 hours post-injection 68 Biodistribution results in LNCaP tumor-bearing NRG mice treated with Ga-CCZ02025. Values ​​are in ID% / g. [Table 9]

[0173] Example 6: Synthesis and Evaluation of CCZ02024 [ka]

[0174] The synthesis of CCZ02024 follows the procedure for the synthesis of CCZ02025 described above, incorporating Glu in place of 4R-F-Glu. Calculated mass [M+2H] 2+ = 763.4, observed value 763.8. CCZ02024 binds to PSMA with high affinity Ki = 1.54 nM (Figure 7, n = 1).

[0175] Example 7: Synthesis and Evaluation of CCZ02015

[0176] The chemical structure of CCZ02015 is shown below. [ka]

[0177] The synthesis of CCZ02015 follows the synthesis procedure for CCZ02009 described above. The difference is that CCZ02015 does not contain a Gly spacer and incorporates an elongated linker, i.e., beta-homoLys, instead of Lys. Calculated mass [M+2H] 2+ = 741.4, actual value 741.5. CCZ02015 bound to PSMA with high affinity Ki = 1.09 ± 0.30 nM (Figure 8, n = 3). 68Ga-CCZ02015 shows good tumor uptake and overall background tissue clearance (Table 10).

[0178] Table 10. Results at 1 and 3 hours after injection 68 Biodistribution results in LNCaP tumor-bearing NRG mice treated with Ga-CCZ02015. Values ​​are in ID% / g. [Table 10]

[0179] Example 8: Synthesis and Evaluation of CCZ02019

[0180] The chemical structure of CCZ02019 is shown below. [ka]

[0181] The synthesis of CCZ02019 follows the synthesis procedure for CCZ02015 described above. The difference is that CCZ02019 incorporates 4R-F-Glu into the PSMA binding motif instead of Aad. Calculated mass [M+2H] 2+ =743.4, actual value 743.7. 177 Lu-CCZ02019 shows good tumor uptake and overall background tissue clearance (Table 11).

[0182] Table 11. Results at 3, 24, 72, 144, and 240 hours after injection. 177 Biodistribution results in LNCaP tumor-bearing NRG mice treated with Lu-CCZ02019. Values ​​are in ID% / g. [Table 11]

[0183] Example 9: Synthesis and evaluation of CCZ02012 and CCZ02013

[0184] The chemical structures of CCZ02012 (left) and CCZ02013 (right) are shown below. [ka]

[0185] The syntheses of CCZ02012 and CCZ02013 followed the general synthetic procedure described above for the Lys-ureido-Aad scaffold, incorporating Fmoc-trans-4-aminocyclohexanecarboxylic acid (ACHC) and Fmoc-cis-4-ACHC, respectively, in place of Fmoc-tranexamic acid. For CCZ02012, the calculated mass [M+2H] 2+ = 546.8, measured value 547.1. For CCZ02013, calculated mass [M+2H] 2+ = 546.8, observed 547.2. The use of ACHC, either in trans or cis, did not substantially affect binding to PSMA. CCZ02012 and CCZ02013 bind to PSMA with Ki = 1.67 nM (n = 1) and Ki = 1.53 ± 0.21 nM (n = 2), respectively. Figure 9 shows the binding assay curves for CCZ02012 (9A) and CCZ02013 (9B).

[0186] Example 10: Synthesis and evaluation of CCZ02021 and CCZ02022

[0187] The chemical structures of CCZ02021 and CCZ02022 are shown below. [ka]

[0188] The synthesis of CCZ02021 and CCZ02022 followed the procedure for the synthesis of CCZ02012 described above, with CCZ02021 incorporating a Gly spacer and CCZ02022 incorporating a Gly spacer and beta-homoLys in place of Lys. For CCZ02021, the calculated mass [M+2H] 2+ = 763.4, measured value 763.5. For CCZ02022, calculated mass value [M+2H] 2+= 770.4, observed 770.7. CCZ02021 and CCZ02022 bind to PSMA with Ki = 5.71 nM (n = 1) and Ki = 11.2 nM (n = 1), respectively. Figure 9 shows the binding assay curves for CCZ02021 (10A) and CCZ02022 (10B).

[0189] Example 11: Synthesis and Evaluation of CCZ02034

[0190] The chemical structure of CCZ02034 is shown below. [ka]

[0191] The synthesis of CCZ02034 follows the procedure for the synthesis of CCZ02017 described above, except that CCZ02034 incorporates a crown chelator in place of DOTA. Calculated mass [M+2H] 2+ = 814.4, observed 814.6. CCZ02034 binds to PSMA with Ki = 2.82 nM (n = 1). See Figure 11.

[0192] Example 12: Synthesis and Evaluation of CCZ02005

[0193] The chemical structure of CCZ02005 is shown below. [ka]

[0194] The synthesis of CCZ02005 follows the general procedure described above, incorporating a PEG2 spacer between the albumin binding group and the DOTA chelator. Calculated mass [M+2H] 2+ = 806.9, observed 807.0. CCZ02005 binds to PSMA with Ki = 2.08nM (n = 1). See Figure 12. The binding affinity is comparable to HTK03170, indicating that the addition of a spacer between the albumin binder and the chelator does not substantially affect the binding affinity for PSMA.

[0195] Example 13: Synthesis and Evaluation of CCZ02061

[0196] The chemical structure of CCZ02061 is shown below. [ka]

[0197] The synthesis of CCZ02061 follows the procedure for the synthesis of CCZ02017 described above, incorporating the addition of a Gly spacer between the albumin binding group and the DOTA chelator. Calculated mass [M+2H] 2+ = 798.9, observed value 798.9. CCZ02017 binds to PSMA with Ki = 1.14 ± 0.37 nM (n = 2). See Figure 13. The present invention has been described with respect to one or more embodiments. However, it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the scope of the invention as defined in the following claims. Thus, the scope of the present invention should not be limited by the preferred embodiments described in the above examples, but should be given the broadest interpretation consistent with the description as a whole.

Claims

1. A compound having formula I, or a salt or solvate of formula I, 【Chemistry 1】 During the ceremony, R １ But, -R １ａ R １ｂ -, where R １ａ does not exist or -CH ２ -, -O-, or -S-; R １ｂ But -CH ２ - or -CHF-, R ２ But -(CH ２ ) ３ -O-, -(CH ２ ) ３ -, -(CH ２ ) ４ -, -CH ２ -O-(CH ２ ) ２ - or -CH ２ -S-(CH ２ ) ２ - and L １ が、-S-、-N(R Ｌ１ａ )-C(O)-、-C(O)-N(R Ｌ１ａ )-、-NH-C(O)-NH-、-NH-C(S)-NH-、 【Chemistry 2】 where R Ｌ１ａ is H, methyl, ethyl, or a benzyl group having 0-4 substituents independently selected from halogen, OMe, or SMe; R ３ But C １ -C ４ Alkyl, halogen, OMe, SMe, NH ２ , NO ２ substituted with 0 to 4 substituents independently selected from , CN, or OH; 【Transformation 3】 where 0 to 4 ring carbons are replaced by nitrogen; L ２ が、-S-、-N(R Ｌ２ａ )-C(O)-、-C(O)-N(R Ｌ２ａ )-、-NH-C(O)-NH-、-NH-C(S)-NH-、 【Chemistry 4】 where R Ｌ２ａ is H, methyl, or ethyl; n1 and n2 each represent 0 to 2; Ring A has 0 to 3 double bonds and is bonded at the meta or para position; L ３ , L ４ , L ５ｂ , L ５ｃ , L ６ , and L ７ are each independently -S-, -N(R Ｌ３ａ )-C(O)-, -C(O)-N(R Ｌ３ａ ) -, -NH-C(O)-NH-, -NH-C(S)-NH-, 【Transformation 5】 where each R Ｌ３ａ is independently H, methyl, or ethyl; n3, n4, and n5 each independently represent 0 to 4; Each R ４ are independently linear, branched, and / or cyclic C ｎ６ alkylenyl, alkenylenyl, and / or alkynylenyl, where each n6 independently is 1-20, and any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted with oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphate; R ５ａ -X ｂｒ (R ５ｃ )-R ５ｂ is linear, branched, and / or cyclic C ｎ７ forming alkylenyl, alkenylenyl, and / or alkynylenyl, where n7 is 1-20, and any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted with oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphate; R ５ａ , R ５ｂ , and R ５ｃ one, two, or three of which are optionally absent, and X ｂｒ is CH or N, and X ｂｒ is at least four atoms away from ring A, Each R ６ and each R ７ are independently linear, branched, and / or cyclic C ｎ８ alkylenyl, alkenylenyl, and / or alkynylenyl, where each n8 is independently 1-20, and any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted with oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphate; R ｒａｄ is a radiometal chelator optionally bound by a radiometal, where R ｒａｄ is at least 7 atoms away from ring A, R ａｌｂ is an albumin binder, and said albumin binder is - (CH ２ ) ｎ９ -CH ３ (where n9 is 8 to 20), - (CH ２ ) ｎ１０ -C(O)OH (wherein n10 is 8 to 20), or 【Transformation 6】 (wherein n11 is 1 to 4, and R ８ is I, Br, F, Cl, H, OH, OCH ３ , N.H. ２ , NO ２ , or CH ３ ) and R ａｌｂ is at least 7 atoms away from ring A.

2. R ａｌｂ is 7 to 18 atoms away from ring A, and R ｒａｄ is separated from ring A by 7 to 18 atoms.

3. R １ａ But -CH ２ -, -O-, or -S-, and optionally R １ But -(CH ２ ) ２ The compound of claim 1, wherein

4. R ａｌｂ but, 【Transformation 7】 where n11 is 1 to 4, and R ８ But OCH ３ Or NO ２ 2. The compound of claim 1, wherein:

5. The compound of claim 4, wherein n11 is 3.

6. R ２ But -(CH ２ ) ４ The compound of claim 1, wherein

7. L １ But -N(R Ｌ１ａ )-C(O)- or -C(O)-N(R Ｌ１ａ )-, where L １ａ is H or methyl, and optionally L １ The compound according to claim 1, wherein is -NHC(O)-.

8. R ３ but, 【Transformation 8】 2. The compound of claim 1, wherein:

9. L ２ But -N(R Ｌ２ａ )-C(O)- or -C(O)-N(R Ｌ２ａ )—, where R Ｌ２ａ is H or methyl, and optionally L ２ The compound according to claim 1, wherein is -NHC(O)-.

10. The compound of claim 1, wherein n1 is 0.

11. The compound of claim 1, wherein ring A has 0 double bonds and is attached at the para position.

12. Ring A is 【Chemistry 9】 12. The compound of claim 11, wherein:

13. The compound of claim 1, wherein n2 is 0 or 1.

14. Each L ３ are independently -N(R Ｌ３ａ )-C(O)- or -C(O)-N(R Ｌ３ａ )—, where each R Ｌ３ａ is independently H or methyl, and optionally each L ３ The compound according to claim 1, wherein is -NHC(O)-.

15. Each L ４ are independently -N(R Ｌ４ａ )-C(O)- or -C(O)-N(R Ｌ４ａ )—, where each R Ｌ４ａ is independently H or methyl, and optionally each L ４ The compound according to claim 1, wherein is -NHC(O)-.

16. R ４ The compound of claim 1 , wherein is methylene.

17. The compound of claim 1, wherein n3 is 1.

18. R ５ａ The compound of claim 1 , wherein is not present.

19. The compound has the formula II: 【Chemistry 10】 10. The compound of claim 1 having the formula:

20. X ｂｒ The compound of claim 1 , wherein is CH.

21. R ５ｂ is not present or -(CH ２ ) １－４ The compound of claim 1, wherein

22. R ５ｃ is not present or -(CH ２ ) １－４ The compound of claim 1, wherein

23. L ５ｂ But -N(R Ｌ５ｂ )-C(O)- or -C(O)-N(R Ｌ５ｂ )—, where R Ｌ５ｂ is H or methyl, and optionally L ５ｂ The compound according to claim 1, wherein is -NHC(O)-.

24. L ５ｃ But -N(R Ｌ５ｃ )-C(O)- or -C(O)-N(R Ｌ５ｃ )—, where R Ｌ５ｃ is H or methyl, and optionally L ５ｃ The compound according to claim 1, wherein is -NHC(O)-.

25. Each R ６ But -(CH ２ ) １－４ The compound of claim 1, wherein

26. Each L ６ are independently -N(R Ｌ６ａ )-C(O)- or -C(O)-N(R Ｌ６ａ )—, where each R Ｌ６ａ is independently H or methyl, and optionally each L ６ The compound according to claim 1, wherein is -NHC(O)-.

27. The compound of claim 1, wherein n4 is 0 or 1.

28. Each R ７ But -(CH ２ ) １－４ The compound of claim 1, wherein

29. Each L ７ are independently -N(R Ｌ７ａ )-C(O)- or -C(O)-N(R Ｌ７ａ )—, where each R Ｌ７ａ is independently H or methyl, and optionally each L ７ The compound according to claim 1, wherein is -NHC(O)-.

30. The compound of claim 1, wherein n5 is 0 or 1.

31. X ｂｒ is separated from ring A by at least 5 atoms, optionally by at least 6 atoms.

32. R １ But, -R １ａ R １ｂ -, where R １ａ is not present or -CH ２ - and R １ｂ But -CH ２ - or -CHF-, R ２ But -(CH ２ ) ３ -O-, -(CH ２ ) ３ -, -(CH ２ ) ４ - or -CH ２ -O-(CH ２ ) ２ - and L １ But -N(R Ｌ１ａ )-C(O)-, -C(O)-N(R Ｌ１ａ )-, or -NH-C(O)-NH-, where R Ｌ１ａ is H or methyl, R ３ but, 【Chemistry 11】 and L ２ But -N(R Ｌ２ａ )-C(O)-, -C(O)-N(R Ｌ２ａ )-, -NH-C(O)-NH-, where R Ｌ２ａ is H or methyl, n1 and n2 each represent 0 to 2; Ring A has zero double bonds and is bonded at the meta or para position; L ３ , L ４ , L ５ｂ , L ５ｃ , L ６ , and L ７ are each independently -N(R Ｌ３ａ )-C(O)-, -C(O)-N(R Ｌ３ａ )—, or —NH—C(O)—NH—, where each R Ｌ３ａ is independently H, methyl, or ethyl; n3, n4, and n5 each independently represent 0 to 4; Each R ４ are independently linear C １－ C １０ is alkylenyl, R ５ａ -X ｂｒ (R ５ｃ )-R ５ｂ is linear, branched, and / or cyclic C １－ C ２０ forming alkylenyl, alkenylenyl, and / or alkynylenyl, where any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted with oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphate; ５ａ , R ５ｂ , and R ５ｃ one, two, or three of which are optionally absent, and X ｂｒ is N or CH, and X ｂｒ is at least four atoms away from ring A, Each R ６ and each R ７ are independently linear, branched, and / or cyclic C １－ C ２０ alkylenyl, alkenylenyl, and / or alkynylenyl, where any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted with oxo, hydroxyl, sulfhydryl, amine, amide, urea, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, or phosphate; R ｒａｄ is a radiometal chelator optionally bound by a radiometal, where R ｒａｄ is at least 7 atoms away from ring A, R ａｌｂ but, 【Chemistry 12】 where n11 is 1 to 4, and R ８ is I, Br, F, Cl, H, OH, OCH ３ , N.H. ２ , NO ２ , or CH ３ 2. The compound of claim 1, wherein:

33. R ２ But -(CH ２ ) ３ - or - (CH ２ ) ４ - and L １ But -N(R Ｌ１ａ )-C(O)- or -C(O)-N(R Ｌ１ａ )—, where R Ｌ１ａ is H or methyl, R ３ but, 【Chemistry 13】 and L ２ But -N(R Ｌ２ａ )—C(O)—, or —C(O)—N(R Ｌ２ａ )—, where R Ｌ２ａ is H or methyl, n1 and n2 each represent a number from 0 to 1; L ３ , L ４ , L ５ｂ , L ５ｃ , L ６ , and L ７ are each independently -N(R Ｌ３ａ )-C(O)- or -C(O)-N(R Ｌ３ａ ) - and Here, each R Ｌ３ａ is independently H or methyl; Each R ４ are independently linear C １－ C １０ is alkylenyl, R ５ａ -X ｂｒ (R ５ｃ )-R ５ｂ is linear, branched, and / or cyclic C １－ C １０ alkylenyl, where any carbon bonded to two other carbons is optionally independently replaced by O, and carbons are optionally independently substituted with oxo, hydroxyl, amine, amide, or carboxylic acid; R ５ａ , R ５ｂ , and R ５ｃ one, two, or three of which are optionally absent, and X ｂｒ is N or CH, and X ｂｒ is at least four atoms away from ring A, Each R ６ and each R ７ are independently linear, branched, and / or cyclic C １－ C １０ alkylenyl, where any carbon bonded to two other carbons is optionally independently replaced by N, S, or O, and carbons are optionally independently substituted with oxo, hydroxyl, amine, amide, urea, carboxylic acid; R ａｌｂ but, 【Chemistry 14】 where n11 is 1 to 4, and R ８ But OCH ３ Or NO ２ 33. The compound of claim 32, wherein:

34. L ３ The compound of claim 32, wherein is -NHC(O)-.

35. L ４ The compound of claim 32, wherein is -NHC(O)-.

36. R ４ 33. The compound of claim 32, wherein is methylene.

37. 33. The compound of claim 32, wherein n3 is 1 to 4.

38. 38. The compound of claim 37, wherein n3 is 1 to 2.

39. 38. The compound of claim 37, wherein n3 is 1.

40. 33. The compound of claim 32, wherein n2 is 0 to 1.

41. 41. The compound of claim 40, wherein n2 is 1.

42. R ５ａ The compound of claim 32, wherein is absent.

43. R ５ａ 33. The compound of claim 32, wherein is methylene.

44. Ring A is 【Chemistry 15】 and R ２ But -(CH ２ ) ４ - and R ３ but, 【Chemistry 16】 and n1 is 0, L １ But -N(R Ｌ１ａ )-C(O)- or -C(O)-N(R Ｌ１ａ )—, where R Ｌ１ａ is H, L ２ But -N(R Ｌ２ａ )-C(O)- or -C(O)-N(R Ｌ２ａ )—, where R Ｌ２ａ is H, R １ But, -R １ａ R １ｂ -, where R １ａ But -CH ２ - and R １ｂ But -CH ２ - or -CHF-.

45. R ５ｃ But it doesn't exist, L ５ｃ But -N(R Ｌ３ａ )-C(O)- or -C(O)-N(R Ｌ３ａ )—, where R Ｌ３ａ is H, R ７ is methylene, L ７ But -N(R Ｌ３ａ )-C(O)- or -C(O)-N(R Ｌ３ａ )—, where R Ｌ３ａ is H, n5 is 1, R ａｌｂ but, 【Chemistry 17】 where n11 is 3 and R ８ But OCH ３ Or NO ２ 45. The compound of claim 44, wherein:

46. n2 is 0 or 1; L ３ But -N(R Ｌ３ａ )-C(O)- or -C(O)-N(R Ｌ３ａ )—, where R Ｌ３ａ is H, R ４ is methylene, L ４ But -N(R Ｌ３ａ )-C(O)- or -C(O)-N(R Ｌ３ａ )—, where R Ｌ３ａ is H, n3 is 1, R ５ａ But it doesn't exist, X ｂｒ 45. The compound of claim 44, wherein is CH.

47. R ５ｂ But linear C １－ C ６ is alkylenyl, L ５ｂ But -N(R Ｌ３ａ )-C(O)- or -C(O)-N(R Ｌ３ａ )—, where R Ｌ３ａ is H, R ６ is methylene, L ６ But -N(R Ｌ３ａ )-C(O)- or -C(O)-N(R Ｌ３ａ )—, where R Ｌ３ａ is H, 45. The compound of claim 44, wherein n4 is 0 to 2.

48. R ｒａｄ is selected from Table 2, where R ｒａｄ 10. The compound of claim 1, wherein:

49. R ｒａｄ But DOTA, H ２ macropa, H ４ py4pa, H ４ Pypa, or CROWN, where R ｒａｄ 10. The compound of claim 1, wherein:

50. R ｒａｄ 50. The compound of claim 49, wherein is DOTA.

51. R ｒａｄ is bound by a therapeutic radiometal, optionally said therapeutic radiometal comprising: １６５ Er, ２１２ Bi, １６６ Ho, １４９ Pm, １５９ Gd, １０５ Rh, １０９ Pd, １９６ Au, １９９ Au, １７５ Yb, １４２ Pr, １７７ Lu, １１１ In, ２１３ Bi, ２１２ Pb, ４７ Sc, ９０ Y. ２２５ Ac, １１７ｍ Sn, １５３ Sm, １４９ Tb, １６１ Tb, ２２４ Ra, ２２７ Th, ２２３ Ra, ６４ Cu, or ６７ The compound of claim 1 , wherein the compound is Cu.

52. 1. A compound selected from CCZ02009, CCZ02017, CCZ02008, CCZ02025, CCZ02024, CCZ02015, CCZ02019, CCZ02012, CCZ02005, CCZ02021, CCZ02022, CCZ02059, CCZ02060, CCZ02034, CCZ02061, or CCZ02013, wherein said compound is optionally bound to a radiometal.

53. 1. A compound selected from CCZ02005, CCZ02021, CCZ02022, CCZ02059, CCZ02060, CCZ02034, CCZ02061, wherein said compound is optionally bound to a radiometal.

54. 1. A compound selected from CCZ02009, CCZ02017, CCZ02008, CCZ02025, CCZ02024, CCZ02015, or CCZ02019, wherein said compound is optionally bound to a radiometal.

55. Radioactive metals, １６５ Er, ２１２ Bi, １６６ Ho, １４９ Pm, １５９ Gd, １０５ Rh, １０９ Pd, １９８ Au, １９９ Au, １７５ Yb, １４２ Pr, １７７ Lu, １１１ In, ２１３ Bi, ２１２ Pb, ４７ Sc, ９０ Y. ２２５ Ac, １１７ｍ Sn, １５３ Sm, １４９ Tb, １６１ Tb, ２２４ Ra, ２２７ Th, ２２３ Ra, ６４ Cu, or ６７ The compound of claim 1 , wherein the compound is Cu.

56. Radioactive metals, １７７ Lu or ２２５ 56. The compound of claim 55, wherein said compound is Ac.

57. 57. A pharmaceutical composition comprising a compound according to any one of claims 1 to 56 and one or more pharmaceutically acceptable excipients.

58. The pharmaceutical composition of claim 57 for the treatment of prostate-specific membrane antigen (PSMA)-expressing tumors.

59. 59. The pharmaceutical composition of claim 58, wherein the prostate-specific membrane antigen (PSMA)-expressing tumor is associated with prostate cancer.

60. 59. The pharmaceutical composition of claim 58, wherein the subject is a human.

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